Biotin-decorated redox-responsive micelles from diselenide-linked star-shaped copolymers for the targeted delivery and controlled release of doxorubicin in cancer cells

Polymeric micelles (s-PMs) assembled from star-shaped amphiphilic copolymers functionalized with cancer-homing molecules have been shown to have enormous potential to be used as a delivery tool to achieve longer half-life in the bloodstream, cancer-specific internalization, and controlled release of payloads in tumor cells. Considering the unprecedented thermodynamic stability of s-PMs owing to the entanglement of branched arms, we prepared a biotin-decorated and diselenide-linked star-shaped amphiphilic copolymer, 3s-PCL-SeSe-PEG-biotin, which could undergo self-directed clustering to form uniformly distributed s-PMs with a hydrodynamic diameter (D-h) of 76.27 nm. The s-PMs had appreciable doxorubicin (DOX)-loading content (DLC) and encapsulation efficiency (EE) of 5.83 wt% and 71.02%, respectively. The blank and DOX-loaded 3s-PCL-SeSe-PEG-biotin (DOX@3s-PCL-SeSe-PEG-biotin) micelles maintained their structural integrity; consequently, the D-h did not change markedly in the presence of 50% fetal bovine serum and when diluted with an excess volume of phosphate-buffered saline for extended periods, confirming their colloidal stability. Moreover, DOX@3s-PCL-SeSe-PEG-biotin micelles showed desirable DOX release in the simulated cancer redox pool, which was approximately 93% and 79% in 10 mM glutathione and 0.1% H2O2, respectively, in 72 h. Interestingly, the blank 3s-PCL-SeSe-PEG-biotin micelles were devoid of any inherent cytotoxicity against HaCaT, HeLa, and MDA-MB-231 cell lines (>= 85% cells were metabolically active). In contrast, DOX@3s-PCL-SeSe-PEG-biotin selectively suppressed the proliferation of approximately 77% HeLa and 62% MDA-MB-231 cells compared to approximately 12% of HaCaT cells at 5 mu g/ml. Overall, the diselenide-linked 3s-PCL-SeSe-PEG-biotin resulted in the formation of physiologically stable, cancer-cell specific, and smart s-PMs, which need to be further investigated in vivo.

Automated summary

Polymeric micelles assembled from star-shaped amphiphilic copolymers have potential as a delivery tool for cancer treatment due to their long half-life, cancer-specific internalization, and controlled release of drugs. In this study, a biotin-decorated and diselenide-linked star-shaped amphiphilic copolymer was used to form stable micelles with high drug loading content and encapsulation efficiency. The micelles showed selective cytotoxicity against cancer cells and desirable drug release in a simulated cancer environment.