Cyclic RGD-Decorated Liposomal Gossypol AT-101 Targeting for Enhanced Antitumor Effect

Hao Liu,1 Ruirui Zhang,1 Dan Zhang,1 Chun Zhang,1 Zhuo Zhang,1 Xiujuan Fu,1 Yu Luo,1 Siwei Chen,1 Ailing Wu,2 Weiling Zeng,3 Kunyan Qu,1 Hao Zhang,1 Sijiao Wang,1 Houyin Shi4 1School of Pharmacy, Southwest Medical University, Luzhou City, Sichuan, People’s Republic of China; 2Department of Anesthesiology, The First People’s Hospital of Neijiang, Neijiang, Sichuan, People’s Republic of China; 3Department of Scientific Research, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou City, Sichuan, People’s Republic of China; 4Department of Orthopedics, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou City, Sichuan, People’s Republic of ChinaCorrespondence: Hao LiuSchool of Pharmacy, Southwest Medical University, No. 1 Section 1, Xiang Lin Road, Longmatan District, Luzhou City, Sichuan Province, 646000, People’s Republic of ChinaTel +86 830 3162291Email h_lewis@126.comHouyin ShiDepartment of Orthopedics, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, No. 182 Chunhui Road, Longmatan District, Luzhou City, Sichuan Province, 646000, People’s Republic of ChinaTel +86 830 3162209Email 623340767@qq.comIntroduction: (-)-Gossypol (AT-101), the (-)-enantiomer of the natural compound gossypol, has shown significant inhibitory effects on various types of cancers such as osteosarcoma, myeloma, glioma, lung cancer, and prostate cancer. However, the clinical application of (-)-gossypol was often hindered by its evident side effects and the low bioavailability via oral administration, which necessitated the development of suitable (-)-gossypol preparations to settle the problems. In this study, injectable cyclic RGD (cRGD)-decorated liposome (cRGD-LP) was prepared for tumor-targeted delivery of (-)-gossypol.Methods: The cRGD-LP was prepared based on cRGD-modified lipids. For comparison, a non-cRGD-containing liposome (LP) with a similar chemical composition to cRGD-LP was specially designed. The physicochemical properties of (-)-gossypol-loaded cRGD-LP (Gos/cRGD-LP) were investigated in terms of the drug loading efficiency, particle size, morphology, drug release, and so on. The inhibitory effect of Gos/cRGD-LP on the proliferation of tumor cells in vitro was evaluated using different cell lines. The biodistribution of cRGD-LP in vivo was investigated via the near-infrared (NIR) fluorescence imaging technique. The antitumor effect of Gos/cRGD-LP in vivo was evaluated in PC-3 tumor-bearing nude mice.Results: Gos/cRGD-LP had an average particle size of about 62 nm with a narrow size distribution, drug loading efficiency of over 90%, and sustained drug release for over 96 h. The results of NIR fluorescence imaging demonstrated the enhanced tumor targeting of cRGD-LP in vivo. Moreover, Gos/cRGD-LP showed a significantly enhanced inhibitory effect on PC-3 tumors in mice, with a tumor inhibition rate of over 74% and good biocompatibility.Conclusion: The incorporation of cRGD could significantly enhance the tumor-targeting effect of the liposomes and improve the antitumor effect of the liposomal (-)-gossypol in vivo, which indicated the potential of Gos/cRGD-LP that warrants further investigation for clinical applications of this single-isomer drug.Keywords: RGD peptide, αvβ3 integrin, targeted therapy, AT-101, liposome, fluorescence imaging