期刊
JOURNAL OF BIOMATERIALS SCIENCE-POLYMER EDITION
卷 -, 期 -, 页码 -出版社
TAYLOR & FRANCIS LTD
DOI: 10.1080/09205063.2023.2201815
关键词
Two-stage targeted; liposome; mitochondrial target; hyaluronic acid; MDR
Multidrug resistance is a major challenge in chemotherapy for non-small cell lung cancer. Mitochondria have been identified as a promising target for overcoming drug resistance. A two-stage targeted liposome was successfully developed, with paclitaxel-loaded cationic liposome formulated and further coated with hyaluronic acid. The encapsulated paclitaxel showed improved stability and safety, and the liposomes enhanced cellular uptake and accumulation of paclitaxel in mitochondria, leading to disrupted mitochondrial function, increased apoptosis, and stronger anticancer efficacy.
Multidrug resistance (MDR) has emerged as a prominent challenge contributing to the ineffectiveness of chemotherapy in treating non-small cell lung cancer (NSCLC) patients. Currently, mitochondria of cancer cells are identified as a promising target for overcoming MDR due to their crucial role in intrinsic apoptosis pathway and energy supply centers. Here, a two-stage targeted liposome (HA/TT LP/PTX) was successfully developed via a two-step process: PTX-loaded cationic liposome (TT LP/PTX) were formulated by lipid film hydration & ultrasound technique, followed by further coating with natural anionic polysaccharide hyaluronic acid (HA). TT, an amphipathic polymer conjugate of triphenylphosphine (TPP)-tocopheryl polyethylene glycol succinate (TPGS), was used to modify the liposomes for mitochondrial targeting. The average particle size, zeta potential and encapsulation efficiency (EE%) of HA/TT LP/PTX were found to be 153 nm, -30.3 mV and 92.1% based on the optimal prescription of HA/TT LP/PTX. Compared to cationic liposome, HA-coated liposomes showed improved stability and safety, including biological stability in serum, cytocompatibility, and lower hemolysis percentage. In drug-resistant A549/T cells, HA was shown to improve the cellular uptake of PTX through CD44 receptor-mediated endocytosis and subsequent degradation by hyaluronidase (HAase) in endosomes. Following this, the exposure of TT polymer facilitated the accumulation of PTX within the mitochondria. As a result, the function of mitochondria in A549/T cells was disturbed, leading to an increased ROS level, decreased ATP level, dissipated MMP, and increased G(2)/M phase arrest. This resulted in a higher apoptotic rate and stronger anticancer efficacy.
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