Sustained potentiation of bystander killing via PTEN-loss driven macropinocytosis targeted peptide-drug conjugate therapy in metastatic triple-negative breast cancer

Young Seok Cho, Ha Rin Kim, Seong Jin Park, Seung Woo Chung, Yoon Gun Ko, Joo Hye Yeo, Jinu Lee, Sang Kyoon Kim, Jeong Uk Choi, Sang Yoon Kim, Youngro Byun

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

While conventional approaches for PTEN-loss cancers mainly focus on turning off growth promoting process through modulation of PI3K/AKT pathways, no effective therapeutic treatments that target PTEN-loss cancer cells have yielded results. Moreover, conventional targeted therapies, which are potent against only a subset of cancer cells with limited specificity, bring on temporary response. Here, we report the development of albumin-binding caspase-3 cleavable peptide-drug conjugate (PDC), which utilizes the enhanced albumin metabolism pathway in PTEN-loss cancer cells to enhance the intracellular delivery of chemotherapeutic payload that could exert a bystander killing effect. Albumin metabolism-mediated apoptosis triggered expression of caspase-3 allows the continuous activation of the PDC, accumulation of payloads, sustained upregulation of tumoral caspase-3, and intensified in-situ apoptosis. Importantly, PDC strategy exerts potent therapeutic efficacy against PTEN-loss metastatic triple-negative breast cancer, the highly aggressive and heterogenous nature of which remains a challenge conventional targeted therapies need to overcome. This study thus presents a conceptually novel approach to treat PTEN-loss cancer and creates new translational perspectives of exploiting PTEN-loss for providing an avenue to advance current targeted therapy.

Original languageEnglish
Article number121783
JournalBiomaterials
Volume289
DOIs
Publication statusPublished - 2022 Oct

Bibliographical note

Publisher Copyright:
© 2022 The Authors

All Science Journal Classification (ASJC) codes

  • Mechanics of Materials
  • Ceramics and Composites
  • Bioengineering
  • Biophysics
  • Biomaterials

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