Rational design of multimodal therapeutic nanosystems for effective inhibition of tumor growth and metastasis. (1st September 2018)

• Record Type: Journal Article
• Authors: Wang, Feihu; Huang, Qian; Wang, Yun; Zhang, Wenjun; Lin, Ran; Yu, Yanna; Shen, Yuanyuan; Cui, Honggang; Guo, Shengrong
• Is Part Of: Acta biomaterialia. Volume 77(2018)
• Page Start: 240
• Page End: 254
• Publication Date: 2018-09-01
• Subjects: DOX doxorubicin -- GNRs gold nanorods -- PEI polyethylenimine -- DSPEI disulfide cross-linked short polyethylenimines -- DG DSPEI-GNR -- RDG RGD-PEG-DSPEI-GNR -- RPG RGD-PEG-PEI-25 kDa-GNR -- RDG@DOX DOX-tethered RDG -- LA α-lipoic acid -- NF-κB nuclear factor-kappa B -- VEGF vascular endothelial growth factor -- MMPs matrix metalloproteinases -- RNAi RNA interference -- EB ethidium bromide -- GSH-OEt glutathione reduced ethyl ester -- GSH l-glutathione -- FBS fetal bovine serum -- DMEM Dulbecco's modified Eagle medium -- HMVEC human microvascular endothelial cells -- HRMS high resolution mass spectra -- CLSM confocal laser scanning microscope -- H&E hematoxylin and eosin -- IHC immunohistochemical -- EPR enhanced permeability and retention -- NSET nanosurface energy transfer -- PA photoacoustic; Gold nanorods -- Stimuli-responsive -- Combined therapy -- Tumor growth -- Cancer metastasis; Biomedical materials -- Periodicals; 610.28
• DOI: 10.1016/j.actbio.2018.07.025
• Languages: English
• ISSNs: 1742-7061

Abstract

Graphical abstract: Abstract: Simultaneous inhibition of both tumor growth and metastasis is the key to treating metastatic cancer, yet the development of effective drug delivery systems represents a great challenge since multimodal therapeutic agents must be rationally combined to overcome the biological mechanisms underpinning tumor cell proliferation and invasion. In this context, we report a hybrid therapeutic nanoscale platform that incorporates an anti-proliferative drug, doxorubicin (DOX), and an anti-NF-κB agent, p65-shRNA, for effective treatment of metastatic breast cancer. In our design, we first conjugated DOX via an acid-labile linker onto gold nanorods that were pre-modified with the tumor targeting peptide RGD and a positively charged, disulfide cross-linked short polyethylenimines (DSPEI), and then incorporated shRNA through electrostatic complexation with DSPEI. We show that this "all in one" nanotherapeutic system (RDG/shRNA@DOX) can be effectively internalized through RGD-mediated endocytosis, followed by stimuli-responsive intracellular co-release of DOX and shRNA. Our in vitro experiments suggest that this multimodal system can significantly inhibit cell proliferation, angiogenesis, and invasion of metastatic MDA-MB-435 cancer cells. Systemic administration of RDG/shRNA@DOX into a metastatic mouse model led to enhanced tumor accumulation, and, most importantly, significant inhibition of in situ tumor growth and almost complete suppression of tumor metastasis. We believe this hybrid multimodal nanotherapeutic system provides important insight into the rational design of therapeutic systems for the effective treatment of metastatic carcinoma. Statement of Significance: The key to successfully treat metastatic cancer is the simultaneous inhibition of both tumor growth and metastasis. This represents a great challenge for the design of drug delivery systems since multimodal therapeutic agents must be rationally combined to overcome the respective biological mechanisms underpinning tumor cell proliferation and invasion. Toward this end, we developed a hybrid nanomedicine platform that incorporates an anti-proliferative drug, doxorubicin (DOX), and an anti-NF-κB agent, p65-shRNA, for effective treatment of metastatic breast cancer. We showed that this multimodal system (RDG/shRNA@DOX) enhanced tumor accumulation, led to prolonged circulation, and most importantly, significant inhibition of in situ tumor growth and almost complete suppression of tumor metastasis. We believe this hybrid multimodal nanotherapeutic system provides significant insight into the rational design of therapeutic systems for the effective treatment of metastatic cancer.