Journal
BIOMATERIALS SCIENCE
Volume 1, Issue 6, Pages 633-646Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/c3bm60024f
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Funding
- National Natural Science Foundation of China [51233004, 51273196, 51273037, 51203153, 51273080, 51103015, 51021003, 20904053]
- Jilin Science and Technology Bureau (International Cooperation Project) [20120729]
- Jilin Human Resources and Social Security Bureau [201125020]
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Three derivatives of doxorubicin (DOX) were prepared by modifying DOX with succinic anhydride, cisaconitic anhydride and 2,3-dimethylmaleic anhydride, generating acid-insensitive succinyl-DOX (SAD), acid-sensitive cis-aconityl-DOX (CAD) and 2,3-dimethylmaleyl-DOX (DAD) respectively. The pH and reduction dual-responsive methoxy poly(ethylene glycol)-poly(L-lysine-co-L-cystine) nanogel was employed to encapsulate the DOX derivatives. In vitro release studies showed that drug release could be accelerated in the intracellular acidic and reductive conditions. Confocal laser scanning microscopy and flow cytometry results demonstrated that an enhanced intracellular drug release was observed in glutathione monoester pretreated HeLa cells (a human cervical cell line). The DOX derivatives exhibited a lower accumulation in the nuclei than DOX. Moreover, the CAD and DAD-loaded nanogels showed a comparable anti-proliferative activity to the DOX-loaded nanogel against HeLa and HepG2 cells (a human hepatoma cell line). As a comparison, the SAD-loaded nanogel almost never inhibited cellular proliferation. The above results suggested that the pH and reduction dual-responsive nanogel can efficiently deliver acid-sensitive DOX derivatives into the nuclei of cancer cells for minimizing the side effects and enhancing the inhibition of cellular proliferation.
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