Natural polysaccharides constitute promising material for nano-drug delivery systems (NDDS) due to their excellent biodegradability and biocompatibility. Previously, novel copolymer micelles (His-SA-BSP) were successfully engineered based on the functionalization of Bletilla striata polysaccharides (BSP) by histidine (His) and stearic acid (SA). In this work, the effectiveness of the designed micelles in selectively delivering Doxorubicin (Dox) to tumor cells is evaluated. The obtained results show satisfactory encapsulation efficiency, loading capacity, and drug compatibility of the copolymers. Surface charge conversion and micelle deterioration were observed at pH = 6.5 and pH = 5.0, respectively. In vitro Dox release assays indicate a rapid release of Dox from micelles under acidic conditions of tumor microenvironments. Furthermore, in vitro cytotoxicity and cellular uptake assays performed on Michigan Cancer Foundation-7 (MCF-7) cells suggest that the proposed micelles are safe to use in biological systems, and that they can be easily and selectively accumulated at the tumor site due to pH sensitivity. Endocytosis inhibition and intracellular delivery assays reveal that BSP nanocarriers are mainly delivered to lysosomes by micropinocytosis. The acidic condition of lysosomes (pH = 5.0) then triggers the disintegration micelles, resulting in a fast release of Dox to the nuclei. Finally, in vivo biodistribution and antitumor assessments conducted on MCF-7-BALB/c tumor xenograft mice confirm the enhanced tumor accumulation and antitumor efficacies of the investigated Dox-loaded micelles. In conclusion, the pH-sensitive drug delivery systems designed previously are shown to yield improved accumulation of the drug at the tumor site, enhanced intracellular uptake, and efficient in vivo antitumor efficacy.
Keywords: Antitumor efficacy; Bletilla striata polysaccharides; Self-assembled micelles; Stepwise pH responsiveness; Targeted intracellular delivery.
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