Antibody-modified liposomes for tumor-targeting delivery of timosaponin AIII

Abstract

Lu Lu,1 Yue Ding,2 Yong Zhang,2 Rodney JY Ho,3 Yuan Zhao,4 Tong Zhang,1 Chunrong Guo2 1School of Pharmacy, 2Experiment Center for Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai, China; 3Department of Pharmaceutics, University of Washington, Seattle, WA, USA; 4Center of Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, China Introduction: Timosaponin AIII (TAIII), as a steroid saponin in Anemarrhena asphodeloides, has favorable potential as an antitumor candidate. However, its hydrophobicity and low bioavailability severely limit its in vivo antitumor efficacy. Methods: To overcome this drawback, TAIII-loaded liposomes (LP) were prepared to improve TAIII solubility and extend its circulation time. Furthermore, anti-CD44 antibody-modified LP (CD44-LP) was prepared to enhance the therapeutic index of TAIII. The LP and CD44-LP were also characterized through their biological activity, target selective binding and uptake, and in vivo pharmacokinetics. Results: Compared with free TAIII, both LP and CD44-LP possessed a desirable sustained-release profile in vitro, with ~14.2- and 10.7-fold longer TAIII half-life, respectively, and 1.7- and 1.9-fold larger area under the curve, respectively. LP and CD44-LP enhanced TAIII antitumor activity against HepG2 cells and in a xenograft mouse model without detectable toxicity. In particular, CD44-LP exhibited notably higher cytotoxicity than did LP, with a lower half-maximal inhibitory concentration (48 h). CD44-LP exhibited stronger tumor inhibition, and the tumor inhibitory effect was 1.3-fold that of LP. Furthermore, confocal laser scanning microscopy and in vivo near-infrared imaging of a xenograft mouse model revealed that compared with LP, CD44-LP could effectively enhance tumor accumulation. Conclusion: Taken together, the results indicate that both CD44-LP and LP can considerably extend TAIII circulation time, increase tumor-targeted accumulation, and enhance antitumor activity. Thus, the anti-CD44 antibody-modified liposome is a promising candidate for treating CD44-positive cancer with considerable antitumor effects. Keywords: timosaponin AIII, liposomes, CD44, tumor-targeting drug delivery, receptor-mediated drug targeting

Keywords

• timosaponin AIII
• liposomes
• CD44
• tumor-targeting drug delivery
• receptor mediated drug targeting