Chagasin-based Carriers Designed for the Cancer-targeted Release of Proteases

Abstract

Current approaches to targeted disease therapy which utilize cytotoxic enzymes, such as antibody-enzyme conjugates are typically administered in their activated form. To enhance safety and provide more flexibility in terms of dosing, it would be greatly beneficial to incorporate cancer-responsive elements that enable site-selective activation of the therapeutic enzyme activity. In this study, chagasin, a protease inhibitor protein, was engineered with 11 distinct peptide targeting sequences to serve as a carrier for transporting relevant proteases (papain and bromelain) to targeted cancer cells. Once binding of targeting sequences to their specific receptors is achieved, the structural integrity of the chagasin carrier is anticipated to be compromised, thereby leading to the localized release of the bound proteases. An initial screening against various cancer cell lines (A549, KKU-213, HeLa, SW620, DU-145, and MCF7) identified two chagasin variants, namely cha6 and cha8 that exhibited significant cancer targeting properties. The complexes formed by these protease-bound chagasin carriers then displayed antiproliferative effects against targeted cancer cell lines, thus demonstrating a proof-of-concept therapy based on the cancer-specific release of cytotoxic proteases.

Date of Award	2025
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology
Supervisor	Kenward VONG (Supervisor)