Cetuximab-Modified Human Serum Albumin Nanoparticles Co-Loaded with Doxorubicin and MDR1 siRNA for the Treatment of Drug-Resistant Breast Tumors

Abstract

Xin Yang,1– 3 Yifan Wang,1– 3 Si Chen,1– 3 Shuang Zhang,1– 3 Chunying Cui1– 3 1School of Pharmaceutical Sciences, Capital Medical University, Beijing, 100069, People’s Republic of China; 2Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Beijing, 100069, People’s Republic of China; 3Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Beijing, 100069, People’s Republic of ChinaCorrespondence: Chunying Cui; Shuang ZhangDepartment of Pharmaceutics, School of Pharmaceutical Science, Capital Medical University, No. 10 Youanmenwai Street, Fengtai, Beijing, 100069, People’s Republic of ChinaTel/Fax [phone]Email [email protected]; [email protected]: Breast cancer is the most prevalent cancer among women. Doxorubicin (DOX) is a common chemotherapeutic drug used to treat many different cancers. However, multidrug resistance limits the treatment of breast cancer. MDR1 siRNA (siMDR1) combinatorial therapy has attracted significant attention as a breakthrough therapy for multidrug resistance in tumors. However, naked siRNA is easily degraded by enzymatic hydrolysis requiring an siRNA carrier for its protection. Human serum albumin (HSA) was selected as the carrier due to its excellent biocompatibility, non-toxicity, and non-immunogenicity. Cetuximab was used to modify the HSA nanoparticles in order to target the tumor tissues.Methods: This study used a central composite design response surface methodology (CCD-RSM) to investigate the optimal formula for HSA NPs preparation. Cex-HSA/DOX/MDR1 siRNA (C-H/D/M) was characterized by dynamic light scattering and transmission electron microscopy. The efficacy of C-H/D/M tumor growth inhibitory activity was investigated in vitro and in vivo using confocal imaging, MTT assay, and an MCF-7/ADR tumor-bearing mice model. RT–qPCR, ELISA analysis, and flow cytometry were used to investigate the in vitro antitumor mechanisms of C-H/D/M.Results: The diameter and PDI of the C-H/D/M were 173.57 ± 1.30 nm and 0.027 ± 0.004, respectively. C-H/D/M promoted and maintained the sustained release and the uptake of DOX significantly. After transfection, the MDR1 mRNA and P-gp expression levels were down-regulated by 44.31 ± 3.6% (P < 0.01) and 38.08 ± 2.4% (P < 0.01) in an MCF-7/ADR cell line. The fluorescent images of the treated BALB/c nude mice revealed that C-H/D/M achieved targeted delivery of siMDR1 and DOX into the tumor tissue. The in vivo tumor inhibition results demonstrated that the tumor inhibition rate of the C-H/D/M treated group was 54.05% ± 1.25%. The biosafety results indicated that C-H/D/M did not induce significant damages to the main organs in vivo.Conclusion: C-H/D/M can be used as an ideal non-viral tumor-targeting vector to overcome MDR and enhance the antitumor effect.Keywords: human serum albumin, HSA, multidrug resistance, MDR, co-delivery carrier, small interfere RNA, gene silencing

Keywords

• human serum albumin
• hsa
• multidrug resistance
• mdr
• co-delivery carrier
• small interfere rna
• gene silencing