Facile preparation of core cross-linked nanomicelles based on graft copolymers with pH responsivity and reduction sensitivity for doxorubicin delivery.

To achieve passive targeting and controlled drug release at tumor sites trigged by low pH value and high level of glutathione (GSH), optimized delivery system for doxorubicin (DOX) based on core cross-linked nanomicelles was developed in this research. Particularly, methoxypoly(ethylene glycol)-nitrophenyl carbonate (mPEG-NPC) and 3,4-dihydroxyphenylaceticacid were grafted onto synthesized poly(N,N'-cystamine bisacrylamide-N-Boc-1,2-diaminoethane) (poly(CBA-DAE)) to give methoxypoly(ethylene glycol)-g-poly(N,N'-cystamine bisacrylamide-N-Boc-1, 2-diaminoethane)-g-3, 4-dihydroxyphenylaceticacid (mPEG-g-SS-PCD-DA). Core cross-linked micelles (CCLMs/SS) with a decreased average particle size of 121nm were prepared by adding Fe into uncross-linked micelles (UCLMs/SS) self-assembled from mPEG-g-SS-PCD-DA. DOX-loaded CCLMs/SS exhibited minimal drug leakage (17.3%) under simulated blood conditions compared to DOX-loaded UCLMs/SS (31.3%). Fast drug release (52.4%) of DOX-loaded CCLMs/SS was achieved compared to DOX-loaded CCLMs/CC (32.9%) without disulfide bonds under simulated lysosomes condition over 42h. The cytotoxicity of DOX-loaded CCLMs/SS against A549 cells pretreated with 40mM NHCl was decreased significantly compared to that without NHCl treatment, and it is higher than that of DOX-loaded CCLMs/CC, further confirmed DOX release was triggered by the low pH value and high level of reductive agents of lysosomes. Compared with free DOX, DOX-loaded CCLMs/SS showed enhanced cellular uptake ability during 24h of incubation through endocytosis. Besides, charge conversion of micelles happened when pH varied from 7.4 to 6.5, which facilitates the cellular uptake against A549 cells. In summary, all these results indicated that CCLMs/SS as a new type of intelligent nanocarriers exhibited excellent potential for drug delivery.