Vitamin E-based Tumor Microenvironment PH-Sensitive Micelles For Tumor Growth Inhibition And Anti-Metastasis

Objectives : The uptake efficiency of tumor cells for positively charged nanomedicines is much higher than negatively charged and neutral nanomedicines.However,positively charged nanomedicines are prone to be cleared during blood circulation and toxic to normal tissues.In order to solve the problem mentioned above,we prepared Vitamin E-based micelles with charge-reversible property in tumor microenvironment.The micelles were negatively charged in the blood circulation and normal tissues.While in the slightly acidic tumor microenvironment,the surface charge of the micelles converted into positive charge.This biocompatible drug delivery system exhibited high drug delivery efficiency as well as effective tumor growth inhibition and anti-metastasis effect.Methods:The Vitamin E-based micelles with charge-reversal property(DPVM)were prepared by nanoprecipitation method and were able to load paclitaxel(PTX).The morphology of micelles was characterized by dynamic light scattering(DLS)and transmission electron microscopy using the non-sensitive micelles(SPVM)as control.And the high-performance liquid chromatography was used to determine the drug loading and entrapment efficiency of the micelles.Besides,the in vitro antitumor activity and cell uptake efficiency of micelles were determined by MTT assay and confocal laser scanning microscopy,respectively.Moreover,the mouse xenograft and orthotopic tumor model were applied to evaluate the antitumor and anti-metastasis effect of the micelles.Results:DPVM were stable under normal physiological conditions and the particle size of DPVM was 188 ± 14.4 nm.Under pH 6.8,the surface charge of DPVM converted from negative to positive within 2 h.The half-life of DPVM was 1.91-folds higher than that of free drug.DPVM exhibited higher cytotoxicity in vitro compared with SPVM under pH 6.8.In the 4T1 orthotopic mouse tumor model,DPVM could effectively inhibit the growth of tumor.The number of pulmonary nodules in the DPVM treated group was only 17 ± 4,which was much lower than that of PBS and SPVM.Conclusions:We successfully prepared the Vitamin E-based micelles which were charge-reversible in the slightly acidic tumor microenvironment.DPVM were high biocompatible with relatively high drug loading efficiency.The drug release rate of DPVM was p H-dependent.Besides,DPVM exhibited enhanced antitumor and anti-metastasis effect in vivo.The preparation of the micelles with significant therapeutic effect is simple and this drug delivery system is expected to be applied in the field of tumor treatment.DPVM exhibited following significances:(1)good stability both in plasma and PBS even after dilution,(2)prolonged blood circulation compared with free drug,(3)enhanced extravasation at the tumor site due to the EPR effect,(4)enhanced cellular uptake owing to the charge reversion in slightly acidic tumor microenvironment,(5)ignorable side effects at normal tissues,(6)pH-dependent drug release behavior in tumor microenvironment,(7)significant antitumor effect in both mouse orthotopic and xenograft tumor models as well as anti-metastasis effect in mouse orthotopic tumor model.