Folate-conjugated amphiphilic block copolymers for targeted and efficient delivery of doxorubicin

• Novel FA-conjugated amphiphilic copolymers were synthesized by enzymatic methods.
• The copolymers could self-assemble into nano-micelles with lower cytotoxicity.
• FA-conjugation improved uptake by HeLa cells via FA-receptor-mediated endocytosis.
• The FA-conjugated copolymers exhibited highly potent cytotoxic activity.

In this paper, novel biodegradable amphiphilic block copolymers based on folate-conjugated poly(ethylene glycol)-b-copolycarbonates (FA-PEG-b-P(MAC-co-DTC)) and methoxy poly(ethylene glycol)-b-copolycarbonates (mPEG-b-P(MAC-co-DTC)) were successfully synthesized for targeted and efficient delivery of doxorubicin (DOX) to cancer cells. Immobilized porcine pancreas lipase (IPPL) was employed as the catalyst to perform the ring-opening copolymerization in bulk, while the folate-conjugated poly(ethylene glycol) (FA-PEG) or methoxy poly(ethylene glycol) (mPEG) was used as the initiator. The resulting copolymers, characterized by 1H NMR and GPC, could self-assemble to form nano-sized micelles in aqueous solution by dialysis method. P(MAC-co-DTC) acted as the hydrophobic core, thereby aggregating hydrophilic PEG chains as the outer shell with FA as targeting ligand located at the surface of the polymeric micelles. Transmission electron microscopy (TEM) observation showed that the micelles dispersed in spherical shape with nano-size before and after DOX loading. Both the FA-conjugated and non-conjugated block copolymers showed low cellular cytotoxicity. Furthermore, as compared to the non-conjugated copolymers, much more efficient cellular uptake of the FA-conjugated copolymers via FA-receptor-mediated endocytosis could be observed by confocal laser scanning microscopy (CLSM), while MTT assays also demonstrated highly potent cytotoxic activity against HeLa cells.

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