International Journal of Nanomedicine (Oct 2022)
A Novel Dextran-Based Dual Drug Conjugate Targeted Tumors with High Biodistribution Ratio of Tumors to Normal Tissues
Abstract
Jiaojiao Liu,1 Naining Zhang,1 Jiaan Wu,1 Peng Dong,1 Hongshuai Lv,1 Qi Wang,1 Shenxu Wang,1 Haotong Yang,1 Si Wang,2 Xiaohai Li,2 Jinghua Hu,2 Anny Wang,2 Daisy J Li,2 Yikang Shi1 1National Glycoengineering Research Center, Shandong Key Laboratory of Carbohydrate Chemistry and Glycobiology, NMPA Key Laboratory for Quality Research and Evaluation of Carbohydrate Based Medicine, Shandong University, Qingdao, Shandong, 266237, People’s Republic of China; 2Santolecan Pharmaceuticals LLC, Jupiter, Florida, 33458, USACorrespondence: Yikang Shi, Shandong University, 72 Binhai Road, Jimo, Qingdao, 266237, People’s Republic of China, Tel/Fax +86-532-5863-1418, Email [email protected]: Most chemotherapeutic agents possess poor water solubility and show more significant accumulations in normal tissues than in tumor tissues, resulting in serious side effects. To this end, a novel dextran-based dual drug delivery system with high biodistribution ratio of tumors to normal tissues was developed.Methods: A bi-functionalized dextran was developed, and several negatively charged dextran-based dual conjugates containing two different types of drugs, docetaxel and docosahexaenoic acid (DTX and DHA, respectively) were synthesized. The structures of these conjugates were characterized using nuclear magnetic resonance and liquid chromatography/mass spectrometry (1H-NMR and LC/MS, respectively) analysis. Cell growth inhibition, apoptosis, cell cycle distribution, and cellular uptake were measured in vitro. Drug biodistribution and pharmacokinetics were investigated in mice bearing 4T1 tumors using LC/MS analysis. Drug biodistribution was also explored by in vivo imaging. The effects of these conjugates on tumor growth were evaluated in three mice models.Results: The dextran–docosahexaenoic acid (DHA)– docetaxel (DTX) conjugates caused a significant enhancement of DTX water solubility and improvement in pharmacokinetic characteristics. The optimized dextran–DHA–DTX conjugate A treatment produced a 2.1- to 15.5-fold increase in intra-tumoral DTX amounts for up to 96 h compared to parent DTX treatment. Meanwhile, the concentrations of DTX released from conjugate A in normal tissues were much lower than those of the parent DTX. This study demonstrated that DHA could lead to an improvement in the efficacy of the conjugates and that the conjugate with the shortest linker displayed more activity than conjugates with longer linkers. Moreover, conjugate A completely eradicated all MCF-7 xenograft tumors without causing any obvious side effects and totally outperformed both the conventional DTX formulation and Abraxane in mice.Conclusion: These dextran-based dual drug conjugates may represent an innovative tumor targeting drug delivery system that can selectively deliver anticancer agents to tumors.Keywords: docetaxel, dextran, docosahexaenoic acid, nanoparticle, tumor, chemotherapy
