期刊
JOURNAL OF CONTROLLED RELEASE
卷 321, 期 -, 页码 222-235出版社
ELSEVIER
DOI: 10.1016/j.jconrel.2020.02.025
关键词
Tumor microenvironment; Self-recognizing; Small-molecule assembly; Carrier-free nanodrug; Chemotherapy
资金
- National Natural Science Foundation of China [81871483, 81671813, 61727823]
- United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province [2018ZDSY2001]
Carrier-free nanodrug via small-molecule assembly is a promising alternative strategy for tumor therapy. Thus, developing a self-recognizing carrier-free nanodrug without introduction of foreign ligand is very attractive to meet both targeting and therapeutic requirements while reducing structural complexity. Here we fabricated a tumor microenvironment-activated self-targeting nanodrug, via co-assembly of hydroxycamptothecin (HCPT) and bi-functional methotrexate (MTX, not only has antitumor effect but also shows innate affinity towards folate receptors) followed by surface covering through acidity-responsive polyethylene glycol (PEG). Notably, the morphology and size of MTX-HCPT nanodrug could be tuned by varying the drug-to-drug ratio and assembly time. The PEG shell of our nanodrug could be detached in response to acidic tumor microenvironment, and then MTX could be exposed for self-targeting to enhance tumor cell uptake. Subsequently, the shell-detached nanodrug could be dissociated in relatively stronger acidic lysosomal environment, resulting in burst release of both drugs. Further in vitro and in vivo studies demonstrated that our nanodrug showed a similar to 2.98-fold increase in cancer cell uptake, a similar to 1.25-fold increase in drug accumulation at tumor site, a significantly lower CI50 value of similar to 0.3, a similar to 27.3% improvement in tumor inhibition comparing with the corresponding non-responsive nanodrug. Taken together, the here reported tumor microenvironment-activated self-recognizing nanodrug might be an extremely promising strategy for synergistically enhancing chemotherapy efficiency with minimized side effects.
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