化学
透明质酸
三氟乙酸
胶束
乙二醇
体内
CD44细胞
生物物理学
癌症研究
体外
生物化学
水溶液
医学
有机化学
生物技术
物理化学
解剖
生物
作者
Shalini Gautam,Disha Marwaha,Neha Singh,Nikhil Rai,Madhu Sharma,Pratiksha Tiwari,Sandeep Urandur,Ravi Prakash Shukla,Venkatesh Teja Banala,Prabhat Ranjan Mishra
标识
DOI:10.1021/acs.molpharmaceut.2c00673
摘要
A two-tier approach has been proposed for targeted and synergistic combination therapy against metastatic breast cancer. First, it comprises the development of a paclitaxel (PX)-loaded redox-sensitive self-assembled micellar system using betulinic acid-disulfide-d-α-tocopheryl poly(ethylene glycol) succinate (BA-Cys-T) through carbonyl diimidazole (CDI) coupling chemistry. Second, hyaluronic acid is anchored to TPGS (HA-Cys-T) chemically through a cystamine spacer to achieve CD44 receptor-mediated targeting. We have established that there is significant synergy between PX and BA with a combination index of 0.27 at a molar ratio of 1:5. An integrated system comprising both BA-Cys-T and HA-Cys-T (PX/BA-Cys-T-HA) exhibited significantly higher uptake than PX/BA-Cys-T, indicating preferential CD44-mediated uptake along with the rapid release of drugs in response to higher glutathione concentrations. Significantly higher apoptosis (42.89%) was observed with PX/BA-Cys-T-HA than those with BA-Cys-T (12.78%) and PX/BA-Cys-T (33.38%). In addition, PX/BA-Cys-T-HA showed remarkable enhancement in the cell cycle arrest, improved depolarization of the mitochondrial membrane potential, and induced excessive generation of ROS when tested in the MDA-MB-231 cell line. An in vivo administration of targeted micelles showed improved pharmacokinetic parameters and significant tumor growth inhibition in 4T1-induced tumor-bearing BALB/c mice. Overall, the study indicates a potential role of PX/BA-Cys-T-HA in achieving both temporal and spatial targeting against metastatic breast cancer.
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