Macropinocytosis-targeted peptide-docetaxel conjugate for bystander pancreatic cancer treatment

Young Seok Cho; Hanhee Cho; Ha Rin Kim; Seong Jin Park; Joo Hye Yeo; Yoon Gun Ko; Jinu Lee; Sang Yoon Kim; Kwangmeyung Kim; Youngro Byun

doi:10.1016/j.jconrel.2024.10.070

Macropinocytosis-targeted peptide-docetaxel conjugate for bystander pancreatic cancer treatment

J Control Release. 2024 Nov 5:376:829-841. doi: 10.1016/j.jconrel.2024.10.070. Online ahead of print.

Authors

Young Seok Cho¹, Hanhee Cho², Ha Rin Kim³, Seong Jin Park⁴, Joo Hye Yeo⁵, Yoon Gun Ko⁶, Jinu Lee⁵, Sang Yoon Kim⁷, Kwangmeyung Kim², Youngro Byun⁸

Affiliations

¹ Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergent Science and Technology, Seoul National University, Seoul 08826, Republic of Korea; Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA.
² College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea.
³ Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; School of Medicine, Stanford University, CA 94305, USA.
⁴ Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
⁵ College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon 21983, Republic of Korea.
⁶ Pharosgen Co.Ltd, 2-404 Jangji-dong 892, Seoul 05852, Republic of Korea.
⁷ Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea.
⁸ Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea. Electronic address: yrbyun@snu.ac.kr.

PMID: 39491626
DOI: 10.1016/j.jconrel.2024.10.070

Abstract

Oncogenic Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are highly prevalent in pancreatic ductal adenocarcinoma (PDAC) and have garnered attention as potential targets for targeted therapies, such as KRAS inhibitors. However, the limited therapeutic efficacy of KRAS allele-specific inhibitors necessitate an efficient pan-KRAS cancer cell killing strategy. Here, we have examined enhanced macropinocytosis pathway in KRAS mutant cancer cells and report improved intracellular delivery of albumin-based therapeutics. We further established an albumin-binding peptide-docetaxel conjugate platform (MPD3), which has a caspase-3 cleavable feature, for macropinocytosis-targeted bystander payload delivery and realization of bystander killing of pan-KRAS cancer cells, complemented with caspase-3 mediated activation of MPD3 to bolster tumoral accumulation of cytotoxic payloads. Utilization of in vitro co-culture system of pan-KRAS cancer cells and pharmacodynamic marker staining revealed potent bystander killing effects of MPD3, highlighting MPD3 as an efficient delivery platform against pan-KRAS cancer. Moreover, MPD3 elicited robust anti-tumor activities in both local and liver metastatic PDAC tumor models in mice. Overall, this work establishes a paradigm for developing translational pan-KRAS cancer treatment and broadens the applicability of albumin binding peptide-drug conjugate against albumin-metabolism enriched cancers.

Keywords: Bystander killing; KRAS mutation; Macropinocytosis; Pancreatic cancer; Peptide-drug conjugate.