Editorial

5 pages, 209 KiB

Open AccessEditorial

by Clare Hoskins

Cancers 2020, 12(8), 2127; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12082127 - 31 Jul 2020

Cited by 5 | Viewed by 2764

This Special Issue on Cancer Nanomedicine within Cancers brings together 46 cutting-edge papers covering research within the field along with insightful reviews and opinions reflecting our community [...] Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

Research

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23 pages, 3531 KiB

Open AccessArticle

A Novel pH-Tunable Secondary Conformation Containing Mixed Micellar System in Anticancer Treatment

by Fu-Ying Shih, Wen-Ping Jiang, Xiaojie Lin, Sheng-Chu Kuo, Guan-Jhong Huang, Yu-Chi Hou, Chih-Shiang Chang, Yang Liu and Yi-Ting Chiang

Cancers 2020, 12(2), 503; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12020503 - 21 Feb 2020

Cited by 7 | Viewed by 2701

Abstract

In this study, for the first time, we precisely assembled the poly-γ-benzyl-l-glutamate and an amphiphilic copolymer d-α-tocopherol polyethylene glycol succinate into a mixed micellar system for the embedment of the anticancer drug doxorubicin. Importantly, the intracellular drug-releasing behaviors could be controlled by changing [...] Read more.

In this study, for the first time, we precisely assembled the poly-γ-benzyl-l-glutamate and an amphiphilic copolymer d-α-tocopherol polyethylene glycol succinate into a mixed micellar system for the embedment of the anticancer drug doxorubicin. Importantly, the intracellular drug-releasing behaviors could be controlled by changing the secondary structures of poly-γ-benzyl-l-glutamate via the precise regulation of the buffer’s pH value. Under neutral conditions, the micellar architectures were stabilized by both α-helix secondary structures and the microcrystalline structures. Under acidic conditions (pH 4.0), the interior structures transformed into a coil state with a disordered alignment, inducing the release of the loaded drug. A remarkable cytotoxicity of the Dox-loaded mixed micelles was exhibited toward human lung cancer cells in vitro. The internalizing capability into the cancer cells, as well as the intracellular drug-releasing behaviors, were also identified and observed. The secondary structures containing Dox-loaded mixed micelles had an outstanding antitumor efficacy in human lung cancer A549 cells-bearing nude mice, while little toxicities occurred or interfered with the hepatic or renal functions after the treatments. Thus, these pH-tunable α-helix-containing mixed micelles are innovative and promising for controlled intracellular anticancer drug delivery. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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23 pages, 6634 KiB

Open AccessArticle

Multifunctional Silica-Based Nanoparticles with Controlled Release of Organotin Metallodrug for Targeted Theranosis of Breast Cancer

by Karina Ovejero Paredes, Diana Díaz-García, Victoria García-Almodóvar, Laura Lozano Chamizo, Marzia Marciello, Miguel Díaz-Sánchez, Sanjiv Prashar, Santiago Gómez-Ruiz and Marco Filice

Cancers 2020, 12(1), 187; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12010187 - 12 Jan 2020

Cited by 47 | Viewed by 5196

Abstract

Three different multifunctional nanosystems based on the tethering onto mesoporous silica nanoparticles (MSN) of different fragments such as an organotin-based cytotoxic compound Ph₃Sn{SCH₂CH₂CH₂Si(OMe)₃} (MSN-AP-Sn), a folate fragment (MSN-AP-FA-Sn), and an enzyme-responsive peptide able [...] Read more.

Three different multifunctional nanosystems based on the tethering onto mesoporous silica nanoparticles (MSN) of different fragments such as an organotin-based cytotoxic compound Ph₃Sn{SCH₂CH₂CH₂Si(OMe)₃} (MSN-AP-Sn), a folate fragment (MSN-AP-FA-Sn), and an enzyme-responsive peptide able to release the metallodrug only inside cancer cells (MSN-AP-FA-PEP-S-Sn), have been synthesized and fully characterized by applying physico-chemical techniques. After that, an in vitro deep determination of the therapeutic potential of the achieved multifunctional nanovectors was carried out. The results showed a high cytotoxic potential of the MSN-AP-FA-PEP-S-Sn material against triple negative breast cancer cell line (MDA-MB-231). Moreover, a dose-dependent metallodrug-related inhibitory effect on the migration mechanism of MDA-MB-231 tumor cells was shown. Subsequently, the organotin-functionalized nanosystems have been further modified with the NIR imaging agent Alexa Fluor 647 to give three different theranostic silica-based nanoplatforms, namely, MSN-AP-Sn-AX (AX-1), MSN-AP-FA-Sn-AX (AX-2), and MSN-AP-FA-PEP-S-Sn-AX (AX-3). Their in vivo potential as theranostic markers was further evaluated in a xenograft mouse model of human breast adenocarcinoma. Owing to the combination of the receptor-mediated site targeting and the specific fine-tuned release mechanism of the organotin metallodrug, the nanotheranostic drug MSN-AP-FA-PEP-S-Sn-AX (AX-3) has shown targeted diagnostic ability in combination with enhanced therapeutic activity by promoting the inhibition of tumor growth with reduced hepatic and renal toxicity upon the repeated administration of the multifunctional nanodrug. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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18 pages, 4020 KiB

Open AccessArticle

Oxidation-Triggerable Liposome Incorporating Poly(Hydroxyethyl Acrylate-co-Allyl methyl sulfide) as an Anticancer Carrier of Doxorubicin

by Jin Ah Kim, Dong Youl Yoon and Jin-Chul Kim

Cancers 2020, 12(1), 180; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12010180 - 10 Jan 2020

Cited by 10 | Viewed by 2894

Abstract

Since cancer cells are oxidative in nature, anti-cancer agents can be delivered to cancer cells specifically without causing severe normal cell toxicity if the drug carriers are designed to be sensitive to the intrinsic characteristic. Oxidation-sensitive liposomes were developed by stabilizing dioleoylphosphatidyl ethanolamine [...] Read more.

Since cancer cells are oxidative in nature, anti-cancer agents can be delivered to cancer cells specifically without causing severe normal cell toxicity if the drug carriers are designed to be sensitive to the intrinsic characteristic. Oxidation-sensitive liposomes were developed by stabilizing dioleoylphosphatidyl ethanolamine (DOPE) bilayers with folate-conjugated poly(hydroxyethyl acrylate-co-allyl methyl sulfide) (F-P(HEA-AMS)). The copolymer, synthesized by a free radical polymerization, was surface-active but lost its surface activity after AMS unit was oxidized by H₂O₂ treatment. The liposomes with F-P(HEA-AMS) were sensitive to H₂O₂ concentration (0%, 0.5%, 1.0%, and 2.0%) in terms of release, possibly because the copolymer lost its surface activity and its bilayer-stabilizing ability upon oxidation. Fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM) revealed that doxorubicin (DOX)-loaded liposomes stabilized with folate-conjugated copolymers markedly promoted the transport of the anti-cancer drug to cancer cells. This was possible because the liposomes were readily translocated into the cancer cells via receptor-mediated endocytosis. This liposome would be applicable to the delivery carrier of anticancer drugs. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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19 pages, 3410 KiB

Open AccessArticle

Improvement in the Anti-Tumor Efficacy of Doxorubicin Nanosponges in In Vitro and in Mice Bearing Breast Tumor Models

by Monica Argenziano, Casimiro Luca Gigliotti, Nausicaa Clemente, Elena Boggio, Benedetta Ferrara, Francesco Trotta, Stefania Pizzimenti, Giuseppina Barrera, Renzo Boldorini, Federica Bessone, Umberto Dianzani, Roberta Cavalli and Chiara Dianzani

Cancers 2020, 12(1), 162; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12010162 - 09 Jan 2020

Cited by 45 | Viewed by 5142

Abstract

Doxorubicin (DOX) is an anthracycline widely used in cancer therapy and in particular in breast cancer treatment. The treatment with DOX appears successful, but it is limited by a severe cardiotoxicity. This work evaluated the in vitro and in vivo anticancer effect of [...] Read more.

Doxorubicin (DOX) is an anthracycline widely used in cancer therapy and in particular in breast cancer treatment. The treatment with DOX appears successful, but it is limited by a severe cardiotoxicity. This work evaluated the in vitro and in vivo anticancer effect of a new formulation of β-cyclodextrin nanosponges containing DOX (BNS-DOX). The BNS-DOX effectiveness was evaluated in human and mouse breast cancer cell lines in vitro in terms of effect on cell growth, cell cycle distribution, and apoptosis induction; and in vivo in BALB-neuT mice developing spontaneous breast cancer in terms of biodistribution, cancer growth inhibition, and heart toxicity. BNS-DOX significantly inhibited cancer cell proliferation, through the induction of apoptosis, with higher efficiency than free DOX. The breast cancer growth in BALB-neuT mice was inhibited by 60% by a BNS-DOX dose five times lower than the DOX therapeutic dose, with substantial reduction of tumor neoangiogenesis and lymphangiogenesis. Biodistribution after BNS-DOX treatment revealed a high accumulation of DOX in the tumor site and a low accumulation in the hearts of mice. Results indicated that use of BNS may be an efficient strategy to deliver DOX in the treatment of breast cancer, since it improves the anti-cancer effectiveness and reduces cardiotoxicity. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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26 pages, 3620 KiB

Open AccessArticle

Nanoformulated Zoledronic Acid Boosts the Vδ2 T Cell Immunotherapeutic Potential in Colorectal Cancer

by Daniele Di Mascolo, Serena Varesano, Roberto Benelli, Hilaria Mollica, Annalisa Salis, Maria Raffaella Zocchi, Paolo Decuzzi and Alessandro Poggi

Cancers 2020, 12(1), 104; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12010104 - 31 Dec 2019

Cited by 24 | Viewed by 4205

Abstract

Aminobisphosphonates, such as zoledronic acid (ZA), have shown potential in the treatment of different malignancies, including colorectal carcinoma (CRC). Yet, their clinical exploitation is limited by their high bone affinity and modest bioavailability. Here, ZA is encapsulated into the aqueous core of spherical [...] Read more.

Aminobisphosphonates, such as zoledronic acid (ZA), have shown potential in the treatment of different malignancies, including colorectal carcinoma (CRC). Yet, their clinical exploitation is limited by their high bone affinity and modest bioavailability. Here, ZA is encapsulated into the aqueous core of spherical polymeric nanoparticles (SPNs), whose size and architecture resemble that of biological vesicles. On Vδ2 T cells, derived from the peripheral blood of healthy donors and CRC patients, ZA-SPNs induce proliferation and trigger activation up to three orders of magnitude more efficiently than soluble ZA. These activated Vδ2 T cells kill CRC cells and tumor spheroids, and are able to migrate toward CRC cells in a microfluidic system. Notably, ZA-SPNs can also stimulate the proliferation of Vδ2 T cells from the tumor-infiltrating lymphocytes of CRC patients and boost their cytotoxic activity against patients’ autologous tumor organoids. These data represent a first step toward the use of nanoformulated ZA for immunotherapy in CRC patients. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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12 pages, 655 KiB

Open AccessArticle

Accuracy of Magnetometer-Guided Sentinel Lymphadenectomy after Intraprostatic Injection of Superparamagnetic Iron Oxide Nanoparticles in Prostate Cancer: The SentiMag Pro II Study

by Alexander Winter, Svenja Engels, Philipp Goos, Marie-Christin Süykers, Stefan Gudenkauf, Rolf-Peter Henke and Friedhelm Wawroschek

Cancers 2020, 12(1), 32; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12010032 - 20 Dec 2019

Cited by 16 | Viewed by 2917

Abstract

Radioisotope-guided sentinel lymph node dissection (sLND) has shown high diagnostic reliability in prostate (PCa) and other cancers. To overcome the limitations of the radioactive tracers, magnetometer-guided sLND using superparamagnetic iron oxide nanoparticles (SPIONs) has been successfully used in PCa. This prospective study (SentiMag [...] Read more.

Radioisotope-guided sentinel lymph node dissection (sLND) has shown high diagnostic reliability in prostate (PCa) and other cancers. To overcome the limitations of the radioactive tracers, magnetometer-guided sLND using superparamagnetic iron oxide nanoparticles (SPIONs) has been successfully used in PCa. This prospective study (SentiMag Pro II, DRKS00007671) determined the diagnostic accuracy of magnetometer-guided sLND in intermediate- and high-risk PCa. Fifty intermediate- or high-risk PCa patients (prostate-specific antigen (PSA) ≥ 10 ng/mL and/or Gleason score ≥ 7; median PSA 10.8 ng/mL, IQR 7.4–19.2 ng/mL) were enrolled. After the intraprostatic SPIONs injection a day earlier, patients underwent magnetometer-guided sLND and extended lymph node dissection (eLND, followed by radical prostatectomy. SLNs were detected in in vivo and in ex vivo samples. Diagnostic accuracy of sLND was assessed using eLND as the reference. SLNs were detected in all patients (detection rate 100%), with 447 sentinel lymph nodes SLNs (median 9, IQR 6–12) being identified and 966 LNs (median 18, IQR 15–23) being removed. Thirty-six percent (18/50) of patients had LN metastases (median 2, IQR 1–3). Magnetometer-guided sLND had 100% sensitivity, 97.0% specificity, 94.4% positive predictive value, 100% negative predictive value, 0.0% false negative rate, and 3.0% additional diagnostic value (LN metastases only in SLNs outside the eLND template). In vivo, one positive SLN/LN-positive patient was missed, resulting in a sensitivity of 94.4%. In conclusion, this new magnetic sentinel procedure has high accuracy for nodal staging in intermediate- and high-risk PCa. The reliability of intraoperative SLN detection using this magnetometer system requires verification in further multicentric studies. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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22 pages, 11627 KiB

Open AccessArticle

Magnetic Silica-Coated Iron Oxide Nanochains as Photothermal Agents, Disrupting the Extracellular Matrix, and Eradicating Cancer Cells

by Jelena Kolosnjaj-Tabi, Slavko Kralj, Elena Griseti, Sebastjan Nemec, Claire Wilhelm, Anouchka Plan Sangnier, Elisabeth Bellard, Isabelle Fourquaux, Muriel Golzio and Marie-Pierre Rols

Cancers 2019, 11(12), 2040; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11122040 - 17 Dec 2019

Cited by 25 | Viewed by 3800

Abstract

Cancerous cells and the tumor microenvironment are among key elements involved in cancer development, progression, and resistance to treatment. In order to tackle the cells and the extracellular matrix, we herein propose the use of a class of silica-coated iron oxide nanochains, which [...] Read more.

Cancerous cells and the tumor microenvironment are among key elements involved in cancer development, progression, and resistance to treatment. In order to tackle the cells and the extracellular matrix, we herein propose the use of a class of silica-coated iron oxide nanochains, which have superior magnetic responsiveness and can act as efficient photothermal agents. When internalized by different cancer cell lines and normal (non-cancerous) cells, the nanochains are not toxic, as assessed on 2D and 3D cell culture models. Yet, upon irradiation with near infrared light, the nanochains become efficient cytotoxic photothermal agents. Besides, not only do they generate hyperthermia, which effectively eradicates tumor cells in vitro, but they also locally melt the collagen matrix, as we evidence in real-time, using engineered cell sheets with self-secreted extracellular matrix. By simultaneously acting as physical (magnetic and photothermal) effectors and chemical delivery systems, the nanochain-based platforms offer original multimodal possibilities for prospective cancer treatment, affecting both the cells and the extracellular matrix. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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12 pages, 2512 KiB

Open AccessArticle

An Effective Multi-Stage Liposomal DNA Origami Nanosystem for In Vivo Cancer Therapy

by Stefano Palazzolo, Mohamad Hadla, Concetta Russo Spena, Isabella Caligiuri, Rossella Rotondo, Muhammad Adeel, Vinit Kumar, Giuseppe Corona, Vincenzo Canzonieri, Giuseppe Toffoli and Flavio Rizzolio

Cancers 2019, 11(12), 1997; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11121997 - 12 Dec 2019

Cited by 34 | Viewed by 5277

Abstract

DNA origami systems could be important candidates for clinical applications. Unfortunately, their intrinsic properties such as the activation of non-specific immune system responses leading to inflammation, instability in physiological solutions, and a short in vivo lifetime are the major challenges for real world [...] Read more.

DNA origami systems could be important candidates for clinical applications. Unfortunately, their intrinsic properties such as the activation of non-specific immune system responses leading to inflammation, instability in physiological solutions, and a short in vivo lifetime are the major challenges for real world applications. A compact short tube DNA origami (STDO) of 30 nm in length and 10 nm in width was designed to fit inside the core of a stealth liposome (LSTDO) of about 150 nm to remote load doxorubicin. Biocompatibility was tested in three-dimensional (3D) organoid cultures and in vivo. Efficacy was evaluated in different cell lines and in a xenograft breast cancer mouse model. As described in a previous work, LSTDO is highly stable and biocompatible, escaping the recognition of the immune system. Here we show that LSTDO have an increased toleration in mouse liver organoids used as an ex vivo model that recapitulate the tissue of origin. This innovative drug delivery system (DDS) improves the antitumoral efficacy and biodistribution of doxorubicin in tumor-bearing mice and decreases bone marrow toxicity. Our application is an attractive system for the remote loading of other drugs able to interact with DNA for the preparation of liposomal formulations. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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27 pages, 7318 KiB

Open AccessArticle

A Triple Co-Delivery Liposomal Carrier That Enhances Apoptosis via an Intrinsic Pathway in Melanoma Cells

by Nina Filipczak, Anna Jaromin, Adriana Piwoni, Mohamed Mahmud, Can Sarisozen, Vladimir Torchilin and Jerzy Gubernator

Cancers 2019, 11(12), 1982; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11121982 - 09 Dec 2019

Cited by 24 | Viewed by 3693

Abstract

The effectiveness of existing anti-cancer therapies is based mainly on the stimulation of apoptosis of cancer cells. Most of the existing therapies are somewhat toxic to normal cells. Therefore, the quest for nontoxic, cancer-specific therapies remains. We have demonstrated the ability of liposomes [...] Read more.

The effectiveness of existing anti-cancer therapies is based mainly on the stimulation of apoptosis of cancer cells. Most of the existing therapies are somewhat toxic to normal cells. Therefore, the quest for nontoxic, cancer-specific therapies remains. We have demonstrated the ability of liposomes containing anacardic acid, mitoxantrone and ammonium ascorbate to induce the mitochondrial pathway of apoptosis via reactive oxygen species (ROS) production by the killing of cancer cells in monolayer culture and shown its specificity towards melanoma cells. Liposomes were prepared by a lipid hydration, freeze-and-thaw (FAT) procedure and extrusion through polycarbonate filters, a remote loading method was used for dug encapsulation. Following characterization, hemolytic activity, cytotoxicity and apoptosis inducing effects of loaded nanoparticles were investigated. To identify the anticancer activity mechanism of these liposomes, ROS level and caspase 9 activity were measured by fluorescence and by chemiluminescence respectively. We have demonstrated that the developed liposomal formulations produced a high ROS level, enhanced apoptosis and cell death in melanoma cells, but not in normal cells. The proposed mechanism of the cytotoxic action of these liposomes involved specific generation of free radicals by the iron ions mechanism. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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17 pages, 4845 KiB

Open AccessArticle

Mangiferin-Loaded Polymeric Nanoparticles: Optical Characterization, Effect of Anti-topoisomerase I, and Cytotoxicity

by Francisco Fabian Razura-Carmona, Alejandro Pérez-Larios, Napoleón González-Silva, Mayra Herrera-Martínez, Luis Medina-Torres, Sonia Guadalupe Sáyago-Ayerdi and Jorge Alberto Sánchez-Burgos

Cancers 2019, 11(12), 1965; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11121965 - 06 Dec 2019

Cited by 22 | Viewed by 3735

Abstract

Mangiferin is an important xanthone compound presenting various biological activities. The objective of this study was to develop, characterize physicochemical properties, and evaluate the anti-topoisomerase activity of poly(lactic-co-glycolic acid) (PLGA) nanoparticles containing mangiferin. The nanoparticles were developed by the emulsion solvent evaporation method [...] Read more.

Mangiferin is an important xanthone compound presenting various biological activities. The objective of this study was to develop, characterize physicochemical properties, and evaluate the anti-topoisomerase activity of poly(lactic-co-glycolic acid) (PLGA) nanoparticles containing mangiferin. The nanoparticles were developed by the emulsion solvent evaporation method and the optimal formulation was obtained with a response surface methodology (RSM); this formulation showed a mean size of 176.7 ± 1.021 nm with a 0.153 polydispersibility index (PDI) value, and mangiferin encapsulation efficiency was about 55%. The optimal conditions (6000 rpm, 10 min, and 300 μg of mangiferin) obtained 77% and the highest entrapment efficiency (97%). The in vitro release profile demonstrated a gradual release of mangiferin from 15 to 180 min in acidic conditions (pH 1.5). The fingerprint showed a modification in the maximum absorption wavelength of both the polymer and the mangiferin. Results of anti-toposiomerase assay showed that the optimal formulation (MG4, 25 µg/mL) had antiproliferative activity. High concentrations (2500 µg/mL) of MG4 showed non-in vitro cytotoxic effect on BEAS 2B and HEPG2. Finally, this study showed an encapsulation process with in vitro gastric digestion resistance (1.5 h) and without interfering with the metabolism of healthy cells and their biological activity. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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21 pages, 3821 KiB

Open AccessArticle

Titanate Nanotubes Engineered with Gold Nanoparticles and Docetaxel to Enhance Radiotherapy on Xenografted Prostate Tumors

by Alexis Loiseau, Julien Boudon, Alexandra Oudot, Mathieu Moreau, Romain Boidot, Rémi Chassagnon, Nasser Mohamed Saïd, Stéphane Roux, Céline Mirjolet and Nadine Millot

Cancers 2019, 11(12), 1962; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11121962 - 06 Dec 2019

Cited by 23 | Viewed by 3373

Abstract

Nanohybrids based on titanate nanotubes (TiONts) were developed to fight prostate cancer by intratumoral (IT) injection, and particular attention was paid to their step-by-step synthesis. TiONts were synthesized by a hydrothermal process. To develop the custom-engineered nanohybrids, the surface of TiONts was coated [...] Read more.

Nanohybrids based on titanate nanotubes (TiONts) were developed to fight prostate cancer by intratumoral (IT) injection, and particular attention was paid to their step-by-step synthesis. TiONts were synthesized by a hydrothermal process. To develop the custom-engineered nanohybrids, the surface of TiONts was coated beforehand with a siloxane (APTES), and coupled with both dithiolated diethylenetriaminepentaacetic acid-modified gold nanoparticles (Au@DTDTPA NPs) and a heterobifunctional polymer (PEG₃₀₀₀) to significantly improve suspension stability and biocompatibility of TiONts for targeted biomedical applications. The pre-functionalized surface of this scaffold had reactive sites to graft therapeutic agents, such as docetaxel (DTX). This novel combination, aimed at retaining the AuNPs inside the tumor via TiONts, was able to enhance the radiation effect. Nanohybrids have been extensively characterized and were detectable by SPECT/CT imaging through grafted Au@DTDTPA NPs, radiolabeled with ¹¹¹In. In vitro results showed that TiONts-AuNPs-PEG₃₀₀₀-DTX had a substantial cytotoxic activity on human PC-3 prostate adenocarcinoma cells, unlike initial nanohybrids without DTX (Au@DTDTPA NPs and TiONts-AuNPs-PEG₃₀₀₀). Biodistribution studies demonstrated that these novel nanocarriers, consisting of AuNP- and DTX-grafted TiONts, were retained within the tumor for at least 20 days on mice PC-3 xenografted tumors after IT injection, delaying tumor growth upon irradiation. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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19 pages, 3205 KiB

Open AccessArticle

Verteporfin-Loaded Lipid Nanoparticles Improve Ovarian Cancer Photodynamic Therapy In Vitro and In Vivo

by Thierry Michy, Thibault Massias, Claire Bernard, Laetitia Vanwonterghem, Maxime Henry, Mélanie Guidetti, Guy Royal, Jean-Luc Coll, Isabelle Texier, Véronique Josserand and Amandine Hurbin

Cancers 2019, 11(11), 1760; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11111760 - 08 Nov 2019

Cited by 53 | Viewed by 5195

Abstract

Advanced ovarian cancer is the most lethal gynecological cancer, with a high rate of chemoresistance and relapse. Photodynamic therapy offers new prospects for ovarian cancer treatment, but current photosensitizers lack tumor specificity, resulting in low efficacy and significant side-effects. In the present work, [...] Read more.

Advanced ovarian cancer is the most lethal gynecological cancer, with a high rate of chemoresistance and relapse. Photodynamic therapy offers new prospects for ovarian cancer treatment, but current photosensitizers lack tumor specificity, resulting in low efficacy and significant side-effects. In the present work, the clinically approved photosensitizer verteporfin was encapsulated within nanostructured lipid carriers (NLC) for targeted photodynamic therapy of ovarian cancer. Cellular uptake and phototoxicity of free verteporfin and NLC-verteporfin were studied in vitro in human ovarian cancer cell lines cultured in 2D and 3D-spheroids, and biodistribution and photodynamic therapy were evaluated in vivo in mice. Both molecules were internalized in ovarian cancer cells and strongly inhibited tumor cells viability when exposed to laser light only. In vivo biodistribution and pharmacokinetic studies evidenced a long circulation time of NLC associated with efficient tumor uptake. Administration of 2 mg·kg⁻¹ free verteporfin induced severe phototoxic adverse effects leading to the death of 5 out of 8 mice. In contrast, laser light exposure of tumors after intravenous administration of NLC-verteporfin (8 mg·kg⁻¹) significantly inhibited tumor growth without visible toxicity. NLC-verteporfin thus led to efficient verteporfin vectorization to the tumor site and protection from side-effects, providing promising therapeutic prospects for photodynamic therapy of cancer. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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23 pages, 6417 KiB

Open AccessFeature PaperArticle

Development and Mechanistic Insight into the Enhanced Cytotoxic Potential of Parvifloron D Albumin Nanoparticles in EGFR-Overexpressing Pancreatic Cancer Cells

by Ana Santos-Rebelo, Pradeep Kumar, Viness Pillay, Yahya E. Choonara, Carla Eleutério, Mariana Figueira, Ana S. Viana, Lia Ascensão, Jesús Molpeceres, Patrícia Rijo, Isabel Correia, Joana Amaral, Susana Solá, Cecília M. P. Rodrigues, Maria Manuela Gaspar and Catarina Pinto Reis

Cancers 2019, 11(11), 1733; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11111733 - 05 Nov 2019

Cited by 23 | Viewed by 3801

Abstract

Pancreatic cancer is one of the most lethal cancers, with an extremely poor prognosis. The development of more effective therapies is thus imperative. Natural origin compounds isolated from Plectranthus genus, such as parvifloron D (PvD), have cytotoxic and antiproliferative activity against human tumour [...] Read more.

Pancreatic cancer is one of the most lethal cancers, with an extremely poor prognosis. The development of more effective therapies is thus imperative. Natural origin compounds isolated from Plectranthus genus, such as parvifloron D (PvD), have cytotoxic and antiproliferative activity against human tumour cells. However, PvD is a very low water-soluble compound, being nanotechnology a promising alternative strategy to solve this problem. Therefore, the aim of this study was to optimize a nanosystem for preferential delivery of PvD to pancreatic tumour cells. Albumin nanoparticles (BSA NPs) were produced through a desolvation method. Glucose cross-linking and bioactive functionalization profiles of BSA platform were elucidated and analysed using static lattice atomistic simulations in vacuum. Using the optimized methodology, PvD was encapsulated (yield higher than 80%) while NPs were characterized in terms of size (100–400 nm) and morphology. Importantly, to achieve a preferential targeting to pancreatic cancer cells, erlotinib and cetuximab were attached to the PvD-loaded nanoparticle surface, and their antiproliferative effects were evaluated in BxPC3 and Panc-1 cell lines. Erlotinib conjugated NPs presented the highest antiproliferative effect toward pancreatic tumour cells. Accordingly, cell cycle analysis of the BxPC3 cell line showed marked accumulation of tumour cells in G1-phase and cell cycle arrest promoted by NPs. As a result, erlotinib conjugated PvD-loaded BSA NPs must be considered a suitable and promising carrier to deliver PvD at the tumour site, improving the treatment of pancreatic cancer. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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19 pages, 4610 KiB

Open AccessArticle

Next-Generation Multimodality of Nanomedicine Therapy: Size and Structure Dependence of Folic Acid Conjugated Copolymers Actively Target Cancer Cells in Disabling Cell Division and Inducing Apoptosis

by Manpreet Sambi, Alexandria DeCarlo, Cecile Malardier-Jugroot and Myron R. Szewczuk

Cancers 2019, 11(11), 1698; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11111698 - 01 Nov 2019

Cited by 12 | Viewed by 3402

Abstract

Nanomedicine as a multimodality treatment of cancer utilizes the advantages of nanodelivery systems of drugs. They are superior to the clinical administration of different therapeutic agents in several aspects, including simultaneous delivery of drugs to the active site, precise ratio control of the [...] Read more.

Nanomedicine as a multimodality treatment of cancer utilizes the advantages of nanodelivery systems of drugs. They are superior to the clinical administration of different therapeutic agents in several aspects, including simultaneous delivery of drugs to the active site, precise ratio control of the loading drugs and overcoming multidrug resistance. The role of nanopolymer size and structural shape on the internalization process and subsequent intracellular toxicity is limited. Here, the size and shape dependent mechanism of a functionalized copolymer was investigated using folic acid (FA) covalently bonded to the copolymer poly (styrene-alt-maleic anhydride) (SMA) on its hydrophilic exterior via a biological linker 2,4-diaminobutyric acid (DABA) to target folic acid receptors (FR) overly expressed on cancer cells actively. We recently reported that unloaded FA-DABA-SMA copolymers significantly reduced cancer cell viability, suggesting a secondary therapeutic mechanism of action of the copolymer carrier post-internalization. Here, we investigated the size and shape dependent secondary mechanism of unloaded 350 kDa and 20 kDa FA-DABA-SMA. The 350 kDa and 20 kDa copolymers actively target folic acid receptors (FR) to initialize internationalization, but only the large size and sheet shaped copolymer disables cell division by intracellular disruptions of essential oncogenic proteins including p53, STAT-3 and c-Myc. Furthermore, the 350 kDa FA-DABA-SMA activates early and late apoptotic events in both PANC-1 and MDA-MB-231 cancer cells. These findings indicate that the large size and structural sheet shape of the 350 kDa FA-DABA-SMA copolymer facilitate multimodal tumor targeting mechanisms together with the ability to internalize hydrophobic chemotherapeutics to disable critical oncogenic proteins controlling cell division and to induce apoptosis. The significance of these novel findings reveals copolymer secondary cellular targets and therapeutic actions that extend beyond the direct delivery of chemotherapeutics. This report offers novel therapeutic insight into the intracellular activity of copolymers critically dependent on the size and structural shape of the nanopolymers. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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15 pages, 2797 KiB

Open AccessFeature PaperArticle

Size Matters in the Cytotoxicity of Polydopamine Nanoparticles in Different Types of Tumors

by Celia Nieto, Milena A. Vega, Jesús Enrique, Gema Marcelo and Eva M. Martín del Valle

Cancers 2019, 11(11), 1679; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11111679 - 29 Oct 2019

Cited by 29 | Viewed by 4557

Abstract

Polydopamine has acquired great relevance in the field of nanomedicine due to its physicochemical properties. Previously, it has been reported that nanoparticles synthetized from this polymer are able to decrease the viability of breast and colon tumor cells. In addition, it is well [...] Read more.

Polydopamine has acquired great relevance in the field of nanomedicine due to its physicochemical properties. Previously, it has been reported that nanoparticles synthetized from this polymer are able to decrease the viability of breast and colon tumor cells. In addition, it is well known that the size of therapeutic particles plays an essential role in their effect. As a consequence, the influence of this parameter on the cytotoxicity of polydopamine nanoparticles was studied in this work. For this purpose, polydopamine nanoparticles with three different diameters (115, 200 and 420 nm) were synthetized and characterized. Their effect on the viability of distinct sorts of human carcinomas (breast, colon, liver and lung) and stromal cells was investigated, as well as the possible mechanisms that could be responsible for such cytotoxicity. Moreover, polydopamine nanoparticles were also loaded with doxorubicin and the therapeutic action of the resulting nanosystem was analyzed. As a result, it was demonstrated that a smaller nanoparticle size is related to a more enhanced antiproliferative activity, which may be a consequence of polydopamine’s affinity for iron ions. Smaller nanoparticles would be able to adsorb more lysosomal Fe³⁺ and, when they are loaded with doxorubicin, a synergistic effect can be achieved. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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17 pages, 3898 KiB

Open AccessArticle

Folate Receptor-Targeted Albumin Nanoparticles Based on Microfluidic Technology to Deliver Cabazitaxel

by Fanchao Meng, Yating Sun, Robert J. Lee, Guiyuan Wang, Xiaolong Zheng, Huan Zhang, Yige Fu, Guojun Yan, Yifan Wang, Weiye Deng, Emily Parks, Betty Y.S. Kim, Zhaogang Yang, Wen Jiang and Lesheng Teng

Cancers 2019, 11(10), 1571; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11101571 - 16 Oct 2019

Cited by 34 | Viewed by 3599

Abstract

Microfluidic technology (MF) has improved the formulation of nanoparticles (NPs) by achieving uniform particle size distribution, controllable particle size, and consistency. Moreover, because liquid mixing can be precisely controlled in the pores of the microfluidic chip, maintaining high mixing efficiency, MF exerts higher [...] Read more.

Microfluidic technology (MF) has improved the formulation of nanoparticles (NPs) by achieving uniform particle size distribution, controllable particle size, and consistency. Moreover, because liquid mixing can be precisely controlled in the pores of the microfluidic chip, maintaining high mixing efficiency, MF exerts higher of NP encapsulation efficiency (EE) than conventional methods. MF-NPs-cabazitaxel (CTX) particles (MF-NPs-CTX) were first prepared by encapsulating CTX according to MF. Folate (FA)- Polyethylene glycol (PEG)-NPs-CTX particles (FA-PEG-NPs-CTX) were formulated by connecting FA to MF-NPs-CTX to endow NPs with targeted delivery capability. Accordingly, the mean particle size of FA-PEG-NPs-CTX increased by approximately 25 nm, as compared with MF-NPs-CTX. Upon morphological observation of FA-PEG-NPs-CTX and MF-NPs-CTX by transmission electron microscopy (TEM), all NPs were spherical and particle size distribution was uniform. Moreover, the increased delivery efficiency of CTX in vitro and its strong tumor inhibition in vivo indicated that FA-PEG-NPs-CTX had a powerful tumor-suppressive effect both in vitro and in vivo. In vivo imaging and pharmacokinetic data confirmed that FA-PEG-NPs-CTX had good drug delivery efficiency. Taken together, FA-PEG-NPs-CTX particles prepared using MF showed high efficient and targeted drug delivery and may have a considerable driving effect on the clinical application of targeting albumin NPs. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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16 pages, 5629 KiB

Open AccessArticle

Cocktail Strategy Based on NK Cell-Derived Exosomes and Their Biomimetic Nanoparticles for Dual Tumor Therapy

by Guosheng Wang, Weilei Hu, Haiqiong Chen, Xin Shou, Tingting Ye and Yibing Xu

Cancers 2019, 11(10), 1560; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11101560 - 14 Oct 2019

Cited by 80 | Viewed by 5988

Abstract

Successful cancer therapy requires drugs being precisely delivered to tumors. Nanosized drugs have attracted considerable recent attention, but their toxicity and high immunogenicity are important obstacles hampering their clinical translation. Here we report a novel “cocktail therapy” strategy based on excess natural killer [...] Read more.

Successful cancer therapy requires drugs being precisely delivered to tumors. Nanosized drugs have attracted considerable recent attention, but their toxicity and high immunogenicity are important obstacles hampering their clinical translation. Here we report a novel “cocktail therapy” strategy based on excess natural killer cell-derived exosomes (NKEXOs) in combination with their biomimetic core–shell nanoparticles (NNs) for tumor-targeted therapy. The NNs were self- assembled with a dendrimer core loading therapeutic miRNA and a hydrophilic NKEXOs shell. Their successful fabrication was confirmed by transmission electron microscopy (TEM) and confocal laser scanning microscopy (CLSM). The resulting NN/NKEXO cocktail showed highly efficient targeting and therapeutic miRNA delivery to neuroblastoma cells in vivo, as demonstrated by two-photon excited scanning fluorescence imaging (TPEFI) and with an IVIS Spectrum in vivo imaging system (IVIS), leading to dual inhibition of tumor growth. With unique biocompatibility, we propose this NN/NKEXO cocktail as a new avenue for tumor therapy, with potential prospects for clinical applications. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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16 pages, 4104 KiB

Open AccessArticle

Matryoshka-Type Liposomes Offer the Improved Delivery of Temoporfin to Tumor Spheroids

by Ilya Yakavets, Marie Millard, Laureline Lamy, Aurelie Francois, Dietrich Scheglmann, Arno Wiehe, Henri-Pierre Lassalle, Vladimir Zorin and Lina Bezdetnaya

Cancers 2019, 11(9), 1366; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11091366 - 13 Sep 2019

Cited by 14 | Viewed by 2950

Abstract

The balance between the amount of drug delivered to tumor tissue and the homogeneity of its distribution is a challenge in the efficient delivery of photosensitizers (PSs) in photodynamic therapy (PDT) of cancer. To date, many efforts have been made using various nanomaterials [...] Read more.

The balance between the amount of drug delivered to tumor tissue and the homogeneity of its distribution is a challenge in the efficient delivery of photosensitizers (PSs) in photodynamic therapy (PDT) of cancer. To date, many efforts have been made using various nanomaterials to efficiently deliver temoporfin (mTHPC), one of the most potent photosensitizers. The present study aimed to develop double-loaded matryoshka-type hybrid nanoparticles encapsulating mTHPC/cyclodextrin inclusion complexes in mTHPC-loaded liposomes. This system was expected to improve the transport of mTHPC to target tissues and to strengthen its accumulation in the tumor tissue. Double-loaded hybrid nanoparticles (DL-DCL) were prepared, characterized, and tested in 2D and 3D in vitro models and in xenografted mice in vivo. Our studies indicated that DL-DCL provided deep penetration of mTHPC into the multicellular tumor spheroids via cyclodextrin nanoshuttles once the liposomes had been destabilized by serum proteins. Unexpectedly, we observed similar PDT efficiency in xenografted HT29 tumors for liposomal mTHPC formulation (Foslip^®) and DL-DCL. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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18 pages, 2755 KiB

Open AccessArticle

Hybrid Clustered Nanoparticles for Chemo-Antibacterial Combinatorial Cancer Therapy

by Barbara Cortese, Stefania D’Amone, Mariangela Testini, Patrizia Ratano and Ilaria Elena Palamà

Cancers 2019, 11(9), 1338; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11091338 - 10 Sep 2019

Cited by 14 | Viewed by 3022

Abstract

Background: A great number of therapeutic limitations, such as chemoresistance, high dosage, and long treatments, are still present in cancer therapy, and are often followed by side effects such as infections, which represent the primary cause of death among patients. Methods: [...] Read more.

Background: A great number of therapeutic limitations, such as chemoresistance, high dosage, and long treatments, are still present in cancer therapy, and are often followed by side effects such as infections, which represent the primary cause of death among patients. Methods: We report pH- and enzymatic-responsive hybrid clustered nanoparticles (HC-NPs), composed of a PCL polymeric core loaded with an anticancer drug, such as Imatinib Mesylate (IM), and coated with biodegradable multilayers embedded with antibacterial and anticancer baby-ship silver NPs, as well as a monoclonal antibody for specific targeting of cancer cells conjugated on the surface. Results: The HC-NPs presented an onion-like structure that serially responded to endogenous stimuli. After internalization into targeted cancer cells, the clustered nanoparticles were able to break up, thanks to intracellular proteases which degraded the biodegradable multilayers and allowed the release of the baby-ship NPs and the IM loaded within the pH-sensible polymer present inside the mothership core. In vitro studies validated the efficiency of HC-NPs in human chronic leukemic cells. This cellular model allowed us to demonstrate specificity and molecular targeting sensitivity, achieved by using a combinatorial approach inside a single nano-platform, instead of free administrations. The combinatory effect of chemotherapic drug and AgNPs in one single nanosystem showed an improved cell death efficacy. In addition, HC-NPs showed a good antibacterial capacity on Gram-negative and Gram-positive bacteria. Conclusions: This study shows an important combinatorial anticancer and antimicrobial effect in vitro. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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29 pages, 5392 KiB

Open AccessArticle

A Tunable Nanoplatform of Nanogold Functionalised with Angiogenin Peptides for Anti-Angiogenic Therapy of Brain Tumours

by Irina Naletova, Lorena Maria Cucci, Floriana D’Angeli, Carmelina Daniela Anfuso, Antonio Magrì, Diego La Mendola, Gabriella Lupo and Cristina Satriano

Cancers 2019, 11(9), 1322; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11091322 - 06 Sep 2019

Cited by 23 | Viewed by 3333

Abstract

Angiogenin (ANG), an endogenous protein that plays a key role in cell growth and survival, has been scrutinised here as promising nanomedicine tool for the modulation of pro-/anti-angiogenic processes in brain cancer therapy. Specifically, peptide fragments from the putative cell membrane binding domain [...] Read more.

Angiogenin (ANG), an endogenous protein that plays a key role in cell growth and survival, has been scrutinised here as promising nanomedicine tool for the modulation of pro-/anti-angiogenic processes in brain cancer therapy. Specifically, peptide fragments from the putative cell membrane binding domain (residues 60–68) of the protein were used in this study to obtain peptide-functionalised spherical gold nanoparticles (AuNPs) of about 10 nm and 30 nm in optical and hydrodynamic size, respectively. Different hybrid biointerfaces were fabricated by peptide physical adsorption (Ang_60–68) or chemisorption (the cysteine analogous Ang_60–68Cys) at the metal nanoparticle surface, and cellular assays were performed in the comparison with ANG-functionalised AuNPs. Cellular treatments were performed both in basal and in copper-supplemented cell culture medium, to scrutinise the synergic effect of the metal, which is another known angiogenic factor. Two brain cell lines were investigated in parallel, namely tumour glioblastoma (A172) and neuron-like differentiated neuroblastoma (d-SH-SY5Y). Results on cell viability/proliferation, cytoskeleton actin, angiogenin translocation and vascular endothelial growth factor (VEGF) release pointed to the promising potentialities of the developed systems as anti-angiogenic tunable nanoplaftforms in cancer cells treatment. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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18 pages, 3540 KiB

Open AccessArticle

Multi-Drug/Gene NASH Therapy Delivery and Selective Hyperspectral NIR Imaging Using Chirality-Sorted Single-Walled Carbon Nanotubes

by Md. Tanvir Hasan, Elizabeth Campbell, Olga Sizova, Veronica Lyle, Giridhar Akkaraju, D. Lynn Kirkpatrick and Anton V. Naumov

Cancers 2019, 11(8), 1175; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11081175 - 14 Aug 2019

Cited by 30 | Viewed by 4982

Abstract

Single-walled carbon nanotubes (SWCNTs) can serve as drug delivery/biological imaging agents, as they exhibit intrinsic fluorescence in the near-infrared, allowing for deeper tissue imaging while providing therapeutic transport. In this work, CoMoCAT (Cobalt Molybdenum Catalyst) SWCNTs, chirality-sorted by aqueous two-phase extraction, are utilized [...] Read more.

Single-walled carbon nanotubes (SWCNTs) can serve as drug delivery/biological imaging agents, as they exhibit intrinsic fluorescence in the near-infrared, allowing for deeper tissue imaging while providing therapeutic transport. In this work, CoMoCAT (Cobalt Molybdenum Catalyst) SWCNTs, chirality-sorted by aqueous two-phase extraction, are utilized for the first time to deliver a drug/gene combination therapy and image each therapeutic component separately via chirality-specific SWCNT fluorescence. Each of (7,5) and (7,6) sorted SWCNTs were non-covalently loaded with their specific payload: the PI3 kinase inhibitor targeting liver fibrosis or CCR5 siRNA targeting inflammatory pathways with the goal of addressing these processes in nonalcoholic steatohepatitis (NASH), ultimately to prevent its progression to hepatocellular carcinoma. PX-866-(7,5) SWCNTs and siRNA-(7,6) SWCNTs were each imaged via characteristic SWCNT emission at 1024/1120 nm in HepG2 and HeLa cells by hyperspectral fluorescence microscopy. Wavelength-resolved imaging verified the intracellular transport of each SWCNT chirality and drug release. The therapeutic efficacy of each formulation was further demonstrated by the dose-dependent cytotoxicity of SWCNT-bound PX-866 and >90% knockdown of CCR5 expression with SWCNT/siRNA transfection. This study verifies the feasibility of utilizing chirality-sorted SWCNTs for the delivery and component-specific imaging of combination therapies, also suggesting a novel nanotherapeutic approach for addressing the progressions of NASH to hepatocellular carcinoma. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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17 pages, 1470 KiB

Open AccessArticle

Multifunctional Albumin-Stabilized Gold Nanoclusters for the Reduction of Cancer Stem Cells

by Ana Latorre, Alfonso Latorre, Milagros Castellanos, Ciro Rodriguez Diaz, Ana Lazaro-Carrillo, Tania Aguado, Mercedes Lecea, Sonia Romero-Pérez, Macarena Calero, José María Sanchez-Puelles, Ángeles Villanueva and Álvaro Somoza

Cancers 2019, 11(7), 969; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11070969 - 10 Jul 2019

Cited by 28 | Viewed by 5027

Abstract

Controlled delivery of multiple chemotherapeutics can improve the effectiveness of treatments and reduce side effects and relapses. Here in, we used albumin-stabilized gold nanoclusters modified with doxorubicin and SN38 (AuNCs-DS) as combined therapy for cancer. The chemotherapeutics are conjugated to the nanostructures using [...] Read more.

Controlled delivery of multiple chemotherapeutics can improve the effectiveness of treatments and reduce side effects and relapses. Here in, we used albumin-stabilized gold nanoclusters modified with doxorubicin and SN38 (AuNCs-DS) as combined therapy for cancer. The chemotherapeutics are conjugated to the nanostructures using linkers that release them when exposed to different internal stimuli (Glutathione and pH). This system has shown potent antitumor activity against breast and pancreatic cancer cells. Our studies indicate that the antineoplastic activity observed may be related to the reinforced DNA damage generated by the combination of the drugs. Moreover, this system presented antineoplastic activity against mammospheres, a culturing model for cancer stem cells, leading to an efficient reduction of the number of oncospheres and their size. In summary, the nanostructures reported here are promising carriers for combination therapy against cancer and particularly to cancer stem cells. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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16 pages, 4304 KiB

Open AccessArticle

The Delivery Strategy of Paclitaxel Nanostructured Lipid Carrier Coated with Platelet Membrane

by Ki-Hyun Bang, Young-Guk Na, Hyun Wook Huh, Sung-Joo Hwang, Min-Soo Kim, Minki Kim, Hong-Ki Lee and Cheong-Weon Cho

Cancers 2019, 11(6), 807; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11060807 - 11 Jun 2019

Cited by 52 | Viewed by 4705

Abstract

Strategies for the development of anticancer drug delivery systems have undergone a dramatic transformation in the last few decades. Lipid-based drug delivery systems, such as a nanostructured lipid carrier (NLC), are one of the systems emerging to improve the outcomes of tumor treatments. [...] Read more.

Strategies for the development of anticancer drug delivery systems have undergone a dramatic transformation in the last few decades. Lipid-based drug delivery systems, such as a nanostructured lipid carrier (NLC), are one of the systems emerging to improve the outcomes of tumor treatments. However, NLC can act as an intruder and cause an immune response. To overcome this limitation, biomimicry technology was introduced to decorate the surface of the nanoparticles with various cell membrane proteins. Here, we designed paclitaxel (PT)-loaded nanostructured lipid carrier (PT-NLC) with platelet (PLT) membrane protein because PLT is involved with angiogenesis and interaction of circulating tumor cells. After PLT was isolated from blood using the gravity-gradient method and it was used for coating PT-NLC. Spherical PT-NLC and platelet membrane coated PT-NLC (P-PT-NLC) were successfully fabricated with high encapsulation efficiency (EE) (99.98%) and small particle size (less than 200 nm). The successful coating of PT-NLC with a PLT membrane was confirmed by the identification of CD41 based on transmission electron microscopy (TEM), western blot assay and enzyme-linked immunosorbent assay (ELISA) data. Moreover, the stronger affinity of P-PT-NLC than that of PT-NLC toward tumor cells was observed. In vitro cell study, the PLT coated nanoparticles successfully displayed the anti-tumor effect to SK-OV-3 cells. In summary, the biomimicry carrier system P-PT-NLC has an affinity and targeting ability for tumor cells. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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19 pages, 5133 KiB

Open AccessArticle

A Multifunctional Graphene Oxide Platform for Targeting Cancer

by Nikola Bugárová, Zdenko Špitálsky, Matej Mičušík, Michal Bodík, Peter Šiffalovič, Martina Koneracká, Vlasta Závišová, Martina Kubovčíková, Ivana Kajanová, Miriam Zaťovičová, Silvia Pastoreková, Miroslav Šlouf, Eva Majková and Mária Omastová

Cancers 2019, 11(6), 753; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11060753 - 29 May 2019

Cited by 19 | Viewed by 4518

Abstract

Diagnosis of oncological diseases remains at the forefront of current medical research. Carbonic Anhydrase IX (CA IX) is a cell surface hypoxia-inducible enzyme functionally involved in adaptation to acidosis that is expressed in aggressive tumors; hence, it can be used as a tumor [...] Read more.

Diagnosis of oncological diseases remains at the forefront of current medical research. Carbonic Anhydrase IX (CA IX) is a cell surface hypoxia-inducible enzyme functionally involved in adaptation to acidosis that is expressed in aggressive tumors; hence, it can be used as a tumor biomarker. Herein, we propose a nanoscale graphene oxide (GO) platform functionalized with magnetic nanoparticles and a monoclonal antibody specific to the CA IX marker. The GO platforms were prepared by a modified Hummers and Offeman method from exfoliated graphite after several centrifugation and ultrasonication cycles. The magnetic nanoparticles were prepared by a chemical precipitation method and subsequently modified. Basic characterization of GO, such as the degree of oxidation, nanoparticle size and exfoliation, were determined by physical and chemical analysis, including X-ray photoelectron spectroscopy (XPS), transmission electron microscopy (TEM), energy dispersive X-ray analysis (EDX), and atomic force microscopy (AFM). In addition, the size and properties of the poly-L-lysine-modified magnetic nanoparticles were characterized. The antibody specific to CA IX was linked via an amidic bond to the poly-L-lysine modified magnetic nanoparticles, which were conjugated to GO platform again via an amidic bond. The prepared GO-based platform with magnetic nanoparticles combined with a biosensing antibody element was used for a hypoxic cancer cell targeting study based on immunofluorescence. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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16 pages, 8694 KiB

Open AccessArticle

In Vivo Evaluation of Dual-Targeted Nanoparticles Encapsulating Paclitaxel and Everolimus

by Loujin Houdaihed, James Christopher Evans and Christine Allen

Cancers 2019, 11(6), 752; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11060752 - 29 May 2019

Cited by 13 | Viewed by 3502

Abstract

A synergistic combination of paclitaxel (PTX) and everolimus (EVER) can allow for lower drug doses, reducing the toxicities associated with PTX, while maintaining therapeutic efficacy. Polymeric nanoparticles (NPs) of high stability provide opportunities to modify the toxicity profile of the drugs by ensuring [...] Read more.

A synergistic combination of paclitaxel (PTX) and everolimus (EVER) can allow for lower drug doses, reducing the toxicities associated with PTX, while maintaining therapeutic efficacy. Polymeric nanoparticles (NPs) of high stability provide opportunities to modify the toxicity profile of the drugs by ensuring their delivery to the tumor site at the synergistic ratio while limiting systemic drug exposure and the toxicities that result. The goal of the current study is to evaluate the in vivo fate of human epidermal factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR) dual-targeted PTX+EVER-loaded NPs (Dual-NPs) in an MDA-MB-231-H2N breast cancer (BC) tumor-bearing mouse model. The pharmacokinetic parameters, plasma area under the curve (AUC) and half-life (t_1/2z) were found to be 20-fold and 3 to 4-fold higher, respectively, for the drugs when administered in the Dual-NPs in comparison to the free-drug combination (i.e., PTX+EVER) at an equivalent dose of PTX. While maintaining anti-tumor efficacy, the levels of body weight loss were significantly lower (p < 0.0001) and the overall degree of neurotoxicity was reduced with Dual-NPs treatment in comparison to the free-drug combination when administered at an equivalent dose of PTX. This study suggests that Dual-NPs present a promising platform for the delivery of the PTX and EVER combination with the potential to reduce severe PTX-induced toxicities and in turn, improve quality of life for patients with BC. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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14 pages, 3313 KiB

Open AccessArticle

Hyaluronidase-Responsive Mesoporous Silica Nanoparticles with Dual-Imaging and Dual-Target Function

by Zhi-Yuan Wu, Cheng-Chang Lee and Hsiu-Mei Lin

Cancers 2019, 11(5), 697; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11050697 - 20 May 2019

Cited by 22 | Viewed by 4131

Abstract

Nanoparticle-based drug delivery systems are among the most popular research topics in recent years. Compared with traditional drug carriers, mesoporous silica nanoparticles (MSN) offer modifiable surfaces, adjustable pore sizes and good biocompatibility. Nanoparticle-based drug delivery systems have become a research direction for many [...] Read more.

Nanoparticle-based drug delivery systems are among the most popular research topics in recent years. Compared with traditional drug carriers, mesoporous silica nanoparticles (MSN) offer modifiable surfaces, adjustable pore sizes and good biocompatibility. Nanoparticle-based drug delivery systems have become a research direction for many scientists. With the active target factionalized, scientists could deliver drug carriers into cancer cells successfully. However, drugs in cancer cells could elicit drug resistance and induce cell exocytosis. Thus, the drug cannot be delivered to its pharmacological location, such as the nucleus. Therefore, binding the cell membrane and the nuclear target on the nanomaterial so that the anticancer drug can be delivered to its pharmacological action site is our goal. In this study, MSN-EuGd was synthesized by doping Eu³⁺ and Gd³⁺ during the synthesis of MSN. The surface of the material was then connected to the TAT peptide as the nucleus target for targeting the cancer nucleus and then loaded with the anticancer drug camptothecin (CPT). Then, the surface of MSN-EuGd was bonded to the hyaluronic acid as an active target and gatekeeper. With this system, it is possible and desirable to achieve dual imaging and dual targeting, as well as to deliver drugs to the cell nucleus under a hyaluronidase-controlled release. The experimental approach is divided into three parts. First, we conferred the material with fluorescent and magnetic dual-imaging property by doping Eu³⁺ and Gd³⁺ into the MSN. Second, modification of the cell membrane target molecule and the nucleus target molecule occurred on the surface of the nanoparticle, making the nanoparticle a target drug carrier. Third, the loading of drug molecules into the carrier gave the entire carrier a specific target profile and enabled the ability to treat cancer. In this study, we investigated the basic properties of the drug carrier, including physical properties, chemical properties, and in vitro tests. The result showed that we have successfully designed a drug delivery system that recognizes normal cells and cancer cells and has good anticancer effects. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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18 pages, 4596 KiB

Open AccessArticle

Antitumor Effects of Intra-Arterial Delivery of Albumin-Doxorubicin Nanoparticle Conjugated Microbubbles Combined with Ultrasound-Targeted Microbubble Activation on VX2 Rabbit Liver Tumors

by Jae Hwan Lee, Hyungwon Moon, Hyounkoo Han, In Joon Lee, Doyeon Kim, Hak Jong Lee, Shin-Woo Ha, Hyuncheol Kim and Jin Wook Chung

Cancers 2019, 11(4), 581; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11040581 - 24 Apr 2019

Cited by 21 | Viewed by 3821

Abstract

Image-guided intra-arterial therapies play a key role in the management of hepatic malignancies. However, limited clinical outcomes suggest the need for new multifunctional drug delivery systems to enhance local drug concentration while reducing systemic adverse reactions. Therefore, we developed the albumin-doxorubicin nanoparticle conjugated [...] Read more.

Image-guided intra-arterial therapies play a key role in the management of hepatic malignancies. However, limited clinical outcomes suggest the need for new multifunctional drug delivery systems to enhance local drug concentration while reducing systemic adverse reactions. Therefore, we developed the albumin-doxorubicin nanoparticle conjugated microbubble (ADMB) to enhance therapeutic efficiency by sonoporation under exposure to ultrasound. ADMB demonstrated a size distribution of 2.33 ± 1.34 µm and a doxorubicin loading efficiency of 82.7%. The echogenicity of ADMBs was sufficiently generated in the 2–9 MHz frequency range and cavitation depended on the strength of the irradiating ultrasound. In the VX2 rabbit tumor model, ADMB enhanced the therapeutic efficiency under ultrasound exposure, compared to free doxorubicin. The intra-arterial administration of ADMBs sufficiently reduced tumor growth by five times, compared to the control group. Changes in the ADC values and viable tumor fraction supported the fact that the antitumor effect of ADMBs were enhanced by evidence of necrosis ratio (over 70%) and survival tumor cell fraction (20%). Liver toxicity was comparable to that of conventional therapies. In conclusion, this study shows that tumor suppression can be sufficiently maximized by combining ultrasound exposure with intra-arterial ADMB administration. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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16 pages, 2155 KiB

Open AccessFeature PaperArticle

Plant Virus-Like Particle In Situ Vaccine for Intracranial Glioma Immunotherapy

by Amber Kerstetter-Fogle, Sourabh Shukla, Chao Wang, Veronique Beiss, Peggy L. R. Harris, Andrew E. Sloan and Nicole F. Steinmetz

Cancers 2019, 11(4), 515; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11040515 - 10 Apr 2019

Cited by 51 | Viewed by 5020

Abstract

Despite aggressive multi-modality treatment with surgery, radiation and chemotherapies, malignant glioma inevitably recurs and has dismal survival rates. Recent progress in immunotherapy has led to a resurgence of interest, and immunotherapies are being investigated for treatment of glioma. However, the unique brain anatomy [...] Read more.

Despite aggressive multi-modality treatment with surgery, radiation and chemotherapies, malignant glioma inevitably recurs and has dismal survival rates. Recent progress in immunotherapy has led to a resurgence of interest, and immunotherapies are being investigated for treatment of glioma. However, the unique brain anatomy and a highly immunosuppressive glioma microenvironment pose significant challenges to achieving efficacy. Thus, there is a critical need for assessment of next-generation immunotherapies for glioma. In this study, we have investigated the efficacy of the nanoparticle platform technology based on plant-derived Cowpea mosaic virus like particles (empty CPMV or eCPMV) to instigate a potent immune response against intracranial glioma. CPMV immunotherapy has been shown to efficiently reverse the immunosuppressive tumor microenvironments in pre-clinical murine models of dermal melanoma and metastatic melanoma, metastatic breast cancer, intraperitoneal ovarian cancer and in canine patients with oral melanoma. In the present study, we demonstrate that in situ administration of CPMV immunotherapy in the setting of glioma can effectively recruit unique subset of effector innate and adaptive immune cells to the brain parenchyma while reducing immune suppressive cellular population, leading to regression of intracranial glioma. The in situ CPMV nanoparticle vaccine offers a potent yet safe and localized immunotherapy for intracranial glioma. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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15 pages, 2189 KiB

Open AccessArticle

Improving Payload Capacity and Anti-Tumor Efficacy of Mesenchymal Stem Cells Using TAT Peptide Functionalized Polymeric Nanoparticles

by Gopikrishna Moku, Buddhadev Layek, Lana Trautman, Samuel Putnam, Jayanth Panyam and Swayam Prabha

Cancers 2019, 11(4), 491; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11040491 - 06 Apr 2019

Cited by 53 | Viewed by 5623

Abstract

Mesenchymal stem cells (MSCs) accumulate specifically in both primary tumors and metastases following systemic administration. However, the poor payload capacity of MSCs limits their use in small molecule drug delivery. To improve drug payload in MSCs, we explored polymeric nanoparticles that were functionalized [...] Read more.

Mesenchymal stem cells (MSCs) accumulate specifically in both primary tumors and metastases following systemic administration. However, the poor payload capacity of MSCs limits their use in small molecule drug delivery. To improve drug payload in MSCs, we explored polymeric nanoparticles that were functionalized with transactivator of transcription (TAT) peptide. Paclitaxel loaded poly(DL-lactide-co-glycolide) (PLGA) nanoparticles (15–16% w/w paclitaxel; diameter of 225 ± 7 nm; and zeta potential of −15 ± 4 mV) were fabricated by emulsion-solvent evaporation method, followed by TAT-conjugation to the surface of nanoparticles via maleimide-thiol chemistry. Our studies demonstrated that TAT functionalization improved the intracellular accumulation and retention of nanoparticles in MSCs. Further, nano-engineering of MSCs did not alter the migration and differentiation potential of MSCs. Treatment with nano-engineered MSCs resulted in significant (p < 0.05) inhibition of tumor growth and improved survival (p < 0.0001) in a mouse orthotopic model of lung cancer compared to that with free or nanoparticle encapsulated drug. In summary, our results demonstrated that MSCs engineered using TAT functionalized nanoparticles serve as an efficient carrier for tumor specific delivery of anticancer drugs, resulting in greatly improved therapeutic efficacy. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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18 pages, 2346 KiB

Open AccessArticle

Targeted siRNA Nanoparticles for Mammary Carcinoma Therapy

by Meital Ben-David-Naim, Arie Dagan, Etty Grad, Gil Aizik, Mirjam M. Nordling-David, Alisa Morss Clyne, Zvi Granot and Gershon Golomb

Cancers 2019, 11(4), 442; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11040442 - 29 Mar 2019

Cited by 12 | Viewed by 4155

Abstract

Non-viral, polymeric-based, siRNA nanoparticles (NPs) have been proposed as promising gene delivery systems. Encapsulating siRNA in targeted NPs could confer improved biological stability, extended half-life, enhanced permeability, effective tumor accumulation, and therapy. In this work, a peptide derived from apolipoprotein B100 (ApoB-P), the [...] Read more.

Non-viral, polymeric-based, siRNA nanoparticles (NPs) have been proposed as promising gene delivery systems. Encapsulating siRNA in targeted NPs could confer improved biological stability, extended half-life, enhanced permeability, effective tumor accumulation, and therapy. In this work, a peptide derived from apolipoprotein B100 (ApoB-P), the protein moiety of low-density lipoprotein, was used to target siRNA-loaded PEGylated NPs to the extracellular matrix/proteoglycans (ECM/PGs) of a mammary carcinoma tumor. siRNA against osteopontin (siOPN), a protein involved in breast cancer development and progression, was encapsulated into PEGylated poly(d,l-lactic-co-glycolic acid) (PLGA) NPs using the double emulsion solvent diffusion technique. The NPs obtained possessed desired physicochemical properties including ~200 nm size, a neutral surface charge, and high siOPN loading of ~5 µg/mg. ApoB-P-targeted NPs exhibited both enhanced binding to isolated ECM and internalization by MDA-MB-231 human mammary carcinoma cells, in comparison to non-targeted NPs. Increased accumulation of the targeted NPs was achieved in the primary mammary tumor of mice xenografted with MDA-MB-231 mammary carcinoma cells as well as in the lungs, one of the main sites affected by metastases. siOPN NPs treatment resulted in significant inhibition of tumor growth (similar bioactivity of both formulations), accompanied with significant reduction of OPN mRNA levels (~40% knockdown of mRNA levels). We demonstrated that targeted NPs possessed enhanced tumor accumulation with increased therapeutic potential in mice models of mammary carcinoma. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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20 pages, 4554 KiB

Open AccessArticle

Graphene Oxide-Based Targeting of Extracellular Cathepsin D and Cathepsin L As A Novel Anti-Metastatic Enzyme Cancer Therapy

by Tanveer A. Tabish, Md Zahidul I. Pranjol, David W. Horsell, Alma A. M. Rahat, Jacqueline L. Whatmore, Paul G. Winyard and Shaowei Zhang

Cancers 2019, 11(3), 319; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11030319 - 06 Mar 2019

Cited by 37 | Viewed by 6358

Abstract

Overexpression and secretion of the enzymes cathepsin D (CathD) and cathepsin L (CathL) is associated with metastasis in several human cancers. As a superfamily, extracellularly, these proteins may act within the tumor microenvironment to drive cancer progression, proliferation, invasion and metastasis. Therefore, it [...] Read more.

Overexpression and secretion of the enzymes cathepsin D (CathD) and cathepsin L (CathL) is associated with metastasis in several human cancers. As a superfamily, extracellularly, these proteins may act within the tumor microenvironment to drive cancer progression, proliferation, invasion and metastasis. Therefore, it is important to discover novel therapeutic treatment strategies to target CathD and CathL and potentially impede metastasis. Graphene oxide (GO) could form the basis of such a strategy by acting as an adsorbent for pro-metastatic enzymes. Here, we have conducted research into the potential of targeted anti-metastatic therapy using GO to adsorb these pro-tumorigenic enzymes. Binding of CathD/L to GO revealed that CathD/L were adsorbed onto the surface of GO through its cationic and hydrophilic residues. This work could provide a roadmap for the rational integration of CathD/L-targeting agents into clinical settings. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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12 pages, 2065 KiB

Open AccessArticle

PDL-1 Antibody Drug Conjugate for Selective Chemo-Guided Immune Modulation of Cancer

by Samaresh Sau, Alex Petrovici, Hashem O. Alsaab, Ketki Bhise and Arun K. Iyer

Cancers 2019, 11(2), 232; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11020232 - 16 Feb 2019

Cited by 39 | Viewed by 8888

Abstract

Targeting immune checkpoint molecules such as programmed death ligand-1 (PDL1) is an emerging strategy for anti-cancer therapy. However, transient expression of PDL1 and difficulty in tumor stroma penetration has limited the utility of anti-PDL1 therapy. To overcome these limitations, we report a new [...] Read more.

Targeting immune checkpoint molecules such as programmed death ligand-1 (PDL1) is an emerging strategy for anti-cancer therapy. However, transient expression of PDL1 and difficulty in tumor stroma penetration has limited the utility of anti-PDL1 therapy. To overcome these limitations, we report a new conjugate between the clinically approved PDL1 antibody (PDL1 AB) and drug Doxorubicin (Dox), named PDL1-Dox. We conjugated PDL1-Dox through a hydrazone linker containing a polyethylene glycol (PEG) spacer, which allows it to dissociate in a tumor environment and improves solubility. The purpose of using Dox is to disrupt the tumor extracellular environment so that PDL-1 antibody can penetrate the tumor core. PDL1-Dox demonstrates significant cell killing, disruption of tumor spheroid and induction of apoptosis in a breast cancer cell line. Significant release of IFN-γ suggests PDL1-Dox can upmodulate T cell activation. Optical imaging of dye conjugate supports the selective tumor targeting ability and core penetration of the construct. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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Review

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16 pages, 1558 KiB

Open AccessReview

Effect of Flow-Induced Shear Stress in Nanomaterial Uptake by Cells: Focus on Targeted Anti-Cancer Therapy

by Samar Shurbaji, Gulsen G. Anlar, Essraa A. Hussein, Ahmed Elzatahry and Huseyin C. Yalcin

Cancers 2020, 12(7), 1916; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12071916 - 16 Jul 2020

Cited by 26 | Viewed by 3799

Abstract

Recently, nanomedicines have gained a great deal of attention in diverse biomedical applications, including anti-cancer therapy. Being different from normal tissue, the biophysical microenvironment of tumor cells and cancer cell mechanics should be considered for the development of nanostructures as anti-cancer agents. Throughout [...] Read more.

Recently, nanomedicines have gained a great deal of attention in diverse biomedical applications, including anti-cancer therapy. Being different from normal tissue, the biophysical microenvironment of tumor cells and cancer cell mechanics should be considered for the development of nanostructures as anti-cancer agents. Throughout the last decades, many efforts devoted to investigating the distinct cancer environment and understanding the interactions between tumor cells and have been applied bio-nanomaterials. This review highlights the microenvironment of cancer cells and how it is different from that of healthy tissue. We gave special emphasis to the physiological shear stresses existing in the cancerous surroundings, since these stresses have a profound effect on cancer cell/nanoparticle interaction. Finally, this study reviews relevant examples of investigations aimed at clarifying the cellular nanoparticle uptake behavior under both static and dynamic conditions. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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17 pages, 2926 KiB

Open AccessReview

Riboflavin-Targeted Drug Delivery

by Milita Darguzyte, Natascha Drude, Twan Lammers and Fabian Kiessling

Cancers 2020, 12(2), 295; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12020295 - 27 Jan 2020

Cited by 42 | Viewed by 6145

Abstract

Active targeting can improve the retention of drugs and drug delivery systems in tumors, thereby enhancing their therapeutic efficacy. In this context, vitamin receptors that are overexpressed in many cancers are promising targets. In the last decade, attention and research were mainly centered [...] Read more.

Active targeting can improve the retention of drugs and drug delivery systems in tumors, thereby enhancing their therapeutic efficacy. In this context, vitamin receptors that are overexpressed in many cancers are promising targets. In the last decade, attention and research were mainly centered on vitamin B9 (folate) targeting; however, the focus is slowly shifting towards vitamin B2 (riboflavin). Interestingly, while the riboflavin carrier protein was discovered in the 1960s, the three riboflavin transporters (RFVT 1-3) were only identified recently. It has been shown that riboflavin transporters and the riboflavin carrier protein are overexpressed in many tumor types, tumor stem cells, and the tumor neovasculature. Furthermore, a clinical study has demonstrated that tumor cells exhibit increased riboflavin metabolism as compared to normal cells. Moreover, riboflavin and its derivatives have been conjugated to ultrasmall iron oxide nanoparticles, polyethylene glycol polymers, dendrimers, and liposomes. These conjugates have shown a high affinity towards tumors in preclinical studies. This review article summarizes knowledge on RFVT expression in healthy and pathological tissues, discusses riboflavin internalization pathways, and provides an overview of RF-targeted diagnostics and therapeutics. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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26 pages, 4298 KiB

Open AccessReview

Nanodrug Delivery Systems for the Treatment of Ovarian Cancer

by Jonathan M. Pantshwa, Pierre P. D. Kondiah, Yahya E. Choonara, Thashree Marimuthu and Viness Pillay

Cancers 2020, 12(1), 213; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12010213 - 15 Jan 2020

Cited by 28 | Viewed by 4654

Abstract

Despite advances achieved in medicine, chemotherapeutics still has detrimental side effects with ovarian cancer (OC), accounting for numerous deaths among females. The provision of safe, early detection and active treatment of OC remains a challenge, in spite of improvements in new antineoplastic discovery. [...] Read more.

Despite advances achieved in medicine, chemotherapeutics still has detrimental side effects with ovarian cancer (OC), accounting for numerous deaths among females. The provision of safe, early detection and active treatment of OC remains a challenge, in spite of improvements in new antineoplastic discovery. Nanosystems have shown remarkable progress with impact in diagnosis and chemotherapy of various cancers, due to their ideal size; improved drug encapsulation within its interior core; potential to minimize drug degradation; improve in vivo drug release kinetics; and prolong blood circulation times. However, nanodrug delivery systems have few limitations regarding its accuracy of tumour targeting and the ability to provide sustained drug release. Hence, a cogent and strategic approach has focused on nanosystem functionalization with antibody-based ligands to selectively enhance cellular uptake of antineoplastics. Antibody functionalized nanosystems are (advanced) synthetic candidates, with a broad range of efficiency in specific tumour targeting, whilst leaving normal cells unaffected. This article comprehensively reviews the present status of nanosystems, with particular emphasis on nanomicelles for molecular diagnosis and treatment of OC. In addition, biomarkers of nanosystems provide important prospects as chemotherapeutic strategies to upsurge the survival rate of patients with OC. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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28 pages, 336 KiB

Open AccessReview

Polymeric Nanoparticles for the Treatment of Malignant Gliomas

by Basant Salah Mahmoud, Ali Hamod AlAmri and Christopher McConville

Cancers 2020, 12(1), 175; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12010175 - 10 Jan 2020

Cited by 61 | Viewed by 5221

Abstract

Malignant gliomas are one of the deadliest forms of brain cancer and despite advancements in treatment, patient prognosis remains poor, with an average survival of 15 months. Treatment using conventional chemotherapy does not deliver the required drug dose to the tumour site, owing [...] Read more.

Malignant gliomas are one of the deadliest forms of brain cancer and despite advancements in treatment, patient prognosis remains poor, with an average survival of 15 months. Treatment using conventional chemotherapy does not deliver the required drug dose to the tumour site, owing to insufficient blood brain barrier (BBB) penetration, especially by hydrophilic drugs. Additionally, low molecular weight drugs cannot achieve specific accumulation in cancerous tissues and are characterized by a short circulation half-life. Nanoparticles can be designed to cross the BBB and deliver their drugs within the brain, thus improving their effectiveness for treatment when compared to administration of the free drug. The efficacy of nanoparticles can be enhanced by surface PEGylation to allow more specificity towards tumour receptors. This review will provide an overview of the different therapeutic strategies for the treatment of malignant gliomas, risk factors entailing them as well as the latest developments for brain drug delivery. It will also address the potential of polymeric nanoparticles in the treatment of malignant gliomas, including the importance of their coating and functionalization on their ability to cross the BBB and the chemistry underlying that. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

25 pages, 1400 KiB

Open AccessReview

Exploiting Current Understanding of Hypoxia Mediated Tumour Progression for Nanotherapeutic Development

by Jie Feng, Niall M. Byrne, Wafa Al Jamal and Jonathan A. Coulter

Cancers 2019, 11(12), 1989; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11121989 - 11 Dec 2019

Cited by 18 | Viewed by 6287

Abstract

Hypoxia is one of the most common phenotypes of malignant tumours. Hypoxia leads to the increased activity of hypoxia-inducible factors (HIFs), which regulate the expression of genes controlling a raft of pro-tumour phenotypes. These include maintenance of the cancer stem cell compartment, epithelial-mesenchymal [...] Read more.

Hypoxia is one of the most common phenotypes of malignant tumours. Hypoxia leads to the increased activity of hypoxia-inducible factors (HIFs), which regulate the expression of genes controlling a raft of pro-tumour phenotypes. These include maintenance of the cancer stem cell compartment, epithelial-mesenchymal transition (EMT), angiogenesis, immunosuppression, and metabolic reprogramming. Hypoxia can also contribute to the tumour progression in a HIF-independent manner via the activation of a complex signalling network pathway, including JAK-STAT, RhoA/ROCK, NF-κB and PI3/AKT. Recent studies suggest that nanotherapeutics offer a unique opportunity to target the hypoxic microenvironment, enhancing the therapeutic window of conventional therapeutics. In this review, we summarise recent advances in understanding the impact of hypoxia on tumour progression, while outlining possible nanotherapeutic approaches for overcoming hypoxia-mediated resistance. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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27 pages, 743 KiB

Open AccessReview

Engineered Extracellular Vesicles as a Reliable Tool in Cancer Nanomedicine

by Francesca Susa, Tania Limongi, Bianca Dumontel, Veronica Vighetto and Valentina Cauda

Cancers 2019, 11(12), 1979; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11121979 - 09 Dec 2019

Cited by 66 | Viewed by 6857

Abstract

Fast diagnosis and more efficient therapies for cancer surely represent one of the huge tasks for the worldwide researchers’ and clinicians’ community. In the last two decades, our understanding of the biology and molecular pathology of cancer mechanisms, coupled with the continuous development [...] Read more.

Fast diagnosis and more efficient therapies for cancer surely represent one of the huge tasks for the worldwide researchers’ and clinicians’ community. In the last two decades, our understanding of the biology and molecular pathology of cancer mechanisms, coupled with the continuous development of the material science and technological compounds, have successfully improved nanomedicine applications in oncology. This review argues on nanomedicine application of engineered extracellular vesicles (EVs) in oncology. All the most innovative processes of EVs engineering are discussed together with the related degree of applicability for each one of them in cancer nanomedicines. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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23 pages, 1762 KiB

Open AccessReview

Multifunctional Magnetic Nanowires: Design, Fabrication, and Future Prospects as Cancer Therapeutics

by Abu Bakr A. Nana, Thashree Marimuthu, Pierre P. D. Kondiah, Yahya E. Choonara, Lisa C. Du Toit and Viness Pillay

Cancers 2019, 11(12), 1956; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11121956 - 06 Dec 2019

Cited by 28 | Viewed by 3751

Abstract

Traditional cancer therapeutics are limited by factors such as multi-drug resistance and a plethora of adverse effect. These limitations need to be overcome for the progression of cancer treatment. In order to overcome these limitations, multifunctional nanosystems have recently been introduced into the [...] Read more.

Traditional cancer therapeutics are limited by factors such as multi-drug resistance and a plethora of adverse effect. These limitations need to be overcome for the progression of cancer treatment. In order to overcome these limitations, multifunctional nanosystems have recently been introduced into the market. The employment of multifunctional nanosystems provide for the enhancement of treatment efficacy and therapeutic effect as well as a decrease in drug toxicity. However, in addition to these effects, magnetic nanowires bring specific advantages over traditional nanoparticles in multifunctional systems in terms of the formulation and application into a therapeutic system. The most significant of which is its larger surface area, larger net magnetic moment compared to nanoparticles, and interaction under a magnetic field. This results in magnetic nanowires producing a greater drug delivery and therapeutic platform with specific regard to magnetic drug targeting, magnetic hyperthermia, and magnetic actuation. This, in turn, increases the potential of magnetic nanowires for decreasing adverse effects and improving patient therapeutic outcomes. This review focuses on the design, fabrication, and future potential of multifunctional magnetic nanowire systems with the emphasis on improving patient chemotherapeutic outcomes. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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21 pages, 1238 KiB

Open AccessEditor’s ChoiceReview

Thirty Years of Cancer Nanomedicine: Success, Frustration, and Hope

by Lucia Salvioni, Maria Antonietta Rizzuto, Jessica Armida Bertolini, Laura Pandolfi, Miriam Colombo and Davide Prosperi

Cancers 2019, 11(12), 1855; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11121855 - 25 Nov 2019

Cited by 140 | Viewed by 12621

Abstract

Starting with the enhanced permeability and retention (EPR) effect discovery, nanomedicine has gained a crucial role in cancer treatment. The advances in the field have led to the approval of nanodrugs with improved safety profile and still inspire the ongoing investigations. However, several [...] Read more.

Starting with the enhanced permeability and retention (EPR) effect discovery, nanomedicine has gained a crucial role in cancer treatment. The advances in the field have led to the approval of nanodrugs with improved safety profile and still inspire the ongoing investigations. However, several restrictions, such as high manufacturing costs, technical challenges, and effectiveness below expectations, raised skeptical opinions within the scientific community about the clinical relevance of nanomedicine. In this review, we aim to give an overall vision of the current hurdles encountered by nanotherapeutics along with their design, development, and translation, and we offer a prospective view on possible strategies to overcome such limitations. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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21 pages, 2011 KiB

Open AccessReview

Cancer Cell Membrane-Coated Nanoparticles for Cancer Management

by Jenna C. Harris, Mackenzie A. Scully and Emily S. Day

Cancers 2019, 11(12), 1836; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11121836 - 21 Nov 2019

Cited by 143 | Viewed by 9987

Abstract

Cancer is a global health problem in need of transformative treatment solutions for improved patient outcomes. Many conventional treatments prove ineffective and produce undesirable side effects because they are incapable of targeting only cancer cells within tumors and metastases post administration. There is [...] Read more.

Cancer is a global health problem in need of transformative treatment solutions for improved patient outcomes. Many conventional treatments prove ineffective and produce undesirable side effects because they are incapable of targeting only cancer cells within tumors and metastases post administration. There is a desperate need for targeted therapies that can maximize treatment success and minimize toxicity. Nanoparticles (NPs) with tunable physicochemical properties have potential to meet the need for high precision cancer therapies. At the forefront of nanomedicine is biomimetic nanotechnology, which hides NPs from the immune system and provides superior targeting capabilities by cloaking NPs in cell-derived membranes. Cancer cell membranes expressing “markers of self” and “self-recognition molecules” can be removed from cancer cells and wrapped around a variety of NPs, providing homotypic targeting and circumventing the challenge of synthetically replicating natural cell surfaces. Compared to unwrapped NPs, cancer cell membrane-wrapped NPs (CCNPs) provide reduced accumulation in healthy tissues and higher accumulation in tumors and metastases. The unique biointerfacing capabilities of CCNPs enable their use as targeted nanovehicles for enhanced drug delivery, localized phototherapy, intensified imaging, or more potent immunotherapy. This review summarizes the state-of-the-art in CCNP technology and provides insight to the path forward for clinical implementation. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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24 pages, 868 KiB

Open AccessReview

Targeting Integrins in Cancer Nanomedicine: Applications in Cancer Diagnosis and Therapy

by Ping-Hsiu Wu, Abayomi Emmanuel Opadele, Yasuhito Onodera and Jin-Min Nam

Cancers 2019, 11(11), 1783; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11111783 - 13 Nov 2019

Cited by 67 | Viewed by 6127

Abstract

Due to advancements in nanotechnology, the application of nanosized materials (nanomaterials) in cancer diagnostics and therapeutics has become a leading area in cancer research. The decoration of nanomaterial surfaces with biological ligands is a major strategy for directing the actions of nanomaterials specifically [...] Read more.

Due to advancements in nanotechnology, the application of nanosized materials (nanomaterials) in cancer diagnostics and therapeutics has become a leading area in cancer research. The decoration of nanomaterial surfaces with biological ligands is a major strategy for directing the actions of nanomaterials specifically to cancer cells. These ligands can bind to specific receptors on the cell surface and enable nanomaterials to actively target cancer cells. Integrins are one of the cell surface receptors that regulate the communication between cells and their microenvironment. Several integrins are overexpressed in many types of cancer cells and the tumor microvasculature and function in the mediation of various cellular events. Therefore, the surface modification of nanomaterials with integrin-specific ligands not only increases their binding affinity to cancer cells but also enhances the cellular uptake of nanomaterials through the intracellular trafficking of integrins. Moreover, the integrin-specific ligands themselves interfere with cancer migration and invasion by interacting with integrins, and this finding provides a novel direction for new treatment approaches in cancer nanomedicine. This article reviews the integrin-specific ligands that have been used in cancer nanomedicine and provides an overview of the recent progress in cancer diagnostics and therapeutic strategies involving the use of integrin-targeted nanomaterials. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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13 pages, 2966 KiB

Open AccessEditor’s ChoiceReview

Active Targeting Strategies Using Biological Ligands for Nanoparticle Drug Delivery Systems

by Jihye Yoo, Changhee Park, Gawon Yi, Donghyun Lee and Heebeom Koo

Cancers 2019, 11(5), 640; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11050640 - 08 May 2019

Cited by 427 | Viewed by 16868

Abstract

Targeting nanoparticle (NP) carriers to sites of disease is critical for their successful use as drug delivery systems. Along with optimization of physicochemical properties, researchers have focused on surface modification of NPs with biological ligands. Such ligands can bind specific receptors on the [...] Read more.

Targeting nanoparticle (NP) carriers to sites of disease is critical for their successful use as drug delivery systems. Along with optimization of physicochemical properties, researchers have focused on surface modification of NPs with biological ligands. Such ligands can bind specific receptors on the surface of target cells. Furthermore, biological ligands can facilitate uptake of modified NPs, which is referred to as ‘active targeting’ of NPs. In this review, we discuss recent applications of biological ligands including proteins, polysaccharides, aptamers, peptides, and small molecules for NP-mediated drug delivery. We prioritized studies that have demonstrated targeting in animals over in vitro studies. We expect that this review will assist biomedical researchers working with NPs for drug delivery and imaging. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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19 pages, 1816 KiB

Open AccessReview

Oncogenic Signaling in Tumorigenesis and Applications of siRNA Nanotherapeutics in Breast Cancer

by Nur Izyani Kamaruzman, Noraini Abd Aziz, Chit Laa Poh and Ezharul Hoque Chowdhury

Cancers 2019, 11(5), 632; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11050632 - 06 May 2019

Cited by 25 | Viewed by 5256

Abstract

Overexpression of oncogenes and cross-talks of the oncoproteins-regulated signaling cascades with other intracellular pathways in breast cancer could lead to massive abnormal signaling with the consequence of tumorigenesis. The ability to identify the genes having vital roles in cancer development would give a [...] Read more.

Overexpression of oncogenes and cross-talks of the oncoproteins-regulated signaling cascades with other intracellular pathways in breast cancer could lead to massive abnormal signaling with the consequence of tumorigenesis. The ability to identify the genes having vital roles in cancer development would give a promising therapeutics strategy in combating the disease. Genetic manipulations through siRNAs targeting the complementary sequence of the oncogenic mRNA in breast cancer is one of the promising approaches that can be harnessed to develop more efficient treatments for breast cancer. In this review, we highlighted the effects of major signaling pathways stimulated by oncogene products on breast tumorigenesis and discussed the potential therapeutic strategies for targeted delivery of siRNAs with nanoparticles in suppressing the stimulated signaling pathways. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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18 pages, 1828 KiB

Open AccessFeature PaperReview

Recent Progress in the Theranostics Application of Nanomedicine in Lung Cancer

by Anubhab Mukherjee, Manash Paul and Sudip Mukherjee

Cancers 2019, 11(5), 597; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11050597 - 29 Apr 2019

Cited by 78 | Viewed by 7841

Abstract

Lung cancer is one of the leading causes of cancer-related death worldwide. Non-small cell lung cancer (NSCLC) causes around 80% to 90% of deaths. The lack of an early diagnosis and inefficiency in conventional therapies causes poor prognosis and overall survival of lung [...] Read more.

Lung cancer is one of the leading causes of cancer-related death worldwide. Non-small cell lung cancer (NSCLC) causes around 80% to 90% of deaths. The lack of an early diagnosis and inefficiency in conventional therapies causes poor prognosis and overall survival of lung cancer patients. Recent progress in nanomedicine has encouraged the development of an alternative theranostics strategy using nanotechnology. The interesting physico-chemical properties in the nanoscale have generated immense advantages for nanoparticulate systems for the early detection and active delivery of drugs for a better theranostics strategy for lung cancer. This present review provides a detailed overview of the recent progress in the theranostics application of nanoparticles including liposomes, polymeric, metal and bio-nanoparticles. Further, we summarize the advantages and disadvantages of each approach considering the improvement for the lung cancer theranostics. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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10 pages, 3323 KiB

Open AccessCase Report

Gold Nanorod-Assisted Photothermal Therapy Decreases Bleeding during Breast Cancer Surgery in Dogs and Cats

by Moustafa R. K. Ali, Haithem A. M. Farghali, Yue Wu, Ivan El-Sayed, Ahmed H. Osman, Salah A. Selim and Mostafa A. El-Sayed

Cancers 2019, 11(6), 851; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11060851 - 19 Jun 2019

Cited by 15 | Viewed by 4888

Abstract

For localized tumors, gold nanorod (AuNR)-assisted plasmonic photothermal therapy (PPTT) is a potentially effective alternative to traditional surgery, in which AuNRs absorb near-infrared light and convert it to heat in order to kill cancer cells. However, for large tumors (volume ≥ 20 cm [...] Read more.

For localized tumors, gold nanorod (AuNR)-assisted plasmonic photothermal therapy (PPTT) is a potentially effective alternative to traditional surgery, in which AuNRs absorb near-infrared light and convert it to heat in order to kill cancer cells. However, for large tumors (volume ≥ 20 cm³), an uneven distribution of AuNRs might cause inhomogeneity of the heat distribution inside the tumor. Surgery is frequently recommended for removing large tumors, but it is associated with a high risk of cancer recurrence and metastasis. Here, we applied PPTT before surgery, which showed improved treatment for large tumors. We divided the animals (eight cats/dogs) into two groups: Group I (control), where three cases were solely treated with surgery, laser, or AuNRs alone, resulting in recurrence and metastasis; and Group II, where animals were treated with PPTT before surgery. In Group II, four out of the five cases had tumor regression without any recurrence or metastasis. Interestingly, we observed that applying PPTT before surgery displayed reduced bleeding during tumor removal, supported by histopathology that showed altered blood vessels. In conclusion, our study showed that applying AuNR-assisted PPTT (AuNRs-PPTT) before surgery could significantly affect blood vessels inside the tumor, leading to a decreased amount of bleeding during surgery, which can potentially decrease the risk of metastasis and blood loss during surgery. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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