Drug and Gene Delivery Nanoformulations against Cancer Hallmarks

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Physical Pharmacy and Formulation".

Deadline for manuscript submissions: closed (20 May 2022) | Viewed by 23420

Special Issue Editors

School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland
Interests: porous nanoparticles; hydrogels; triggered drug release; nanotheranostics
Special Issues, Collections and Topics in MDPI journals
1. School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin (TCD), Dublin 2, Ireland
2. Trinity Biomedical Sciences Institute, Trinity College Dublin (TCD), Dublin 2, Ireland
Interests: mesoporous silica nanoparticles; stimuli-responsive nanosystems; targeted drug delivery
Special Issues, Collections and Topics in MDPI journals
1. School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin (TCD), Dublin 2, Ireland
2. Trinity Biomedical Sciences Institute, Trinity College Dublin (TCD), Dublin 2, Ireland
Interests: nanoparticles, hydrogels and drug delivery

Special Issue Information

Dear Colleagues,

In the year 2000, Hanahan and Weinberg proposed a list of six advantageous and complementary biological capabilities that enable tumour growth, survival, and metastatic dissemination, the so-called hallmarks of cancer, with the aim to reduce the intricacy of cancer biology. Such list included sustained proliferative signalling, insensitivity to growth suppressors, cell death resistance, replicative immortality, sustained angiogenesis, and tissue invasion and metastasis. Years later, the same authors added typical cancer features to the list, such as altered energy metabolism and immune surveillance evasion. The definition of cancer hallmarks has encouraged the development of specific therapeutic approaches directed to their inhibition, which is expected to slow down or prevent cancer growth.  

This Special Issue aims to bring together recently developed therapeutic strategies based on drug/gene nanocarriers targeted to obstacle tumour progression acting on one or multiple hallmarks. We invite reviews or original articles on all aspects of “Drug and Gene Delivery Nanoformulations against Cancer Hallmarks”.

Dr. Eduardo Ruiz-Hernandez
Dr. Amelia Ultimo
Dr. Luiza C. S. Erthal
Guest Editors

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Keywords

  • Nanomedicine
  • Cancer hallmarks
  • Drug/gene delivery systems
  • Nanocarriers
  • Cancer therapy

Published Papers (8 papers)

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Research

Jump to: Review

22 pages, 2723 KiB  
Article
Multicellular Ovarian Cancer Model for Evaluation of Nanovector Delivery in Ascites and Metastatic Environments
by Stephen J. Winter, Hunter A. Miller and Jill M. Steinbach-Rankins
Pharmaceutics 2021, 13(11), 1891; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13111891 - 08 Nov 2021
Cited by 6 | Viewed by 1784
Abstract
A novel multicellular model composed of epithelial ovarian cancer and fibroblast cells was developed as an in vitro platform to evaluate nanovector delivery and ultimately aid the development of targeted therapies. We hypothesized that the inclusion of peptide-based scaffold (PuraMatrix) in the spheroid [...] Read more.
A novel multicellular model composed of epithelial ovarian cancer and fibroblast cells was developed as an in vitro platform to evaluate nanovector delivery and ultimately aid the development of targeted therapies. We hypothesized that the inclusion of peptide-based scaffold (PuraMatrix) in the spheroid matrix, to represent in vivo tumor microenvironment alterations along with metastatic site conditions, would enhance spheroid cell growth and migration and alter nanovector transport. The model was evaluated by comparing the growth and migration of ovarian cancer cells exposed to stromal cell activation and tissue hypoxia. Fibroblast activation was achieved via the TGF-β1 mediated pathway and tissue hypoxia via 3D spheroids incubated in hypoxia. Surface-modified nanovector transport was assessed via fluorescence and confocal microscopy. Consistent with previous in vivo observations in ascites and at distal metastases, spheroids exposed to activated stromal microenvironment were denser, more contractile and with more migratory cells than nonactivated counterparts. The hypoxic conditions resulted in negative radial spheroid growth over 5 d compared to a radial increase in normoxia. Nanovector penetration attenuated in PuraMatrix regardless of surface modification due to a denser environment. This platform may serve to evaluate nanovector transport based on ovarian ascites and metastatic environments, and longer term, it provide a means to evaluate nanotherapeutic efficacy. Full article
(This article belongs to the Special Issue Drug and Gene Delivery Nanoformulations against Cancer Hallmarks)
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14 pages, 4400 KiB  
Article
siRNA-Loaded Hydroxyapatite Nanoparticles for KRAS Gene Silencing in Anti-Pancreatic Cancer Therapy
by Dandan Luo, Xiaochun Xu, M. Zubair Iqbal, Qingwei Zhao, Ruibo Zhao, Jabeen Farheen, Quan Zhang, Peiliang Zhang and Xiangdong Kong
Pharmaceutics 2021, 13(9), 1428; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13091428 - 08 Sep 2021
Cited by 17 | Viewed by 2464
Abstract
Pancreatic carcinoma (PC) is greatly induced by the KRAS gene mutation, but effective targeted delivery for gene therapy has not existed. Small interfering ribonucleic acid (siRNA) serves as an advanced therapeutic modality and holds great promise for cancer treatment. However, the development of [...] Read more.
Pancreatic carcinoma (PC) is greatly induced by the KRAS gene mutation, but effective targeted delivery for gene therapy has not existed. Small interfering ribonucleic acid (siRNA) serves as an advanced therapeutic modality and holds great promise for cancer treatment. However, the development of a non-toxic and high-efficiency carrier system to accurately deliver siRNA into cells for siRNA-targeted gene silencing is still a prodigious challenge. Herein, polyethylenimine (PEI)-modified hydroxyapatite (HAp) nanoparticles (HAp-PEI) were fabricated. The siRNA of the KRAS gene (siKras) was loaded onto the surface of HAp-PEI via electrostatic interaction between siRNA and PEI to design the functionalized HAp-PEI nanoparticle (HAp-PEI/siKras). The HAp-PEI/siKras was internalized into the human PC cells PANC-1 to achieve the maximum transfection efficiency for active tumor targeting. HAp-PEI/siKras effectively knocked down the expression of the KRAS gene and downregulated the expression of the Kras protein in vitro. Furthermore, the treatment with HAp-PEI/siKras resulted in greater anti-PC cells’ (PANC-1, BXPC-3, and CFPAC-1) efficacy in vitro. Additionally, the HAp-PEI exhibited no obvious in vitro cytotoxicity in normal pancreatic HPDE6-C7 cells. These findings provided a promising alternative for the therapeutic route of siRNA-targeted gene engineering for anti-pancreatic cancer therapy. Full article
(This article belongs to the Special Issue Drug and Gene Delivery Nanoformulations against Cancer Hallmarks)
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11 pages, 1809 KiB  
Article
A Self-Assembling Amphiphilic Peptide Dendrimer-Based Drug Delivery System for Cancer Therapy
by Dandan Zhu, Huanle Zhang, Yuanzheng Huang, Baoping Lian, Chi Ma, Lili Han, Yu Chen, Shengmei Wu, Ning Li, Wenjie Zhang and Xiaoxuan Liu
Pharmaceutics 2021, 13(7), 1092; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13071092 - 17 Jul 2021
Cited by 13 | Viewed by 2797
Abstract
Despite being a mainstay of clinical cancer treatment, chemotherapy is limited by its severe side effects and inherent or acquired drug resistance. Nanotechnology-based drug-delivery systems are widely expected to bring new hope for cancer therapy. These systems exploit the ability of nanomaterials to [...] Read more.
Despite being a mainstay of clinical cancer treatment, chemotherapy is limited by its severe side effects and inherent or acquired drug resistance. Nanotechnology-based drug-delivery systems are widely expected to bring new hope for cancer therapy. These systems exploit the ability of nanomaterials to accumulate and deliver anticancer drugs at the tumor site via the enhanced permeability and retention effect. Here, we established a novel drug-delivery nanosystem based on amphiphilic peptide dendrimers (AmPDs) composed of a hydrophobic alkyl chain and a hydrophilic polylysine dendron with different generations (AmPD KK2 and AmPD KK2K4). These AmPDs assembled into nanoassemblies for efficient encapsulation of the anti-cancer drug doxorubicin (DOX). The AmPDs/DOX nanoformulations improved the intracellular uptake and accumulation of DOX in drug-resistant breast cancer cells and increased permeation in 3D multicellular tumor spheroids in comparison with free DOX. Thus, they exerted effective anticancer activity while circumventing drug resistance in 2D and 3D breast cancer models. Interestingly, AmPD KK2 bearing a smaller peptide dendron encapsulated DOX to form more stable nanoparticles than AmPD KK2K4 bearing a larger peptide dendron, resulting in better cellular uptake, penetration, and anti-proliferative activity. This may be because AmPD KK2 maintains a better balance between hydrophobicity and hydrophilicity to achieve optimal self-assembly, thereby facilitating more stable drug encapsulation and efficient drug release. Together, our study provides a promising perspective on the design of the safe and efficient cancer drug-delivery nanosystems based on the self-assembling amphiphilic peptide dendrimer. Full article
(This article belongs to the Special Issue Drug and Gene Delivery Nanoformulations against Cancer Hallmarks)
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18 pages, 2400 KiB  
Article
Combined Method to Remove Endotoxins from Protein Nanocages for Drug Delivery Applications: The Case of Human Ferritin
by Filippo Silva, Leopoldo Sitia, Raffaele Allevi, Arianna Bonizzi, Marta Sevieri, Carlo Morasso, Marta Truffi, Fabio Corsi and Serena Mazzucchelli
Pharmaceutics 2021, 13(2), 229; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13020229 - 06 Feb 2021
Cited by 11 | Viewed by 3328
Abstract
Protein nanocages represent an emerging candidate among nanoscaled delivery systems. Indeed, they display unique features that proved to be very interesting from the nanotechnological point of view such as uniform structure, stability in biological fluids, suitability for surface modification to insert targeting moieties [...] Read more.
Protein nanocages represent an emerging candidate among nanoscaled delivery systems. Indeed, they display unique features that proved to be very interesting from the nanotechnological point of view such as uniform structure, stability in biological fluids, suitability for surface modification to insert targeting moieties and loading with different drugs and dyes. However, one of the main concerns regards the production as recombinant proteins in E. coli, which leads to a product with high endotoxin contamination, resulting in nanocage immunogenicity and pyrogenicity. Indeed, a main challenge in the development of protein-based nanoparticles is finding effective procedures to remove endotoxins without affecting protein stability, since every intravenous injectable formulation that should be assessed in preclinical and clinical phase studies should display endotoxins concentration below the admitted limit of 5 EU/kg. Different strategies could be employed to achieve such a result, either by using affinity chromatography or detergents. However, these strategies are not applicable to protein nanocages as such and require implementations. Here we propose a combined protocol to remove bacterial endotoxins from nanocages of human H-ferritin, which is one of the most studied and most promising protein-based drug delivery systems. This protocol couples the affinity purification with the Endotrap HD resin to a treatment with Triton X-114. Exploiting this protocol, we were able to obtain excellent levels of purity maintaining good protein recovery rates, without affecting nanocage interactions with target cells. Indeed, binding assay and confocal microscopy experiments confirm that purified H-ferritin retains its capability to specifically recognize cancer cells. This procedure allowed to obtain injectable formulations, which is preliminary to move to a clinical trial. Full article
(This article belongs to the Special Issue Drug and Gene Delivery Nanoformulations against Cancer Hallmarks)
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Review

Jump to: Research

27 pages, 7090 KiB  
Review
2D Nanosheets—A New Class of Therapeutic Formulations against Cancer
by Ravichandran Manisekaran, René García-Contreras, Aruna-Devi Rasu Chettiar, Paloma Serrano-Díaz, Christian Andrea Lopez-Ayuso, Ma Concepción Arenas-Arrocena, Genoveva Hernández-Padrón, Luz M. López-Marín and Laura Susana Acosta-Torres
Pharmaceutics 2021, 13(11), 1803; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13111803 - 28 Oct 2021
Cited by 13 | Viewed by 2600
Abstract
Researchers in cancer nanomedicine are exploring a revolutionary multifaceted carrier for treatment and diagnosis, resulting in the proposal of various drug cargos or “magic bullets” in this past decade. Even though different nano-based complexes are registered for clinical trials, very few products enter [...] Read more.
Researchers in cancer nanomedicine are exploring a revolutionary multifaceted carrier for treatment and diagnosis, resulting in the proposal of various drug cargos or “magic bullets” in this past decade. Even though different nano-based complexes are registered for clinical trials, very few products enter the final stages each year because of various issues. This prevents the formulations from entering the market and being accessible to patients. In the search for novel materials, the exploitation of 2D nanosheets, including but not limited to the highly acclaimed graphene, has created extensive interest for biomedical applications. A unique set of properties often characterize 2D materials, including semiconductivity, high surface area, and their chemical nature, which allow simple decoration and functionalization procedures, structures with high stability and targeting properties, vectors for controlled and sustained release of drugs, and materials for thermal-based therapies. This review discusses the challenges and opportunities of recently discovered 2D nanosheets for cancer therapeutics, with special attention paid to the most promising design technologies and their potential for clinical translation in the future. Full article
(This article belongs to the Special Issue Drug and Gene Delivery Nanoformulations against Cancer Hallmarks)
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31 pages, 2923 KiB  
Review
Advances of Nanomedicine in Radiotherapy
by Wei Liu, Bo Chen, Haocheng Zheng, Yun Xing, Guiyuan Chen, Peijie Zhou, Liting Qian and Yuanzeng Min
Pharmaceutics 2021, 13(11), 1757; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13111757 - 21 Oct 2021
Cited by 21 | Viewed by 3251
Abstract
Radiotherapy (RT) remains one of the current main treatment strategies for many types of cancer. However, how to improve RT efficiency while reducing its side effects is still a large challenge to be overcome. Advancements in nanomedicine have provided many effective approaches for [...] Read more.
Radiotherapy (RT) remains one of the current main treatment strategies for many types of cancer. However, how to improve RT efficiency while reducing its side effects is still a large challenge to be overcome. Advancements in nanomedicine have provided many effective approaches for radiosensitization. Metal nanoparticles (NPs) such as platinum-based or hafnium-based NPs are proved to be ideal radiosensitizers because of their unique physicochemical properties and high X-ray absorption efficiency. With nanoparticles, such as liposomes, bovine serum albumin, and polymers, the radiosensitizing drugs can be promoted to reach the tumor sites, thereby enhancing anti-tumor responses. Nowadays, the combination of some NPs and RT have been applied to clinical treatment for many types of cancer, including breast cancer. Here, as well as reviewing recent studies on radiotherapy combined with inorganic, organic, and biomimetic nanomaterials for oncology, we analyzed the underlying mechanisms of NPs radiosensitization, which may contribute to exploring new directions for the clinical translation of nanoparticle-based radiosensitizers. Full article
(This article belongs to the Special Issue Drug and Gene Delivery Nanoformulations against Cancer Hallmarks)
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17 pages, 3173 KiB  
Review
Recent Advances of Nanotechnology-Facilitated Bacteria-Based Drug and Gene Delivery Systems for Cancer Treatment
by Chaojie Zhu, Zhiheng Ji, Junkai Ma, Zhijie Ding, Jie Shen and Qiwen Wang
Pharmaceutics 2021, 13(7), 940; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13070940 - 24 Jun 2021
Cited by 15 | Viewed by 3940
Abstract
Cancer is one of the most devastating and ubiquitous human diseases. Conventional therapies like chemotherapy and radiotherapy are the most widely used cancer treatments. Despite the notable therapeutic improvements that these measures achieve, disappointing therapeutic outcome and cancer reoccurrence commonly following these therapies [...] Read more.
Cancer is one of the most devastating and ubiquitous human diseases. Conventional therapies like chemotherapy and radiotherapy are the most widely used cancer treatments. Despite the notable therapeutic improvements that these measures achieve, disappointing therapeutic outcome and cancer reoccurrence commonly following these therapies demonstrate the need for better alternatives. Among them, bacterial therapy has proven to be effective in its intrinsic cancer targeting ability and various therapeutic mechanisms that can be further bolstered by nanotechnology. In this review, we will discuss recent advances of nanotechnology-facilitated bacteria-based drug and gene delivery systems in cancer treatment. Therapeutic mechanisms of these hybrid nanoformulations are highlighted to provide an up-to-date understanding of this emerging field. Full article
(This article belongs to the Special Issue Drug and Gene Delivery Nanoformulations against Cancer Hallmarks)
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17 pages, 4190 KiB  
Review
Combining Gold Nanoparticles with Other Radiosensitizing Agents for Unlocking the Full Potential of Cancer Radiotherapy
by Abdulaziz Alhussan, Ece Pinar Demirci Bozdoğan and Devika B. Chithrani
Pharmaceutics 2021, 13(4), 442; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13040442 - 25 Mar 2021
Cited by 18 | Viewed by 2398
Abstract
About half of cancer patients (50%) receive radiotherapy (RT) for the treatment of local tumors. However, one of the main obstacles in RT is the close proximity of adjacent organs at risk, resulting in treatment doses being limited by significant tissue toxicity, hence [...] Read more.
About half of cancer patients (50%) receive radiotherapy (RT) for the treatment of local tumors. However, one of the main obstacles in RT is the close proximity of adjacent organs at risk, resulting in treatment doses being limited by significant tissue toxicity, hence preventing the necessary dose escalation that would guarantee local control. Effective local cancer therapy is needed to avoid progression of tumors and to decrease the development of systemic metastases which may further increase the possibility of resection. In an effort to do so, radiosensitizing agents are introduced to further increase damage to the tumor while minimizing normal tissue toxicity. Cisplatin and docetaxel (DTX) are currently being used as radiation dose enhancers in RT. Recent research shows the potential of gold nanoparticles (GNPs) as a radiosensitizing agent. GNPs are biocompatible and have been tested in phase I clinical trials. The focus will be on exploring the effects of adding other radiosensitizing agents such as DTX and cisplatin to the GNP-RT platform. Therefore, a combined use of local radiosensitizing agents, such as GNPs, with currently available radiosensitizing drugs could make a significant impact in future RT. The ultimate goal is to develop treatments that have limited or nonexistent side effects to improve the quality of life of all cancer patients. Full article
(This article belongs to the Special Issue Drug and Gene Delivery Nanoformulations against Cancer Hallmarks)
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