Abstract:

Succinic anhydride(SA) and cis-aconitic anhydride(CA) were used to modify doxorubicin(DOX), obtaining acid-insensitive SA-DOX(SAD) and acid-sensitive CA-DOX(CAD), respectively. SAD or CAD, and carboxyl group terminated monomethoxyl poly(ethylene glycol)(mPEG-COOH) were conjugated onto poly(L-lysine)(PLL), yielding acid-insensitive PLL-g-mPEG/SAD and acid-sensitive PLL-g-mPEG/CAD, respectively. The chemical structures of PLL-DOX conjugates were characterized by ¹H NMR and FTIR. The drug conjugating content was determined with UV-Vis spectrophotometer. Dynamic laser scattering(DLS) measurements revealed that the amphiphilic PLL-DOX conjugates could self-assemble into nanoparticles in phosphate buffer(PB) at pH=7.4. In vitro release profiles revealed that the DOX release from PLL-g-mPEG/CAD could be accelerated at acid conditions(pH=5.3 and 6.8), while that from PLL-g-mPEG/SAD was slow at all test pH(5.3, 6.8 and 7.4). The acid-sensitive DOX release from PLL-g-mPEG/CAD conjugates ensured higher concentration of free DOX in tumor and more pronounced antitumor efficacy. In vitro methyl thiazolyl tetrazolium assay demonstrated that PLL-g-mPEG/CAD had enhanced tumor proliferation inhibition activity comparing with acid-insensitive PLL-g-mPEG/SAD. Therefore, PLL-g-mPEG/CAD conjugates might be further developed as potential smart antitumor drugs with controlled DOX release.

Key words: Doxorubicin, Poly(L-lysine), Tumor-acidity-sensitive, Tumor cell proliferation inhibition