Synthesis and Characterization of Tumor-acidity-sensitive Poly (L-lysine) -doxorubicin Conjugates

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 H-1 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.