Biophysical delivery of peptides: Applicability for cancer therapy

Abstract

There is a current trend towards evaluation of molecular agents for treatment of a variety of ailments, including cancer. One class of such biomolecules is proteins, and their shortened versions, peptides. Use of peptidic entities has been hindered by poor bioavailability in vivo and the high cost involved in mass-producing these macromolecular drugs. The need for localized delivery is being met with the development of various biophysical means, which include devices and aids, mainly transdermal and invasive implants. In addition, various cell-based delivery modalities, which include the use of spore-forming bacteria and stem cells, are being explored. This review discusses these methods in turn, and examines ways by which these can be enhanced for peptide delivery to tumors.

Introduction

The latter half of the 21st century brought about the identification of a number of bioactive proteins which were limited in their clinical application because of their low therapeutic value (reviewed in [44]). The completion of the Human Genome Project (HUGO) has revealed that our species has about 30,000 genes, with more than half of them encoding unknown proteins. This pool of unknown proteins may be a valuable reservoir of drug candidates, or serve as targets for protein or peptide-based drug R&D. Furthermore, it is anticipated that many more proteins post-translationally modified will exhibit novel functions, some of which may be harnessed for the development of therapeutics.

Theoretically at least, the specific mode of action of peptides and proteins requires that low doses are needed. However, these macromolecules are inherently susceptible to enzymatic degradation and have poor bioavailability. In certain cases, frequent administration at excessively high doses is required to obtain therapeutic effects in vivo, which in turn evoke to side-effects such as immune responses. Generation of antibodies has reduced the safety and efficacy of therapeutic proteins in patients with severe deficiency disorders such as adenosine deaminase deficiency [8] and hemophilia A [1]. At the cellular level, delivery of proteins and large peptides in vivo is hindered by three-dimensional structure, spatial occupation and hydrophilic/hydrophobic features. However, there are several proteins and peptides that have made their way into pharmacopeia and these include insulin (for management of diabetes), arginine vasopressin (blood pressure), erythropoietin (anaemia), cyclosporin (organ rejection following transplantation), interferon (cancer), and exendin (diabetes).

A renewed interest in the field of protein- and peptide-based therapeutics has come about with the advent of the proteomics era. In close collaboration with the genomics field, proteomics has fuelled a renewed interest amongst researchers and importantly by big pharma for research and development (R&D) of potential peptidic agents. High throughput protocols to both discover and screen peptide-based drugs have been implemented. The current review focuses on studies performed in vivo with both proteins and peptides. There are a plethora of studies performed in vitro in which certain classes of devices perform very well. However, in general, in vitro performance of a device may not correctly predict its performance in vivo.