Dual-targeting liposomal delivery of sorafenib and docetaxel for enhanced synergistic therapy in advanced hepatocellular carcinoma

Abstract

Patients with advanced hepatocellular carcinoma (HCC) are not sensitive to sorafenib (SOR), therefore, combination therapy is required. In this study, an improved thin-film dispersion and post-insertion anchoring technique was utilized to construct a dual-targeted co-delivery SOR and docetaxel (DTX) liposome drug delivery system, folate/chondroitin sulfate with SOR/DTX-modified liposomes (FA/CS@SDLP), to jointly enhance the anti-recurrence and metastasis of HCC. FA/CS@SDLP can establish the gradual release of the two drugs because of successful lysosomal escape in the condensed hyaluronidase environment. The results indicated that modification with folate (FA) and chondroitin sulfate (CS) significantly enhanced the cellular uptake of FA/CS@SDLP and the internalization of SOR/DTX in HepG2 cells through FA and CD44 receptor-mediated endocytosis. Compared to free drugs or the mono-targeted liposomal system (FA@SDLP), FA/CS@SDLP presented higher potency against HepG2 cells regarding pro-apoptosis, anti-proliferation, and anti-metastasis (migration and invasion). Moreover, a more satisfactory antitumor efficacy was observed for FA/CS@SDLP in the pulmonary metastasis of HCC in a mouse model. In summary, dual-targeted co-delivery of liposomes can synergistically treat HCC recurrence and metastasis, providing a new approach for the clinically accurate treatment of HCC.

Keywords

Sorafenib / Docetaxel / Dual-targeting liposomes / Combination therapy / Advanced hepatocellular carcinoma

Availability of data and material

The data generated or analyzed in this study have been included in a published article. These data will be available upon request.

Fundings

This work was financially supported by the National Natural Science Foundation of China [grant number 81373363]; the China Post-doctoral Science Foundation [grant number 2018M632431]; the Innovation Project of Jiangsu Province [grant number KYCX18-0758]; the China Science and Technology Development Fund and the National Major Scientific and Technological Special Project for “Significant New Drugs Development” during the Twelfth Five-year Plan Period [grant number 2015ZX09501001]; the Science and Technology Development Fund, Macau SAR [FDCT No.0159/2020/A3, 005/2023/SKL]; and the Macau Research Committee of the University of Macau [grant number MYRGGRG2023-00214-ICMS-UMDF, MYRG2022-00189-ICMS].

Ethics statement

All animal procedures complied with the Guidelines for the Care and Use of the Pharmic Laboratory Animal Center of China Pharmaceutical University, and the experiments were approved by the Animal Ethics Committee of China Pharmaceutical University (2022-03-006).

CRediT authorship contribution statement

Yawen Yao: Writing - original draft, Visualization, Investigation, Conceptualization. Yue Hu: Methodology, Investigation, Formal analysis. Xinwang Meng: Validation, Methodology, Investigation. Fenyan Feng: Resources, Methodology, Investigation. Feng Xu: Resources, Methodology. Guangji Wang: Project administration, Funding acquisition. Hua Yu: Writing - review & editing, Visualization, Funding acquisition. Juan Li: Supervision, Resources, Funding acquisition.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

We thank the Cellular and Molecular Biology Center of China Pharmaceutical University and the Pathology and PDX Efficacy Evaluation Center of China Pharmaceutical University for providing the instruments used in this study.

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.pscia.2024.100046.

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