Precision Delivery of Drugs and Imaging Agents with Peptides

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 26865

Special Issue Editors

Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 14b, 50411 Tartu, Estonia
Interests: affinity targeting; nanomedicine; in vivo peptide phage display; tumor-homing peptides; tumor-penetrating peptides; iRGD; neuropilin-1; tumor-assciated macrophages
Special Issues, Collections and Topics in MDPI journals
Institute of Technology, University of Tartu, Nooruse 1, 50411 Tartu, Estonia
Interests: CPP; cell-penetrating peptides; drug delivery systems; transfection reagents; gene therapy; molecular diagnostics; isothermal nucleic acid amplification

Special Issue Information

Dear Colleagues,

Systemic targeting of vascular ZIP codes with homing peptides is an increasingly recognized strategy that can be used to improve the biodistribution profile and to increase potency of drugs. Another class of transport peptides, cell-penetrating peptides (CPP), are widely used to trigger robust intracellular uptake of molecular and nanoscale payloads. Peptides have several advantages over other classes of affinity ligands, including a small size (and thus improved tissue penetration, straightforward synthesis, and low cost), low immunogenicity, and biocompatibility.

This Special Issue will provide insights into peptide-based precision targeting from top experts from around the world. Original research and reviews in the issue summarize preclinical and clinical applications of peptide-based targeting for delivery of molecular and nanoscale diagnostic and therapeutic payloads in the context of cancer, cardiovascular and pulmonary diseases, and regenerative medicine.

Prof. Dr. Tambet Teesalu
Dr. Kaido Kurrikoff
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • peptide
  • tumor-penetrating peptide
  • cell-penetrating peptide
  • cancer
  • regenerative medicine
  • cardiovascular disease
  • molecular imaging
  • precision therapy

Published Papers (10 papers)

Order results
Result details
Select all
Export citation of selected articles as:

Editorial

Jump to: Research

3 pages, 177 KiB  
Editorial
Editorial on Special Issue “Precision Delivery of Drugs and Imaging Agents with Peptides”
by Kaido Kurrikoff and Tambet Teesalu
Pharmaceutics 2022, 14(3), 486; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14030486 - 23 Feb 2022
Viewed by 1223
Abstract
Homing peptides and cell-penetrating peptides allow for systemic targeting of diseased tissues and/or efficient intracellular delivery of payloads [...] Full article
(This article belongs to the Special Issue Precision Delivery of Drugs and Imaging Agents with Peptides)

Research

Jump to: Editorial

17 pages, 1650 KiB  
Article
Predicting Transiently Expressed Protein Yields: Comparison of Transfection Methods in CHO and HEK293
by Ly Porosk, Jekaterina Nebogatova, Heleri Heike Härk, Birgit Vunk, Piret Arukuusk, Urve Toots, Mart Ustav, Ülo Langel and Kaido Kurrikoff
Pharmaceutics 2022, 14(9), 1949; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14091949 - 14 Sep 2022
Cited by 5 | Viewed by 3937
Abstract
Therapeutic proteins are currently at the apex of innovation in pharmaceutical medicine. However, their industrial production is technically challenging and improved methods for transient transfection of mammalian cell cultures are necessary. We aimed to find a fast, microliter-scale transfection assay that allows the [...] Read more.
Therapeutic proteins are currently at the apex of innovation in pharmaceutical medicine. However, their industrial production is technically challenging and improved methods for transient transfection of mammalian cell cultures are necessary. We aimed to find a fast, microliter-scale transfection assay that allows the prediction of protein expression in the transient production settings. We used an array of lipid, polymeric and cell-penetrating peptide transfection reagents, and compared their performance in various high throughput transfection assays to their performance in protein (antibody) expression in professional protein-producer cell lines. First, we show that some of the most frequently used microliter-scale transfection efficacy assays fail to predict performance in the protein production in milliliter and liter scale settings. We found that CHO suspension culture post-transfection EGFP(+) population and SEAP quantitation correlate with large-scale protein production, whereas the adhesion culture assays and transfection of pLuc are non-predictive. Second, we demonstrated that cell-penetrating peptide-based transfection achieves significantly higher protein yields compared to PEI and lipoplex methods in both CHO and HEK293 producer cell lines. In this work we demonstrate a CPP-based transient protein expression approach that significantly outperformed the current industry standard workhorse method of PEI. Full article
(This article belongs to the Special Issue Precision Delivery of Drugs and Imaging Agents with Peptides)
Show Figures

Figure 1

14 pages, 5423 KiB  
Article
PL1 Peptide Engages Acidic Surfaces on Tumor-Associated Fibronectin and Tenascin Isoforms to Trigger Cellular Uptake
by Prakash Lingasamy, Kristina Põšnograjeva, Sergei Kopanchuk, Allan Tobi, Ago Rinken, Ignacio J. General, Eliana K. Asciutto and Tambet Teesalu
Pharmaceutics 2021, 13(12), 1998; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13121998 - 24 Nov 2021
Cited by 5 | Viewed by 2008
Abstract
Tumor extracellular matrix (ECM) is a high-capacity target for the precision delivery of affinity ligand-guided drugs and imaging agents. Recently, we developed a PL1 peptide (sequence: PPRRGLIKLKTS) for systemic targeting of malignant ECM. Here, we map the dynamics of PL1 binding to its [...] Read more.
Tumor extracellular matrix (ECM) is a high-capacity target for the precision delivery of affinity ligand-guided drugs and imaging agents. Recently, we developed a PL1 peptide (sequence: PPRRGLIKLKTS) for systemic targeting of malignant ECM. Here, we map the dynamics of PL1 binding to its receptors Fibronectin Extra Domain B (FN-EDB) and Tenascin C C-isoform (TNC-C) by computational modeling and cell-free binding studies on mutated receptor proteins, and study cellular binding and internalization of PL1 nanoparticles in cultured cells. Molecular dynamics simulation and docking analysis suggested that the engagement of PL1 peptide with both receptors is primarily driven by electrostatic interactions. Substituting acidic amino acid residues with neutral amino acids at predicted PL1 binding sites in FN-EDB (D52N-D49N-D12N) and TNC-C (D39N-D45N) resulted in the loss of binding of PL1 nanoparticles. Remarkably, PL1-functionalized nanoparticles (NPs) were not only deposited on the target ECM but bound the cells and initiated a robust cellular uptake via a pathway resembling macropinocytosis. Our studies establish the mode of engagement of the PL1 peptide with its receptors and suggest applications for intracellular delivery of nanoscale payloads. The outcomes of this work can be used for the development of PL1-derived peptides with improved stability, affinity, and specificity for precision targeting of the tumor ECM and malignant cells. Full article
(This article belongs to the Special Issue Precision Delivery of Drugs and Imaging Agents with Peptides)
Show Figures

Figure 1

13 pages, 2057 KiB  
Article
Selective Targeting and Tissue Penetration to the Retina by a Systemically Administered Vascular Homing Peptide in Oxygen Induced Retinopathy (OIR)
by Maria Vähätupa, Niklas Salonen, Hannele Uusitalo-Järvinen and Tero A. H. Järvinen
Pharmaceutics 2021, 13(11), 1932; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13111932 - 15 Nov 2021
Cited by 4 | Viewed by 2207
Abstract
Pathological angiogenesis is the hallmark of ischemic retinal diseases among them retinopathy of prematurity (ROP) and proliferative diabetic retinopathy (PDR). Oxygen-induced retinopathy (OIR) is a pure hypoxia-driven angiogenesis model and a widely used model for ischemic retinopathies. We explored whether the vascular homing [...] Read more.
Pathological angiogenesis is the hallmark of ischemic retinal diseases among them retinopathy of prematurity (ROP) and proliferative diabetic retinopathy (PDR). Oxygen-induced retinopathy (OIR) is a pure hypoxia-driven angiogenesis model and a widely used model for ischemic retinopathies. We explored whether the vascular homing peptide CAR (CARSKNKDC) which recognizes angiogenic blood vessels can be used to target the retina in OIR. We were able to demonstrate that the systemically administered CAR vascular homing peptide homed selectively to the preretinal neovessels in OIR. As a cell and tissue-penetrating peptide, CAR also penetrated into the retina. Hyperoxia used to induce OIR in the retina also causes bronchopulmonary dysplasia in the lungs. We showed that the CAR peptide is not targeted to the lungs in normal mice but is targeted to the lungs after hyperoxia-/hypoxia-treatment of the animals. The site-specific delivery of the CAR peptide to the pathologic retinal vasculature and the penetration of the retinal tissue may offer new opportunities for treating retinopathies more selectively and with less side effects. Full article
(This article belongs to the Special Issue Precision Delivery of Drugs and Imaging Agents with Peptides)
Show Figures

Graphical abstract

16 pages, 6316 KiB  
Article
Enhanced Detection of Desmoplasia by Targeted Delivery of Iron Oxide Nanoparticles to the Tumour-Specific Extracellular Matrix
by Meenu Chopra, Jiansha Wu, Yen Ling Yeow, Louise Winteringham, Tristan D. Clemons, Martin Saunders, Venkata Ramana Kotamraju, Ruth Ganss, Kirk W. Feindel and Juliana Hamzah
Pharmaceutics 2021, 13(10), 1663; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13101663 - 12 Oct 2021
Cited by 5 | Viewed by 2242
Abstract
Diagnostic imaging of aggressive cancer with a high stroma content may benefit from the use of imaging contrast agents targeted with peptides that have high binding affinity to the extracellular matrix (ECM). In this study, we report the use of superparamagnetic iron-oxide nanoparticles [...] Read more.
Diagnostic imaging of aggressive cancer with a high stroma content may benefit from the use of imaging contrast agents targeted with peptides that have high binding affinity to the extracellular matrix (ECM). In this study, we report the use of superparamagnetic iron-oxide nanoparticles (IO-NP) conjugated to a nonapeptide, CSGRRSSKC (CSG), which specifically binds to the laminin-nidogen-1 complex in tumours. We show that CSG-IO-NP accumulate in tumours, predominantly in the tumour ECM, following intravenous injection into a murine model of pancreatic neuroendocrine tumour (PNET). In contrast, a control untargeted IO-NP consistently show poor tumour uptake, and IO-NP conjugated to a pentapeptide. CREKA that bind fibrin clots in blood vessels show restricted uptake in the angiogenic vessels of the tumours. CSG-IO-NP show three-fold higher intratumoral accumulation compared to CREKA-IO-NP. Magnetic resonance imaging (MRI) T2-weighted scans and T2 relaxation times indicate significant uptake of CSG-IO-NP irrespective of tumour size, whereas the uptake of CREKA-IO-NP is only consistent in small tumours of less than 3 mm in diameter. Larger tumours with significantly reduced tumour blood vessels show a lack of CREKA-IO-NP uptake. Our data suggest CSG-IO-NP are particularly useful for detecting stroma in early and advanced solid tumours. Full article
(This article belongs to the Special Issue Precision Delivery of Drugs and Imaging Agents with Peptides)
Show Figures

Figure 1

21 pages, 3745 KiB  
Article
Systemically Administered Homing Peptide Targets Dystrophic Lesions and Delivers Transforming Growth Factor-β (TGFβ) Inhibitor to Attenuate Murine Muscular Dystrophy Pathology
by Aqsa Iqbal, Ulrike May, Stuart N. Prince, Tero A.H. Järvinen and Ahlke Heydemann
Pharmaceutics 2021, 13(9), 1506; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13091506 - 18 Sep 2021
Cited by 6 | Viewed by 2787
Abstract
Muscular dystrophy is a progressively worsening and lethal disease, where accumulation of functionality-impairing fibrosis plays a key pathogenic role. Transforming growth factor-β1 (TGFβ1) is a central signaling molecule in the development of fibrosis in muscular dystrophic humans and mice. Inhibition of TGFβ1 has [...] Read more.
Muscular dystrophy is a progressively worsening and lethal disease, where accumulation of functionality-impairing fibrosis plays a key pathogenic role. Transforming growth factor-β1 (TGFβ1) is a central signaling molecule in the development of fibrosis in muscular dystrophic humans and mice. Inhibition of TGFβ1 has proven beneficial in mouse models of muscular dystrophy, but the global strategies of TGFβ1 inhibition produce significant detrimental side effects. Here, we investigated whether murine muscular dystrophy lesion-specific inhibition of TGFβ1 signaling by the targeted delivery of therapeutic decorin (a natural TGFβ inhibitor) by a vascular homing peptide CAR (CARSKNKDC) would reduce skeletal muscle fibrosis and pathology and increase functional characteristics of skeletal muscle. We demonstrate that CAR peptide homes to dystrophic lesions with specificity in two muscular dystrophy models. Recombinant fusion protein consisting of CAR peptide and decorin homes selectively to sites of skeletal muscle damage in mdxDBA2/J and gamma-sarcoglycan deficient DBA2/J mice. This targeted delivery reduced TGFβ1 signaling as demonstrated by reduced nuclear pSMAD staining. Three weeks of targeted decorin treatment decreased both membrane permeability and fibrosis and improved skeletal muscle function in comparison to control treatments in the mdxD2 mice. These results show that selective delivery of decorin to the sites of skeletal muscle damage attenuates the progression of murine muscular dystrophy. Full article
(This article belongs to the Special Issue Precision Delivery of Drugs and Imaging Agents with Peptides)
Show Figures

Graphical abstract

16 pages, 5337 KiB  
Article
Selective Moonlighting Cell-Penetrating Peptides
by Rafael Morán-Torres, David A. Castillo González, Maria Luisa Durán-Pastén, Beatriz Aguilar-Maldonado, Susana Castro-Obregón and Gabriel Del Rio
Pharmaceutics 2021, 13(8), 1119; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13081119 - 22 Jul 2021
Cited by 5 | Viewed by 2645
Abstract
Cell penetrating peptides (CPPs) are molecules capable of passing through biological membranes. This capacity has been used to deliver impermeable molecules into cells, such as drugs and DNA probes, among others. However, the internalization of these peptides lacks specificity: CPPs internalize indistinctly on [...] Read more.
Cell penetrating peptides (CPPs) are molecules capable of passing through biological membranes. This capacity has been used to deliver impermeable molecules into cells, such as drugs and DNA probes, among others. However, the internalization of these peptides lacks specificity: CPPs internalize indistinctly on different cell types. Two major approaches have been described to address this problem: (i) targeting, in which a receptor-recognizing sequence is added to a CPP, and (ii) activation, where a non-active form of the CPP is activated once it interacts with cell target components. These strategies result in multifunctional peptides (i.e., penetrate and target recognition) that increase the CPP’s length, the cost of synthesis and the likelihood to be degraded or become antigenic. In this work we describe the use of machine-learning methods to design short selective CPP; the reduction in size is accomplished by embedding two or more activities within a single CPP domain, hence we referred to these as moonlighting CPPs. We provide experimental evidence that these designed moonlighting peptides penetrate selectively in targeted cells and discuss areas of opportunity to improve in the design of these peptides. Full article
(This article belongs to the Special Issue Precision Delivery of Drugs and Imaging Agents with Peptides)
Show Figures

Figure 1

14 pages, 5814 KiB  
Article
Evaluation of a Keratin 1 Targeting Peptide-Doxorubicin Conjugate in a Mouse Model of Triple-Negative Breast Cancer
by Azam Saghaeidehkordi, Shiuan Chen, Sun Yang and Kamaljit Kaur
Pharmaceutics 2021, 13(5), 661; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13050661 - 05 May 2021
Cited by 12 | Viewed by 3248
Abstract
Chemotherapy is the main treatment for triple-negative breast cancer (TNBC), a subtype of breast cancer that is aggressive with a poor prognosis. While chemotherapeutics are potent, these agents lack specificity and are equally toxic to cancer and nonmalignant cells and tissues. Targeted therapies [...] Read more.
Chemotherapy is the main treatment for triple-negative breast cancer (TNBC), a subtype of breast cancer that is aggressive with a poor prognosis. While chemotherapeutics are potent, these agents lack specificity and are equally toxic to cancer and nonmalignant cells and tissues. Targeted therapies for TNBC treatment could lead to more safe and efficacious drugs. We previously engineered a breast cancer cell targeting peptide 18-4 that specifically binds cell surface receptor keratin 1 (K1) on breast cancer cells. A conjugate of peptide 18-4 and doxorubicin (Dox) containing an acid-sensitive hydrazone linker showed specific toxicity toward TNBC cells. Here, we report the in vivo evaluation of the K1 targeting peptide-Dox conjugate (PDC) in a TNBC cell-derived xenograft mouse model. Mice treated with the conjugate show significantly improved antitumor efficacy and reduced off-target toxicity compared to mice treated with Dox or saline. After six weekly treatments, on day 35, the mice treated with PDC (2.5 mg Dox equivalent/kg) showed significant reduction (1.5 times) in tumor volume compared to mice treated with Dox (2.5 mg/kg). The mice treated with the conjugate showed significantly higher (1.4 times) levels of Dox in tumors and lower (1.3–2.2 times) levels of Dox in other organs compared to mice treated with Dox. Blood collected at 15 min showed 3.6 times higher concentration of the drug (PDC and Dox) in mice injected with PDC compared to the drug (Dox) in mice injected with Dox. The study shows that the K1 targeting PDC is a promising novel modality for treatment of TNBC, with a favorable safety profile, and warrants further investigation of K1 targeting conjugates as TNBC therapeutics. Full article
(This article belongs to the Special Issue Precision Delivery of Drugs and Imaging Agents with Peptides)
Show Figures

Graphical abstract

16 pages, 1943 KiB  
Article
Transportan Peptide Stimulates the Nanomaterial Internalization into Mammalian Cells in the Bystander Manner through Macropinocytosis
by Yue-Xuan Li, Yushuang Wei, Rui Zhong, Ling Li and Hong-Bo Pang
Pharmaceutics 2021, 13(4), 552; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13040552 - 14 Apr 2021
Cited by 9 | Viewed by 1908
Abstract
Covalent coupling with cell-penetrating peptides (CPPs) has been a common strategy to facilitate the cell entry of nanomaterial and other macromolecules. Though efficient, this strategy requires chemical modifications on nanomaterials, which is not always desired for their applications. Recent studies on a few [...] Read more.
Covalent coupling with cell-penetrating peptides (CPPs) has been a common strategy to facilitate the cell entry of nanomaterial and other macromolecules. Though efficient, this strategy requires chemical modifications on nanomaterials, which is not always desired for their applications. Recent studies on a few cationic CPPs have revealed that they can stimulate the cellular uptake of nanoparticles (NPs) simply via co-administration (bystander manner), which bypasses the requirement of chemical modification. In this study, we investigated the other classes of CPPs and discovered that transportan (TP) peptide, an amphiphilic CPP, also exhibited such bystander activities. When simply co-administered, TP peptide enabled the cells to engulf a variety of NPs, as well as common solute tracers, while these payloads had little or no ability to enter the cells by themselves. This result was validated in vitro and ex vivo, and TP peptide showed no physical interaction with co-administered NPs (bystander cargo). We further explored the cell entry mechanism for TP peptide and its bystander cargo, and showed that it was mediated by a receptor-dependent macropinocytosis process. Together, our findings improve the understanding of TP-assisted cell entry, and open up a new avenue to apply this peptide for nanomaterial delivery. Full article
(This article belongs to the Special Issue Precision Delivery of Drugs and Imaging Agents with Peptides)
Show Figures

Graphical abstract

13 pages, 2355 KiB  
Article
Tumor Activated Cell Penetrating Peptides to Selectively Deliver Immune Modulatory Drugs
by Dina V. Hingorani, Maria F. Camargo, Maryam A. Quraishi, Stephen R. Adams and Sunil J. Advani
Pharmaceutics 2021, 13(3), 365; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13030365 - 10 Mar 2021
Cited by 8 | Viewed by 3431
Abstract
Recent advances in immunotherapy have revolutionized cancer therapy. Immunotherapies can engage the adaptive and innate arms of the immune system. Therapeutics targeting immune checkpoint inhibitors (i.e., CTLA-4; PD-1, and PD-L1) have shown efficacy for subsets of cancer patients by unleashing an adaptive antitumor [...] Read more.
Recent advances in immunotherapy have revolutionized cancer therapy. Immunotherapies can engage the adaptive and innate arms of the immune system. Therapeutics targeting immune checkpoint inhibitors (i.e., CTLA-4; PD-1, and PD-L1) have shown efficacy for subsets of cancer patients by unleashing an adaptive antitumor immune response. Alternatively, small molecule immune modulators of the innate immune system such as toll-like receptor (TLR) agonists are being developed for cancer therapy. TLRs function as pattern recognition receptors to microbial products and are also involved in carcinogenesis. Reisquimod is a TLR 7/8 agonist that has antitumor efficacy. However, systemic delivery free resiquimod has proven to be challenging due to toxicity of nonspecific TLR 7/8 activation. Therefore, we developed a targeted peptide-drug conjugate strategy for systemic delivery of resiquimod. We designed an activatable cell penetrating peptide to deliver resiquimod specifically to the tumor tissue while avoiding normal tissues. The activatable cell penetrating peptide (ACPP) scaffold undergoes enzymatic cleavage by matrix metalloproteinases 2/9 in the extracellular matrix followed by intracellular lysosomal cathepsin B mediated release of the free resiquimod. Importantly, when conjugated to ACPP; the tumor tissue concentration of resiquimod was more than 1000-fold greater than that of surrounding non-cancerous tissue. Moreover, systemic ACPP-resiquimod delivery produced comparable therapeutic efficacy to localized free resiquimod in syngeneic murine tumors. These results highlight a precision peptide-drug conjugate delivery. Full article
(This article belongs to the Special Issue Precision Delivery of Drugs and Imaging Agents with Peptides)
Show Figures

Figure 1

Back to TopTop