Efficient production and enhanced tumor delivery of engineered extracellular vesicles.
Efficient production and enhanced tumor delivery of engineered extracellular vesicles.
复制标题
DOI：
10.1016/j.biomaterials.2016.07.003
复制
发表时间：
2016-10
期刊：
影响因子：
14
通讯作者：
Pavlakis GN
中科院分区：
文献类型：
--
作者：
Watson DC;Bayik D;Srivatsan A;Bergamaschi C;Valentin A;Niu G;Bear J;Monninger M;Sun M;Morales-Kastresana A;Jones JC;Felber BK;Chen X;Gursel I;Pavlakis GN
细胞外囊泡（EV），包括外泌体和微囊泡，是参与多种生理过程的纳米级细胞间通讯工具。由于它们的生物学特性，它们也是全身递送治疗性化合物如细胞因子、化疗药物、siRNA和病毒载体的有希望的候选物。然而，低EV生产率和通过肝巨噬细胞快速清除施用的EV限制了它们作为治疗媒介物的潜在用途。我们已经使用中空纤维生物反应器来有效生产具有异二聚体细胞因子复合物白细胞介素-15：白细胞介素-15受体α的生物活性EV。与常规细胞培养相比，生物反应器培养产生约40倍的EV/mL条件培养基。生物物理学分析和比较蛋白质组学表明，在生物反应器制备的EV更多样化的人口，而血清蛋白质污染物仅在传统的文化EV制剂检测。我们还确定了清道夫受体A类家族（SR-A）作为一种新的单核细胞/巨噬细胞摄取受体的EV。用硫酸葡聚糖体内阻断SR-A显著降低了小鼠EV肝脏清除率，同时增强了肿瘤蓄积。这些发现促进了EV治疗方法的发展。
Extracellular vesicles (EV), including exosomes and microvesicles, are nano-sized intercellular communication vehicles that participate in a multitude of physiological processes. Due to their biological properties, they are also promising candidates for the systemic delivery of therapeutic compounds, such as cytokines, chemotherapeutic drugs, siRNAs and viral vectors. However, low EV production yield and rapid clearance of administered EV by liver macrophages limit their potential use as therapeutic vehicles. We have used a hollow-fiber bioreactor for the efficient production of bioactive EV bearing the heterodimeric cytokine complex Interleukin-15:Interleukin-15 receptor alpha. Bioreactor culture yielded ~40-fold more EV per mL conditioned medium, as compared to conventional cell culture. Biophysical analysis and comparative proteomics suggested a more diverse population of EV in the bioreactor preparations, while serum protein contaminants were detectable only in conventional culture EV preparations. We also identified the Scavenger Receptor Class A family (SR-A) as a novel monocyte/macrophage uptake receptor for EV. In vivo blockade of SR-A with dextran sulfate dramatically decreased EV liver clearance in mice, while enhancing tumor accumulation. These findings facilitate development of EV therapeutic methods.
登录
查看更多内容
DOI：
10.1016/j.jconrel.2014.12.013
发表时间：
2015-02-10
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Smyth T;Kullberg M;Malik N;Smith-Jones P;Graner MW;Anchordoquy TJ
通讯作者：
Anchordoquy TJ
影响因子：
46.9
作者：
Alvarez-Erviti, Lydia;Seow, Yiqi;Wood, Matthew J. A.
通讯作者：
Wood, Matthew J. A.
影响因子：
14
作者：
Gyoergy, Bence;Fitzpatrick, Zachary;Crommentuijn, Matheus H. W.;Mu, Dakai;Maguire, Casey A.
通讯作者：
Maguire, Casey A.
外泌体作为帕金森氏病疗法的药物。
DOI：
10.1016/j.jconrel.2015.03.033
发表时间：
2015-06-10
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Haney MJ;Klyachko NL;Zhao Y;Gupta R;Plotnikova EG;He Z;Patel T;Piroyan A;Sokolsky M;Kabanov AV;Batrakova EV
通讯作者：
Batrakova EV
影响因子：
16
作者：
Imai T;Takahashi Y;Nishikawa M;Kato K;Morishita M;Yamashita T;Matsumoto A;Charoenviriyakul C;Takakura Y
通讯作者：
Takakura Y