Rational design of multimodal therapeutic nanosystems for effective inhibition of tumor growth and metastasis
Rational design of multimodal therapeutic nanosystems for effective inhibition of tumor growth and metastasis
复制标题
合理设计多模式治疗纳米系统，有效抑制肿瘤生长和转移
DOI：
10.1016/j.actbio.2018.07.025
复制
发表时间：
2018-09-01
影响因子：
9.7
通讯作者：
Guo, Shengrong
中科院分区：
文献类型：
--
作者：
Wang, Feihu;Huang, Qian;Guo, Shengrong
同时抑制肿瘤生长和转移是治疗转移性癌症的关键，但开发有效的药物传递系统是一项巨大的挑战，因为多种治疗药物必须合理组合，以克服肿瘤细胞增殖和侵袭的生物学机制。在此背景下，我们报道了一种混合治疗纳米级平台，该平台结合了抗增殖药物阿霉素（DOX）和抗nf - κ B药物p65-shRNA，可有效治疗转移性乳腺癌。在我们的设计中，我们首先通过酸不稳定的连接剂将DOX偶联到用肿瘤靶向肽RGD和带正电荷的二硫交联短聚亚胺（DSPEI）预先修饰的金纳米棒上，然后通过与DSPEI的静电络合将shRNA纳入其中。我们表明，这种“all in one”纳米治疗系统（RDG/shRNA@DOX）可以通过rgd介导的内吞作用有效地内化，随后是刺激反应性的DOX和shRNA在细胞内的共同释放。我们的体外实验表明，这种多模式系统可以显著抑制转移性MDA-MB-435癌细胞的细胞增殖、血管生成和侵袭。在转移性小鼠模型中全身给药RDG/shRNA@DOX导致肿瘤积累增强，最重要的是，显著抑制原位肿瘤生长，几乎完全抑制肿瘤转移。我们相信这种混合多模态纳米治疗系统为有效治疗转移性癌的治疗系统的合理设计提供了重要的见解。成功治疗转移性肿瘤的关键是同时抑制肿瘤生长和转移。这对药物传递系统的设计是一个巨大的挑战，因为必须合理地组合多模式治疗药物，以克服各自的生物学机制，支持肿瘤细胞增殖和侵袭。为此，我们开发了一种混合纳米药物平台，该平台结合了抗增殖药物阿霉素（DOX）和抗nf - κ B药物p65-shRNA，用于有效治疗转移性乳腺癌。我们发现，这种多模式系统（RDG/shRNA@DOX）增强了肿瘤积累，延长了循环，最重要的是，显著抑制了原位肿瘤生长，几乎完全抑制了肿瘤转移。我们相信这种混合多模态纳米治疗系统为有效治疗转移性癌症的治疗系统的合理设计提供了重要的见解。(C) 2018材料学报Elsevier Ltd.出版。版权所有。
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-kappa B 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 SignificanceThe 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-kappa B 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. (C) 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.