An Environmentally Responsive Molecular Engineering Framework for Subcellular Drug Translocalization
Abstract
AbstractThe power of drugs lies in their ability to reach their target sites and remain in place for a sufficient duration to exert their therapeutic effects. However, for some drugs, lysosomal phagocytosis presents ongoing challenges. In this study, an engineered organelles visualization drug‐delivery system (OVDS) is introduced as a subcellular drug visualization and redistribution framework that facilitates the movement of drug molecules from one organelle, specifically lysosomes, to another, such as the mitochondria. As a proof‐of‐concept study, an OVDS is developed to facilitate the translocation of 10‐hydroxycamptothecin (HCPT) from the lysosomes to mitochondria. This modification of subcellular HCPT distribution allows the evasion of lysosome‐mediated HCPT resistance in cancer cells. Unlike traditional chemotherapeutic approaches, when HCPT is incorporated into the OVDS framework (HCPT‐OVDS), the positive charge of the OVDS facilitates protonation, thereby enabling HCPT to escape lysosomes and enter mitochondria. Using HCPT‐OVDS, substantial drug accumulation is achieved at the target sites in HCPT‐resistant cells, with up to 70 ± 6% efficient subcellular translocalization and a 12.8 fold enhancement in cytotoxicity. Overall, the HCPT‐OVDS represents an innovative engineering framework for subcellular spatial redistribution and offers a promising solution for addressing cancer drug resistance.
Article Details
Authors (11)
Guiqian Fang
State Key Laboratory of Advanced Drug Delivery and Release Systems School of Pharmaceutical Sciences School of Life Sciences Medical Science and Technology Innovation Center Shandong First Medical University & Shandong Academy of Medical Sciences Jinan Shandong 250117 P. R. China
Daili Liu
State Key Laboratory of Advanced Drug Delivery and Release Systems School of Pharmaceutical Sciences School of Life Sciences Medical Science and Technology Innovation Center Shandong First Medical University & Shandong Academy of Medical Sciences Jinan Shandong 250117 P. R. China
Qingjie Bai
State Key Laboratory of Advanced Drug Delivery and Release Systems School of Pharmaceutical Sciences School of Life Sciences Medical Science and Technology Innovation Center Shandong First Medical University & Shandong Academy of Medical Sciences Jinan Shandong 250117 P. R. China
Xintian Shao
State Key Laboratory of Advanced Drug Delivery and Release Systems School of Pharmaceutical Sciences School of Life Sciences Medical Science and Technology Innovation Center Shandong First Medical University & Shandong Academy of Medical Sciences Jinan Shandong 250117 P. R. China
Zhidong Liu
Department of Thoracic Surgery, Beijing Chest Hospital, Beijing
Qingqiang Yao
Yongfang Yuan
Kewu Zeng
State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical Sciences Peking University Beijing 100191 P. R. China
Xiaoyuan Chen
Xiaofei Chen
School of Materials Science and Engineering
Qixin Chen