OBJECTIVE To synthesize a stimulus-sensitive precursor polymer (PEG-DOX) from polyethylene glycol and doxorubicin, encapsulate melphalan(MEL) to prepare MEL/PEG-DOX nanometer micelles, and investigate its synergistic anti-tumor effect in vitro. METHODS Through Schiff base reaction, the pegylated dithionyl hydrazide (TPH) was combined with DOX to form a pH/reduction sensitive PEG-DOX prodrug nanocarrier, and MEL/PEG-DOX loaded micelle was prepared by its self-assembly property.The morphology was observed by transmission electron microscopy, the particle size and potential were measured by particle size analyzer, drug loading and encapsulation rate were measured by ultrafiltration, drug release of micelles was evaluated by dialysis, and cytotoxicity was evaluated by MTT. RESULTS The stimulation response PEG-DOX precursor polymer was verified by H-NMR.The mean particle size of peg-dox carrier was (188±2.4) nm, and the polydispersion coefficient (PDI) was (0.255±0.008). The mean particle size of MEL/PEG-DOX loaded micelles was (299.7±2.4) nm, the polydispersion coefficient (PDI) was 0.301±0.03, and the Zeta potential was (-0.385±0.02) mV. DOX drug-polymer interactions (14.85±0.24)%, the encapsulation rate was (85.78±0.37)%, MEL drug-polymer interactions (7.36±0.36)%, the encapsulation rate was (38.79±0.42)%.The results of drug release experiments in vitro showed that MEL/PEG-DOX micelles were sensitive to reduction and pH, and the reduction sensitivity was greater than that of pH. Cytotoxicity analysis showed that DOX and MEL were released together in cells, achieving the joint killing of tumor cells. CONCLUSION MEL/PEG-DOX can be specifically released in the tumor microenvironment, which has a coordinating effect on tumor cells and a good application prospect.
Key words
polyethylene glycol /
nanoprodrug /
doxorubicin /
melphalan
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