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

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

  • Biomaterials. 2022 Oct:289:121783. doi: 10.1016/j.biomaterials.2022.121783.
Young Seok Cho 1,  Ha Rin Kim 2,  Seong Jin Park 2,  Seung Woo Chung 3,  Yoon Gun Ko 4,  Joo Hye Yeo 5,  Jinu Lee 5,  Sang Kyoon Kim 6,  Jeong Uk Choi 7,  Sang Yoon Kim 8,  Youngro Byun 9
Affiliations

Affiliations

  • 1 Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergent Science and Technology, Seoul National University, Seoul, 08826, Republic of Korea.
  • 2 Research Institute of Pharmaceutical Sciences, College of Pharmacy, 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 Pharosgen Co.Ltd, 2-404 Jangji-dong 892, Seoul, 05852, Republic of Korea.
  • 5 College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, 21983, Republic of Korea.
  • 6 Laboratory Animal Center, Daegu Gyeongbuk Medical Innovation Foundation, Daegu, Republic of Korea.
  • 7 College of Pharmacy, Chonnam University, Gwangju, 61186, Republic of Korea.
  • 8 Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea. Electronic address: [email protected].
  • 9 Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea. Electronic address: [email protected].
PMID: 36084486 DOI: 10.1016/j.biomaterials.2022.121783
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.

Keywords

Bystander killing; Caspase-3; Macropinocytosis; Metastatic triple-negative breast cancer; PTEN-Loss; Peptide-drug conjugate.

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