多重耐药
药品
化疗
癌症化疗
癌症研究
药理学
抗药性
癌症
化学
医学
内科学
生物
微生物学
作者
Jianqin Wan,Lingling Huang,Jiangting Cheng,Huangfu Qi,Jiahui Jin,Hangxiang Wang
出处
期刊:Theranostics
[Ivyspring International Publisher]
日期:2021-01-01
卷期号:11 (9): 4137-4154
被引量:9
摘要
Rationale: Prodrug strategies that render the drug temporarily inactive through a cleavable linkage are able to modulate the physicochemical properties of drugs for adaptive nanoparticle (NP) formulation. Here we used cabazitaxel as a model compound to test the validity of our balancing NP stability and specific drug activation strategy. Methods: Cabazitaxel is conjugated to hydrophobic polylactide fragments with varying chain lengths via a self-immolation linkage, yielding polymeric prodrugs that can be reactivated by reductive agents in cells. Following a nanoprecipitation protocol, cabazitaxel prodrugs can be stably entrapped in amphiphilic polyethylene-block-polylactide matrices to form core-shell nanotherapies with augmented colloidal stability. Results: Upon cellular uptake followed by intracellular reduction, the NPs spontaneously release chemically unmodified cabazitaxel and exert high cytotoxicity. Studies with near-infrared dye-labeled NPs demonstrate that the nanodelivery of the prodrugs extends their systemic circulation, accompanied with increased drug concentrations at target tumor sites. In preclinical mouse xenograft models, including two paclitaxel-resistant xenograft models, the nanotherapy shows a remarkably higher efficacy in tumor suppression and an improved safety profile than free cabazitaxel. Conclusion: Collectively, our approach enables more effective and less toxic delivery of the cabazitaxel drug, which could be a new generalizable strategy for re-engineering other toxic and water-insoluble therapeutics.
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