Core-crosslinked amphiphilic biodegradable copolymer based on the complementary multiple hydrogen bonds of nucleobases: synthesis, self-assembly and in vitro drug delivery

Abstract

Nucleobases (adenine and thymine) were conjugated to the amphiphilic biodegradable copolymers methoxyl poly(ethylene glycol)-b-poly(L-lactide-co-2-methyl-2-allyloxycarbonylpropylene carbonate) (mPEG-b-P(LA-co-MAC)). The hydrogen bonds between adenine (A) and thymine (T) were confirmed by 1H NMR titration experiments and FT-IR. It was found that the incorporation of nucleobases into the hydrophobic segment of the amphiphilic copolymers could be used for core-crosslinking of the formed micelles containing a lowered critical micelle concentration (CMC) via hydrogen bond interaction between A and T in aqueous solution. The anticancer drug doxorubicin (DOX) was encapsulated into the copolymer micelles. The in vitro drug release profile showed that the incorporation of nucleobases significantly restricted DOX release at pH 7.4, because of the compact crosslinking structure of micelles. However, a much faster release rate was observed at pH 5.0, due to the dissociation of hydrogen bonds between nucleobases. This character facilitates drug delivery in the acidic tumor micro-environment inside the endosome. Meanwhile, the DOX-loaded core-cross-linked micelles could be efficiently internalized into cancer cells and exhibit similar anticancer efficacy as free DOX against MDA-MB-231 cells. Therefore, the complementary multiple hydrogen bonds of nucleobases provided a convenient tool to stabilize the micelle structures by forming core-crosslinking, and could be further applied for controlled drug delivery.