Synthesis, characterization, and in vitro and in vivo evaluation of a novel pectin-adriamycin conjugate.
Adriamycin (ADM) has been widely used in the treatment of many types of solid malignant tumor. However, cardiotoxicity, multidrug resistance and a short half-life in vivo are significant problems that limit its clinical application. To resolve these problems, a novel pectin-adriamycin conjugate (PAC) was synthesized by attaching ADM to low-methoxylated pectin via an amide linkage. The ADM content and weight-average molecular weight (Mw) of PAC were greater than 25% (w/w) and 50,360 g/mol, respectively. PAC was highly stable in plasma, but 33.2% of ADM was released from PAC after incubation for 30 h with lysosomes derived from rat liver. PAC was distributed uniformly in the cytoplasm of most A549 cells and accumulated in the nucleus of a few A549 cells after incubation for 30 h. At concentrations equivalent to 0.125-1.000 microg of ADM/mL, PAC did not inhibit the growth of either A594 or B16 cells to the same extent as free ADM or a mixture of ADM and pectin. Interestingly, at all concentrations, PAC inhibited the growth of 2780cp cells in vitro significantly more effectively than ADM or the mixture of ADM and pectin. The anticancer effect of PAC in vivo was evaluated with C57BL/6 mice bearing pulmonary metastases of B16 cells. Compared with ADM and the mixture of ADM and pectin, PAC suppressed tumor growth significantly and prolonged the mean survival time of the B16-inoculated mice. PAC has great potential for development as a tumor targeting polymer-drug.
Tang
Xiao-Hai
XH
School of Chemical Engineering, Sichuan University, Chengdu, China. pharmmateceo@yahoo.com.cn
Xie
Ping
P
Ding
Yi
Y
Chu
Liang-Yin
LY
Hou
Jing-Ping
JP
Yang
Jin-Liang
JL
Song
Xin
X
Xie
Yong-Mei
YM
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000737:chemistry*; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles; D010368:Pectins / Q000737:chemistry*; D013055:Spectrophotometry, Infrared; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D004317:Doxorubicin; D010368:Pectins