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已发表论文
适配体介导的双载药脂质体纳米系统通过 mTOR/HIF-1α/VEGF 通路协同治疗肝细胞癌
Authors Wei A, Zhong Z, Zhang Y, He J , Pang H, Xia X , Zhang X
Received 29 July 2025
Accepted for publication 20 January 2026
Published 31 January 2026 Volume 2026:21 556912
DOI https://doi.org/10.2147/IJN.S556912
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 3
Editor who approved publication: Professor Eng San Thian
Aiqiu Wei,1,* Ziyi Zhong,1,* Yiming Zhang,1 Jincheng He,1 Haihe Pang,2 Xinhua Xia,1 Xiaoqing Zhang1
1School of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, People’s Republic of China; 2Hunan Kelun Pharmaceutical Co., Ltd, Yueyang, 414024, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Xinhua Xia, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, People’s Republic of China, Email xiaxinhua001@hnucm.edu.cn Xiaoqing Zhang, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, People’s Republic of China, Email zxq20210723@163.com
Purpose: Cantharidin (CTD) is a natural anticancer compound whose clinical application is limited by poor water solubility, low bioavailability, and significant toxicity. To develop a more effective and safer therapeutic strategy, we proposed a synergistic combination therapy by integrating CTD with staurosporine (STS), a protein kinase inhibitor that shares complementary mechanisms of action targeting the mTOR/HIF-1α/VEGF pathway. We further developed an aptamer-guided liposomal nanosystem for the co-delivery of CTD and STS (Apt/CTD-STS/NL), aiming to enhance tumor targeting, improve bioavailability, and reduce the systemic toxicity of both drugs.
Methods: We constructed aptamer-guided co-delivery nanoliposomes encapsulating CTD and STS (Apt/CTD-STS/NL). The targeted delivery efficiency, synergistic antitumor efficacy, and biocompatibility of this nanosystem were comprehensively evaluated through both in vitro and in vivo experiments.
Results: Apt/CTD-STS/NL achieved approximately 1.3-fold higher cellular uptake in HCC cells compared to non-targeted liposomes in vitro. In vivo, it demonstrated superior tumor accumulation. In a murine HCC model, Apt/CTD-STS/NL exhibited the strongest tumor growth inhibition (79.50 ± 4.39%), significantly outperforming free CTD, STS, or single-drug loaded liposomes. Mechanistic studies revealed that the core synergy between CTD and STS enabled simultaneous inhibition of the key oncoproteins mTOR, HIF-1α, and VEGF, thereby disrupting tumor proliferation, survival, and angiogenesis.
Conclusion: This study demonstrates a novel targeted nanoplatform that combines an active ingredient from traditional Chinese medicine with a modern kinase inhibitor. This strategy achieves a synergistic anti-HCC effect through multi-pathway inhibition and offers a promising approach for cancer therapy with enhanced efficacy and reduced toxicity.
Keywords: cantharidin, staurosporine, aptamer, drug co-delivery, hepatocellular carcinoma
1School of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, People’s Republic of China; 2Hunan Kelun Pharmaceutical Co., Ltd, Yueyang, 414024, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Xinhua Xia, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, People’s Republic of China, Email xiaxinhua001@hnucm.edu.cn Xiaoqing Zhang, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, People’s Republic of China, Email zxq20210723@163.com
Purpose: Cantharidin (CTD) is a natural anticancer compound whose clinical application is limited by poor water solubility, low bioavailability, and significant toxicity. To develop a more effective and safer therapeutic strategy, we proposed a synergistic combination therapy by integrating CTD with staurosporine (STS), a protein kinase inhibitor that shares complementary mechanisms of action targeting the mTOR/HIF-1α/VEGF pathway. We further developed an aptamer-guided liposomal nanosystem for the co-delivery of CTD and STS (Apt/CTD-STS/NL), aiming to enhance tumor targeting, improve bioavailability, and reduce the systemic toxicity of both drugs.
Methods: We constructed aptamer-guided co-delivery nanoliposomes encapsulating CTD and STS (Apt/CTD-STS/NL). The targeted delivery efficiency, synergistic antitumor efficacy, and biocompatibility of this nanosystem were comprehensively evaluated through both in vitro and in vivo experiments.
Results: Apt/CTD-STS/NL achieved approximately 1.3-fold higher cellular uptake in HCC cells compared to non-targeted liposomes in vitro. In vivo, it demonstrated superior tumor accumulation. In a murine HCC model, Apt/CTD-STS/NL exhibited the strongest tumor growth inhibition (79.50 ± 4.39%), significantly outperforming free CTD, STS, or single-drug loaded liposomes. Mechanistic studies revealed that the core synergy between CTD and STS enabled simultaneous inhibition of the key oncoproteins mTOR, HIF-1α, and VEGF, thereby disrupting tumor proliferation, survival, and angiogenesis.
Conclusion: This study demonstrates a novel targeted nanoplatform that combines an active ingredient from traditional Chinese medicine with a modern kinase inhibitor. This strategy achieves a synergistic anti-HCC effect through multi-pathway inhibition and offers a promising approach for cancer therapy with enhanced efficacy and reduced toxicity.
Keywords: cantharidin, staurosporine, aptamer, drug co-delivery, hepatocellular carcinoma