Self‐Assembled Antimitotic Peptide Vesicle Designed fromα,β‐Tubulin Heterodimer Interface for Anticancer Drug Delivery

Abstract

AbstractPeptide based anticancer molecule act simultaneously as potent anticancer therapeutic as well as unique drug delivery vehicle for the targeted delivery of often cytotoxic abysmally bioavailable anticancer drugs to their designated organelle. The atypical self‐assembling propensity of peptides gives rise to distinct nanostructures capable of encapsulating various drug payload. Among three different types of cytoskeletons presents in eukaryotes, microtubule plays a quintessential role during the course of cell cycle. Microtubule‐targeting agents continues to be the most unwavering classes of antineoplastic drugs for the treatment of cancer. Any intervention to the dynamic tubulin assembly‐disassembly process will definitely lead to complete perturbation of total cell division process. Several tubulin targeted antimitotic drugs had been designed as well as discovered to disrupt this dynamic nature of tubulin monomers either by inducing extensive polymerization or depolymerization, thereby facilitating overall cell cycle arrest. However, in cancer cells, aberrant mTOR activity causes growing resistance against numerous tubulin targeted drugs inducing metastasization, and simultaneous invasion to new healthy tissues. In recent years, numerous tubulin targeted drugs have been found to have high activity in a combination with mTOR inhibitors like tacrolimus, everolimus (RAD001) etc. but restrained bioavailability, non‐specificity and quick excretion are the major impediments for the successful implementation. Combining the immense importance of protein‐peptide interaction for the development of future anticancer therapeutics as well as self‐assembling propensity of peptides we have taken a unique approach to craft a microtubule targeting antimitotic peptide designed fromα,β‐tubulin heterodimer interface, which promotes bothin vitroandin vivotubulin depolymerization, exhibiting middling toxicity towards MCF7 cells, causing cell cycle arrest. Further AFM images of this β‐sheet forming peptide reveals that this peptide upon self‐assembly give rise to spectacular vesicle structural characteristics which can be used as a vehicle for a combination delivery of Docetaxel and RAD001 in order to enhance their individual therapeutic potency. Encapsulation of propidium iodide and concomitant release studies suggest that Pep‐4 vesicles could be a potential candidate for tubulin targeted sustained release of therapeutics. Here, our designed peptide vesicles are found to capable for the delivery of tubulin targeting drug Docetaxel along with an well‐known mTOR inhibiting drug RAD001 successfully to breast cancer cell line in order to achieve a robust symbiotic effect.