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

Abstract

Introduction (-)-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.

Active targeting schemes for nano-drug delivery systems in osteosarcoma therapeutics

“…The affinity of cRGDyk (cyclo (Arg-Gly-Asp-d-Tyr-Lys)) for αvβ5 integrins, which are mainly overexpressed in HCT-116 cells, has been reported to be much weaker than that for αvβ3 integrins. By contrast, cRGDfC (cyclo (Arg-Gly-Asp-d-Phe-Cys)) has a high targeting affinity for αvβ5 integrins [ 19 ]. Therefore, when selecting RGD as a targeting ligand, researchers need to evaluate the type of integrin expressed on the OS surface carefully to improve delivery efficiency.…”

Strategic developments in the drug delivery of natural product dihydromyricetin: applications, prospects, and challenges

“…The effects of optical isomers are often different. For example, (−)gossypol has significant anticancer properties, while (+)gossypol has almost no such biological activities (H Liu, Zhang, et al., 2022 ). Since the pharmacological effects of (+)DHM and (−)DHM can be different, it is necessary to develop monoisomer drug preparations in the future to reduce ineffective substances for patients and avoid potential adverse/side effects (Tong et al., 2015 ).…”

Recent advances in NIR-II fluorescence based theranostic approaches for glioma

“…Instead of MBs, Shi et al applied a similar strategy to liposomes, and investigated the precise delivery of (–)-gossypol (AT-101) as a drug for the treatment of glioma ( Liu H. et al, 2022 ). The application of AT-101 is limited because of its hydrophobicity and non-tumor specific biodistribution.…”