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Biomedicines
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Development, Manufacture and Clinical Application of Drug Conjugates in Cancer...
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Development, Manufacture and Clinical Application of Drug Conjugates in Cancer Therapy

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Immunology and Immunotherapy".

Deadline for manuscript submissions: closed (30 April 2016) | Viewed by 47248

Special Issue Editor

Prof. Dr. Michael A. Firer

E-Mail Website
Guest Editor
Department of Chemical Engineering and Adelson School of Medicine, Ariel University, Ariel 4070000, Israel
Interests: targeted drug delivery; peptide-drug-conjugates; Cellular immunotherapy; animal models of cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Recent years have seen a surge in the development and clinical application of small molecules targeting mutated or overexpressed proteins in cancer cells. Despite initial clinical successes, inevitably these treatments fail as cancer cells, through various mechanisms, develop resistance to these compounds. In this situation, the opportunity to specifically deliver potent cytotoxic drugs to cancer drugs by their conjugation to cancer cell targeting biologicals because more cogent.

Over the last two decades, a great deal of effort has been invested in the development and testing of targeted drug delivery systems (TDDS). They have demonstrated several important advantages over free drug chemotherapy. Thus far, however, only antibody-drug conjugates have succeeded in reaching the clinical stage.

This Special Issue will present up-to-date and critically discussions of TDDS. The issue will cover the use of antibodies, peptides, proteins, and other structures as drug carriers; issues of manufacture and regulation of carrier-drug-conjugates; and clinical and diagnostic applications.

Prof. Dr. Michael A. Firer
Guest Editor

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. Biomedicines 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 2600 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

  • biology of drug delivery via carrier-drug conjugates
  • overcoming cancer cell drug resistance with carrier-drug conjugates
  • carrier alternatives—antibodies, peptides, proteins, small ligands, nanostructures
  • technologies for discovering novel targeting agents
  • carrier-drug conjugation chemistries
  • manufacturing and regulatory issues of carrier-drug conjugates
  • clinical experience with carrier-drug conjugates for cancer therapy
  • expanding the clinical opportunities for carrier-drug conjugates

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Published Papers (5 papers)

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Research

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2306 KiB  
Article
Design, Synthesis and Biochemical Evaluation of Novel Selective Estrogen Receptor Ligand Conjugates Incorporating an Endoxifen-Combretastatin Hybrid Scaffold
by Niall O. Keely, Miriam Carr, Bassem Yassin, Gloria Ana, David G. Lloyd, Daniela Zisterer and Mary J. Meegan
Biomedicines 2016, 4(3), 15; https://doi.org/10.3390/biomedicines4030015 - 20 Jul 2016
Cited by 15 | Viewed by 6051
Abstract
Nuclear-receptors are often overexpressed in tumours and can thereby be used as targets when designing novel selective chemotherapeutic agents. To date, many conjugates incorporating an estrogen receptor (ER) ligand have been synthesised in order to direct chemical agents to tissue sites containing ERs. [...] Read more.
Nuclear-receptors are often overexpressed in tumours and can thereby be used as targets when designing novel selective chemotherapeutic agents. To date, many conjugates incorporating an estrogen receptor (ER) ligand have been synthesised in order to direct chemical agents to tissue sites containing ERs. A series of ER ligand conjugates were synthesised incorporating an antagonistic ER ligand scaffold based on endoxifen, covalently-bound via an amide linkage to a variety of combretastatin-based analogues, which may act as antimitotic agents. These novel endoxifen-combretastatin hybrid scaffold analogues were biochemically evaluated in order to determine their antiproliferative and cytotoxicity effects in both the ER-positive MCF-7 and the ER-negative MDA-MB-231 human breast cancer cell lines. ER competitive binding assays were carried out to assess the binding affinity of the lead conjugate 28 towards both the ERα and ERβ isoforms. In results from the NCI 60-cell line screen, the lead conjugate 28 displayed potent and highly selective antiproliferative activity towards the MCF-7 human cancer cell line (IC50 = 5 nM). In the ER-binding assays, the lead conjugate 28 demonstrated potent ER competitive binding in ERα (IC50 value: 0.9 nM) and ERβ (IC50 value: 4.7 nM). Preliminary biochemical results also demonstrate that the lead conjugate 28 may exhibit pure antagonism. This series makes an important addition to the class of ER antagonists and may have potential applications in anticancer therapy. Full article
(This article belongs to the Special Issue Development, Manufacture and Clinical Application of Drug Conjugates in Cancer Therapy)
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1512 KiB  
Article
Synthesis and Preliminary Biological Evaluations of Fluorescent or 149Promethium Labeled Trastuzumab-Polyethylenimine
by Jonathan Fitzsimmons, Tapan Nayak, Cathy Cutler and Robert Atcher
Biomedicines 2016, 4(1), 1; https://doi.org/10.3390/biomedicines4010001 - 30 Dec 2015
Cited by 2 | Viewed by 6673
Abstract
Background: Radioimmunotherapy utilize a targeting antibody coupled to a therapeutic isotope to target and treat a tumor or disease. In this study we examine the synthesis and cell binding of a polymer scaffold containing a radiotherapeutic isotope and a targeting antibody. Methods: The [...] Read more.
Background: Radioimmunotherapy utilize a targeting antibody coupled to a therapeutic isotope to target and treat a tumor or disease. In this study we examine the synthesis and cell binding of a polymer scaffold containing a radiotherapeutic isotope and a targeting antibody. Methods: The multistep synthesis of a fluorescent or 149Promethium-labeled Trastuzumab-polyethyleneimine (PEI), Trastuzumab, or PEI is described. In vitro uptake, internalization and/or the binding affinity to the Her2/neu expressing human breast adenocarcinoma SKBr3 cells was investigated with the labeled compounds. Results: Fluorescent-labeled Trastuzumab-PEI was internalized more into cells at 2 and 18 h than fluorescent-labeled Trastuzumab or PEI. The fluorescent-labeled Trastuzumab was concentrated on the cell surface at 2 and 18 h and the labeled PEI had minimal uptake. DOTA-PEI was prepared and contained an average of 16 chelates per PEI; the compound was radio-labeled with 149Promethium and conjugated to Trastuzumab. The purified 149Pm-DOTA-PEI-Trastuzumab had a radiochemical purity of 96.7% and a specific activity of 0.118 TBq/g. The compound demonstrated a dissociation constant for the Her2/neu receptor of 20.30 ± 6.91 nM. Conclusion: The results indicate the DOTA-PEI-Trastuzumab compound has potential as a targeted therapeutic carrier, and future in vivo studies should be performed. Full article
(This article belongs to the Special Issue Development, Manufacture and Clinical Application of Drug Conjugates in Cancer Therapy)
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Review

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1024 KiB  
Review
Antibody–Drug Conjugates for Cancer Therapy
by Adam C. Parslow, Sagun Parakh, Fook-Thean Lee, Hui K. Gan and Andrew M. Scott
Biomedicines 2016, 4(3), 14; https://doi.org/10.3390/biomedicines4030014 - 11 Jul 2016
Cited by 78 | Viewed by 13731
Abstract
Antibody–drug conjugates (ADCs) take advantage of the specificity of a monoclonal antibody to deliver a linked cytotoxic agent directly into a tumour cell. The development of these compounds provides exciting opportunities for improvements in patient care. Here, we review the key issues impacting [...] Read more.
Antibody–drug conjugates (ADCs) take advantage of the specificity of a monoclonal antibody to deliver a linked cytotoxic agent directly into a tumour cell. The development of these compounds provides exciting opportunities for improvements in patient care. Here, we review the key issues impacting on the clinical success of ADCs in cancer therapy. Like many other developing therapeutic classes, there remain challenges in the design and optimisation of these compounds. As the clinical applications for ADCs continue to expand, key strategies to improve patient outcomes include better patient selection for treatment and the identification of mechanisms of therapy resistance. Full article
(This article belongs to the Special Issue Development, Manufacture and Clinical Application of Drug Conjugates in Cancer Therapy)
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617 KiB  
Review
Plant Toxin-Based Immunotoxins for Cancer Therapy: A Short Overview
by Letizia Polito, Alice Djemil and Massimo Bortolotti
Biomedicines 2016, 4(2), 12; https://doi.org/10.3390/biomedicines4020012 - 1 Jun 2016
Cited by 63 | Viewed by 9002
Abstract
Immunotoxins are chimeric proteins obtained by linking a toxin to either an intact antibody or an antibody fragment. Conjugation can be obtained by chemical or genetic engineering, where the latter yields recombinant conjugates. An essential requirement is that the target molecule recognized by [...] Read more.
Immunotoxins are chimeric proteins obtained by linking a toxin to either an intact antibody or an antibody fragment. Conjugation can be obtained by chemical or genetic engineering, where the latter yields recombinant conjugates. An essential requirement is that the target molecule recognized by the antibody is confined to the cell population to be deleted, or at least that it is not present on stem cells or other cell types essential for the organism’s survival. Hundreds of different studies have demonstrated the potential for applying immunotoxins to many models in pre-clinical studies and in clinical trials. Immunotoxins can be theoretically used to eliminate any unwanted cell responsible for a pathological condition. The best results have been obtained in cancer therapy, especially in hematological malignancies. Among plant toxins, the most frequently employed to generate immunotoxins are ribosome-inactivating proteins, the most common being ricin. This review summarizes the various approaches and results obtained in the last four decades by researchers in the field of plant toxin-based immunotoxins for cancer therapy. Full article
(This article belongs to the Special Issue Development, Manufacture and Clinical Application of Drug Conjugates in Cancer Therapy)
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564 KiB  
Review
Recent Innovations in Peptide Based Targeted Drug Delivery to Cancer Cells
by Yosi Gilad, Michael Firer and Gary Gellerman
Biomedicines 2016, 4(2), 11; https://doi.org/10.3390/biomedicines4020011 - 26 May 2016
Cited by 80 | Viewed by 10976
Abstract
Targeted delivery of chemotherapeutics and diagnostic agents conjugated to carrier ligands has made significant progress in recent years, both in regards to the structural design of the conjugates and their biological effectiveness. The goal of targeting specific cell surface receptors through structural compatibility [...] Read more.
Targeted delivery of chemotherapeutics and diagnostic agents conjugated to carrier ligands has made significant progress in recent years, both in regards to the structural design of the conjugates and their biological effectiveness. The goal of targeting specific cell surface receptors through structural compatibility has encouraged the use of peptides as highly specific carriers as short peptides are usually non-antigenic, are structurally simple and synthetically diverse. Recent years have seen many developments in the field of peptide based drug conjugates (PDCs), particularly for cancer therapy, as their use aims to bypass off-target side-effects, reducing the morbidity common to conventional chemotherapy. However, no PDCs have as yet obtained regulatory approval. In this review, we describe the evolution of the peptide-based strategy for targeted delivery of chemotherapeutics and discuss recent innovations in the arena that should lead in the near future to their clinical application. Full article
(This article belongs to the Special Issue Development, Manufacture and Clinical Application of Drug Conjugates in Cancer Therapy)
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