Surfactant Assisted Rapid-Release Liposomal Strategies Enhance the Antitumor Efficiency of Bufalin Derivative and Reduce Cardiotoxicity

• Main Authors: Gao L, Zhang L, He F, Chen J, Zhao M, Li S, Wu H, Liu Y, Zhang Y, Ping Q, Hu L, Qiao H
• Format: Article
• Language: English
• Published: Dove Medical Press 2021-05-01
• Series: International Journal of Nanomedicine
• Subjects: bufalin derivative; liposome; rapid-release; antitumor; cardiotoxicity
• Online Access: https://www.dovepress.com/surfactant-assisted-rapid-release-liposomal-strategies-enhance-the-ant-peer-reviewed-fulltext-article-IJN

Lina Gao,1 Lei Zhang,1 Fengjun He,1 Jing Chen,1 Meng Zhao,1 Simin Li,1 Hao Wu,1 Yumeng Liu,1 Yinan Zhang,1,2 Qineng Ping,3 Lihong Hu,1,2 Hongzhi Qiao1,2,4 1Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, People’s Republic of China; 2State Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, People’s Republic of China; 3Department of Pharmaceutics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, People’s Republic of China; 4Jiangsu Engineering Research Center for Efficient Delivery System of TCM, Nanjing University of Chinese Medicine, Nanjing, 210023, People’s Republic of ChinaCorrespondence: Hongzhi Qiao; Lihong HuState Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Pharmacy, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Nanjing, 210023, People’s Republic of ChinaEmail [e-mail]; [e-mail]: BF211, a derivative of bufalin (BF), shows significantly improved solubility and potent antitumor efficiency compared to BF. Unfortunately, the unwanted toxicity such as cardiotoxicity caused by unspecific distribution has hindered its clinical use.Methods: PEGylated BF211 liposomes (BF211@Lipo) were designed and optimizely prepared based on the pre-prescription research. In vitro and in vivo cardiotoxicity was evaluated. In vivo pharmacokinetics and biodistribution of BF211@Lipo were investigated. In vivo antitumor activity and toxicity were evaluated in HepG2 cell xenograft models. The rapid-release triggered by Poloxamer 188 (P188) was assessed in vitro and in vivo.Results: The optimized BF211@Lipo displayed a spherical morphology with a size of (164.6 ± 10.3) nm and a high encapsulation efficiency of (93.24 ± 2.15) %. The in vivo concentration–time curves of BF211 loaded in liposomes showed a prolonged half-life in plasma and increased tumor accumulation. No obvious abnormality in electrocardiograms was observed in guinea pigs even at 9 mg/kg. Moreover, to improve the efficient release of BF211@Lipo, a surfactant-assisted rapid-release strategy was developed, and the release-promoting mechanism was revealed by the fluorescence resonance energy transfer (FRET) and fluorescence nanoparticle tracking analysis (fl-NTA) technology. Sequential injection of BF211@Lipo and P188 could ignite the “cold” liposomes locally in tumor regions, facilitating the burst release of BF211 and enhancing the therapeutic index.Conclusion: Our progressive efforts that begin with preparation technology and dosage regimen enable BF211 to like a drug, providing a promising nano platform to deliver the cardiac glycosides and alleviate the side effects by decreasing unspecific biodistribution.Keywords: bufalin derivative, liposome, rapid-release, antitumor, cardiotoxicity