Caspase-3 mediated switch therapy of self-triggered and long-acting prodrugs for metastatic TNBC.

Abstract

Triple-negative breast cancer (TNBC) is characterized by its highly heterogeneous microenvironment and propensity for aggressive behavior, both of which represent, along with poor prognosis and high incidence of relapse, the main challenges of curing the disease. Although recent progress in targeted chemotherapy combinations has shown promising outcomes, conventional targeted chemotherapeutic approaches have relied on exploiting the expression of certain molecules or proteins overexpressed on cancer cells as drug targets, which have demonstrated limited clinical benefit against metastatic cancers. Here, we describe a tumoral caspase-3 mediated peptide-doxorubicin conjugates (PDC) switch therapy that adopts two different caspase-3 cleavable PDCs, RGDEVD-DOX (TPD1) and EMC-KGDEVD-DOX (MPD1), for targeting metastatic triple-negative breast cancer (mTNBC). First, using TPD1, an integrin αVβ3 based targeted strategy was utilized to target tumor cells or tumor vasculature associated with the highly malignant progression of mTNBC. TPD1 triggered the tumor cell-specific initial apoptosis and the induction of caspase-3 expression in the target tumor site. Then MPD1 was administered sequentially, which is an albumin-binding prodrug, and activated by induced caspase-3 in order to maintain the tumoral caspase-3 level and release the cytotoxic payload. The PDC switch therapy markedly accumulated doxorubicin in the tumor site and augmented tumor-specific in situ amplification of apoptosis. Importantly, the PDC switch therapy exerted a bystander killing effect on the neighboring cancer cells thus demonstrating potent therapeutic efficacy against both local and metastatic cancers. Given the limited therapeutic outcomes with conventional targeted therapies, our strategy of regulating the expression of caspase-3 level as a drug target could provide as a more durable and effective alternative in the treatment of highly heterogeneous mTNBC.

• Authors: Ha Rin Kim, Young Seok Cho, Seung Woo Chung, Jeong Uk Choi, Yoon Gun Ko, Seong Jin Park, Sang Yoon Kim, Youngro Byun
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 346 Pg. 136-147 (06 2022) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 35447298 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• Antineoplastic Agents
• Peptides
• Prodrugs
• Doxorubicin
• Caspase 3

Topics

• Antineoplastic Agents (therapeutic use)
• Caspase 3 (metabolism)
• Cell Line, Tumor
• Doxorubicin
• Humans
• Peptides (chemistry)
• Prodrugs
• Triple Negative Breast Neoplasms (therapy)
• Tumor Microenvironment