Biotin‐decorated redox‐responsive micelles from diselenide‐linked star‐shaped copolymers for the targeted delivery and controlled release of doxorubicin in cancer cells
Yihenew Simegniew Birhan, Endiries Yibru Hanurry, Tefera Worku Mekonnen, Haile Fentahun Darge, Yu‐Hsuan Lin, Ming‐Chien Yang, Hsieh‐Chih Tsai
Abstract
Abstract 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% H 2 O 2 , 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 μg/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.