Peptide‐mediated targeted drug delivery

Abstract

Targeted drug delivery to specific group of cells offers an attractive strategy to minimize the undesirable side effects and achieve the therapeutic effect with a lower dose. Both linear and cyclic peptides have been explored as trafficking moiety due to ease of synthesis, structural simplicity, and low probability of undesirable immunogenicity. Peptides derived from sequence of cell surface proteins, such as intercellular adhesion molecule-1 (ICAM-1), LHRH, Bombesin, and LFA-1, have shown potent binding affinity to the target cell surface receptors. Moreover, peptides derived from ICAM-1 receptor can be internalized by the leukemic T-cells along with the conjugated moiety offering the promise to selectively treat cancers and autoimmune diseases. Systematic analyses have revealed that physicochemical properties of the drug-peptide conjugates and their mechanism of receptor-mediated cellular internalization are important controlling factors for developing a successful targeting system. This review is focused on understanding the factors involved in the development of an effective drug-peptide conjugate with an emphasis on the chemistry and biology of the conjugates. Reported results on several promising drug-peptide conjugates have been critically evaluated. The approaches and results presented here will serve as a guide to systematically approach targeted delivery of cytotoxic drug molecules using peptides for treatment of several diseases.

Low-Molecular-Weight Polymer–Drug Conjugates for Synergistic Anticancer Activity of Camptothecin and Doxorubicin Combinations

“…Low conjugation efficiencies were expected as multiple polymer and drug modifications were required to achieve the final products. Ester bonds are the most commonly used in literature due to ease of synthesis, and also represent hydrolytically labile bonds; amide-linked conjugates represent hydrolytically stable bonds, whereas hydrazone linkers are hydrolytically degraded at endosomal pH 5.0 but stable at physiological pH 7.4 [11,34]. In vitro cancer cell cytotoxicity studies in Figure 5A show that the cleavable conjugates, ester-linked DOX (DOXePVA) and hydrazone-linked DOX (DOXhPVA), are active against cancer cells, whereas the noncleavable amide-linked DOX (DOXaPVA) is not.…”

GnRH-Gemcitabine Conjugates for the Treatment of Androgen-Independent Prostate Cancer: Pharmacokinetic Enhancements Combined with Targeted Drug Delivery

“…The synthesis of drug-peptide conjugates for the receptormediated targeted delivery to a specific group of cells usually involves the conjugation of the drug with a targeting peptide via an appropriate linker, which could in turn facilitate the chemical or enzymatic release of the drug once the conjugate enters the cancer cells via a receptor mediated endocytosis mechanism. Amongst several functional groups employed to connect the drug to the linker, 40 ester linkages have been widely utilized since the release of the drug can proceed via an enzymatic (i.e. esterase) hydrolysis of the ester bond.…”

Synthesis and Biological Evaluation of RGD-Conjugated MEK1/2 Kinase Inhibitors for Integrin-Targeted Cancer Therapy

“…Peptide-drug conjugation is one of the most promising strategies to overcome the undesired side effects of anti-cancer drugs by the selective delivery of drug conjugates to tumor cells [10]. These peptides recognize and bind to specific receptors with high-affinity, on the tumor-cell surfaces.…”