Preparation and evaluation of reduction-responsive nanomicelles for K-Ras(G12C)mutant tumors
Objective To synthesize a series of reduction-sensitive macromolecular predrugs from thiolated polyethylene glycol of different molecular weights and K-Ras(G12C)inhibitor 6 to prepare nanomicelles,and to screened the optimal nanomicelle(PERIs micelles)to evaluate its physicochemical property and anti-tumor effect in vitro.Methods Through disulfide bonds,the thiolated polyethylene glycol was combined with K-Ras(G12C)inhibitor 6 to form reduction sensitive PERIs predrug nanocarriers,and PERIs micelles were prepared by its self-assembly property.The morphology was observed by transmission electron microscopy.The particle size and Zeta potential were measured by particle size analyzer.The critical micelle concentration was determined by pyrene-based fluorescence probe.Drug loading and encapsulation rate were measured indirectly.Drug release of the micelles was evaluated by dialysis,and cytotoxicity was evaluated by CCK-8.Results A series of reduction-sensitive macromolecular predrugs(PERI)were verified by 1H-NMR.Based on the size,surface potential and drug loading,PERIs micelles(Mw:2000)was screened for subsequent experiments.The mean particle size was(95.76±1.8)nm with a polydispersity index of(0.189±0.0084),Zeta potential was-(7.07±0.14)mV,critical micelle concentration was 0.875 μg·mL-1,the drug loading was(11.5±0.16)％and the encapsulation rate was(71.6±0.83)％.The drug release experiments in vitro showed that PERIs were sensitive to reduction.Cytotoxicity analysis showed that PERIs effectively inhibited the proliferation of tumor cells.Conclusion The prepared PERIs micelles(Mw:2000)exhibits uniform particle size,good dispersion and stability,sustained drug release,and strong proliferation inhibition of tumor cells.
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