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

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

  • J Control Release. 2022 Jun;346:136-147. doi: 10.1016/j.jconrel.2022.04.014.
Ha Rin Kim 1 Young Seok Cho 2 Seung Woo Chung 3 Jeong Uk Choi 4 Yoon Gun Ko 5 Seong Jin Park 1 Sang Yoon Kim 6 Youngro Byun 7
Affiliations

Affiliations

  • 1 Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
  • 2 Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergent Science and Technology, Seoul National University, Seoul 08826, Republic of Korea.
  • 3 Center for Nanomedicine, Wilmer Eye Institute and Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
  • 4 College of Pharmacy, Chonnam University, Gwangju 61186, Republic of Korea.
  • 5 Pharosgen Co.Ltd, Seoul 05852, South Korea.
  • 6 Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, South Korea.
  • 7 Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea. Electronic address: yrbyun@snu.ac.kr.
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.

Keywords

Caspase-3; Heterogeneity; Metastasis; Peptide-drug conjugate; Switch therapy; TNBC.

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