Seek & Destroy, use of targeting peptides for cancer detection and drug delivery

Abstract

Accounting for 16 million new cases and 9 million deaths annually, cancer leaves a great number of patients helpless. It is a complex disease and still a major challenge for the scientific and medical communities. The efficacy of conventional chemotherapies is often poor and patients suffer from off-target effects. Each neoplasm exhibits molecular signatures - sometimes in a patient specific manner - that may completely differ from the organ of origin, may be expressed in markedly higher amounts and/or in different location compared to the normal tissue. Although adding layers of complexity in the understanding of cancer biology, this cancer-specific signature provides an opportunity to develop targeting agents for early detection, diagnosis, and therapeutics. Chimeric antibodies, recombinant proteins or synthetic polypeptides have emerged as excellent candidates for specific homing to peripheral and central nervous system cancers. Specifically, peptide ligands benefit from their small size, easy and affordable production, high specificity, and remarkable flexibility regarding their sequence and conjugation possibilities. Coupled to imaging agents, chemotherapies and/or nanocarriers they have shown to increase the on-site delivery, thus allowing better tumor mass contouring in imaging and increased efficacy of the chemotherapies associated with reduced adverse effects. Therefore, some of the peptides alone or in combination have been tested in clinical trials to treat patients. Peptides have been well-tolerated and shown absence of toxicity. This review aims to offer a view on tumor targeting peptides that are either derived from natural peptide ligands or identified using phage display screening. We also include examples of peptides targeting the high-grade malignant tumors of the central nervous system as an example of the complex therapeutic management due to the tumor's location. Peptide vaccines are outside of the scope of this review.

Site-specific amino acid substitution in dodecameric peptides determines the stability and unfolding ofc-MYCquadruplex promoting apoptosis in cancer cells

“…They exhibit minimal drug-drug interaction, less immunogenicity, faster blood clearance, and better intra-tumoral diffusion due to lower molecular weight and excellent tolerability in the patients. Therapeutic peptides are also amenable to rational design for high-affinity intracellular interaction with target quadruplexes ( 48 ). Opposed to the small molecules, peptide candidates provide exquisite specificity to their in vivo targets due to structural and functional diversity that enable them to fold into a complementary shape relative to the dynamic topology of the target quadruplex.…”

Exploring Novel Molecular Targets for the Treatment of High-Grade Astrocytomas Using Peptide Therapeutics: An Overview

“…This short half-life prevents the development of drug resistance and increases their safety, though it may also reduce their efficacy. This constraint can be prevented by chemical modifications of the peptide sequence, for instance by integration of D-amino acids, cyclization, use of unnatural amino acids that are uncleavable by endogenous proteases, and blocking the access to the N-and C-terminal fragments [28]. Another drawback of peptides concerns their poor oral bioavailability.…”

“…TTPs, also known as homing peptides, target specific markers that are expressed only by tumor cells, vasculature, and microenvironment. They can be used to deliver chemotherapeutics or cytotoxic peptides specifically to cancerous cells, without affecting normal tissues [26,28].…”

Novel unit B cryptophycin analogues as payloads for targeted therapy

“…In recent years the targeted delivery of cytotoxic agents has emerged as a highly promising method to tackle selectivity issues [ 36 – 40 ]. Cryptophycin-52 and many analogues lack an addressable group to conjugate the toxin to a homing device.…”