Theranostics 2019; 9(2):355-368. doi:10.7150/thno.29137

Research Paper

Chemotherapy priming of the Pancreatic Tumor Microenvironment Promotes Delivery and Anti-Metastasis Efficacy of Intravenous Low-Molecular-Weight Heparin-Coated Lipid-siRNA Complex

Qianwen Yu, Yue Qiu, Xiaoxiao Chen, Xuhui Wang, Ling Mei, Haiyao Wu, Kai Liu, Yayuan Liu, Man Li, Zhirong Zhang, Qin He

Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041, China

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Citation:
Yu Q, Qiu Y, Chen X, Wang X, Mei L, Wu H, Liu K, Liu Y, Li M, Zhang Z, He Q. Chemotherapy priming of the Pancreatic Tumor Microenvironment Promotes Delivery and Anti-Metastasis Efficacy of Intravenous Low-Molecular-Weight Heparin-Coated Lipid-siRNA Complex. Theranostics 2019; 9(2):355-368. doi:10.7150/thno.29137. Available from http://www.thno.org/v09p0355.htm

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a type of malignant tumor with high lethality. Its high tumor cell-density and large variety of extracellular matrix (ECM) components present major barriers for drug delivery.

Methods: Paclitaxel-loaded PEGylated liposomes (PTX-Lip) were used as a tumor-priming agent to induce tumor cell apoptosis and decrease the abundance of ECM to promote cellular uptake and tumor delivery of nanodrugs. Paclitaxel exerts anti-cancer effects but, paradoxically, exacerbates cancer metastasis and drug resistance by increasing the expression of apoptotic B-cell lymphoma-2 protein (BCL-2). Thus, low-molecular-weight heparin-coated lipid-siRNA complex (LH-Lip/siBCL-2) was constructed to inhibit cancer metastasis and silence BCL-2 by BCL-2 siRNA (siBCL-2).

Results: Significant tumor growth inhibition efficacy was observed, accompanied by obvious inhibition of cancer metastasis in vivo.

Conclusion: These results suggested our sequential delivery of PTX-Lip and LH-Lip/siBCL-2 might provide a practical approach for PDAC or other ECM-rich tumors.

Keywords: pancreatic cancer, tumor priming, low-molecular-weight heparin, chemo-gene therapy, metastasis