Acetal-modified dextran microparticles with controlled degradation kinetics and surface functionality for gene delivery in phagocytic and non-phagocytic cells.
Acetal-modified dextran microparticles with controlled degradation kinetics and surface functionality for gene delivery in phagocytic and non-phagocytic cells.
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DOI：
10.1002/adma.201000307
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发表时间：
2010-08-24
影响因子：
29.4
通讯作者：
Frechet, Jean M. J.
中科院分区：
文献类型：
--
作者：
Cohen, Joel A.;Beaudette, Tristan T.;Cohen, Jessica L.;Brooders, Kyle E.;Bachelder, Eric M.;Frechet, Jean M. J.
在体内控制遗传物质的细胞内递送用于疫苗或其他治疗应用仍然是非病毒递送系统的主要挑战。[1,2]作为一种替代阳离子聚合物和脂质，通常用于在体外质粒转染中形成纳米级复合物，[3-6]由可生物降解聚合物（如聚乳酸-羟基乙酸酯）（PLGA）和酸敏感聚邻位酯（poe）和水凝胶)制成的微颗粒已被用作体内质粒DNA载体。[6-9]由于它们的大小（通常为1-10 μm），这些颗粒被动地靶向免疫系统的吞噬抗原呈递细胞（APCs），用于DNA疫苗的应用此外，这些颗粒可以减轻阳离子聚合物和脂质在体内靶向、毒性和稳定性方面的缺点尽管前景很好，但迄今为止探索的微颗粒输送系统通常会出现超过50%的被封装质粒不受控制的初始爆发释放，这与任何内置的触发释放机制都没有关系，因此很难在特定刺激下实现快速而可控的释放此外，迄今为止，很少有报道试图将这些系统的应用扩展到非吞噬细胞，这些细胞在全身的数量要大得多。在这里，我们报告了一种可调的模块化质粒传递系统，我们假设，它将克服这些问题，同时允许系统地研究转染效率对各种配方参数的依赖，包括降解动力学，阳离子混合聚合物的使用，以及转染非吞噬细胞的表面功能化。我们最近开发了一种基于缩醛修饰葡聚糖（Ac-DEX，图1a）的酸敏感递送系统，[11]是一种疏水聚合物，可以很容易地加工成微粒，这可能解决上述递送问题。Ac-DEX的独特之处在于，它可以通过改变聚合物主链上快速水解的无环缩醛与缓慢水解的环缩醛的比例来控制可调的降解速率在内体条件下（pH 5），颗粒降解率可以在几分钟到几天的时间内调节。水解降解后，Ac-DEX可以还原为fda批准的葡聚糖，而不会产生酸性副产物
Controlled intracellular delivery of genetic material for vaccine or other therapeutic applications in vivo remains a major challenge for non-viral delivery systems.[1, 2] As an alternative to cationic polymers and lipids commonly used to form nano-scale complexes for in vitro plasmid transfection,[3–6] microparticles made from biodegradable polymers such as poly (lactide-co-glycolide)(PLGA) and acid-sensitive poly (ortho esters)(POEs) and hydrogels have been pursued as in vivo plasmid DNA carriers.[6–9] Due to their size (typically 1–10 μm), these particles passively target phagocytic antigen presenting cells (APCs) of the immune system for DNA vaccine applications.[8] In addition, these particles may alleviate the shortcomings of cationic polymers and lipids with regard to in vivo targeting, toxicity, and stability.[3] Despite their promise, microparticulate delivery systems explored to date often suffer from uncontrolled initial burst release of upwards of 50% of the encapsulated plasmid, independent of any built-in triggered-release mechanism, making it difficult to achieve rapid yet controlled release in response to a specific stimulus.[10] Furthermore, there have been few reports to date of attempts to extend the application of these systems to target non-phagocytic cells, which are present in much greater quantity throughout the body. Herein we report a tunable and modular microparticle system for plasmid delivery that, we hypothesized, would overcome these problems and simultaneously allow the systematic study of the dependence of transfection efficiency on various formulation parameters including degradation kinetics, use of cationic blend polymers, and surface functionalization for the transfection of non-phagocytic cells.We recently developed an acid-sensitive delivery system based on acetal-modified dextran (Ac-DEX, Figure 1a),[11] a hydrophobic polymer that can be readily processed into microparticles, which may address the delivery issues described above. Ac-DEX is unique in its ability to provide a tunable degradation rate that is readily controlled by varying the ratio of faster-hydrolyzing acyclic acetals to slower-hydrolyzing cyclic acetals on the polymer backbone.[12] Particle degradation rates can be tuned over the course of minutes to days under endosomal conditions (pH 5). Upon hydrolytic degradation, Ac-DEX reverts back to FDA-approved dextran without the generation of acidic byproducts, which could
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影响因子：
10.8
作者：
Little, SR;Lynn, DM;Langer, R
通讯作者：
Langer, R
影响因子：
3.8
作者：
Adami, RC;Collard, WT;Rice, KG
通讯作者：
Rice, KG
DOI：
10.1073/pnas.0901592106
发表时间：
2009-04-07
影响因子：
11.1
作者：
Broaders, Kyle E.;Cohen, Joel A.;Frechet, Jean M. J.
通讯作者：
Frechet, Jean M. J.
影响因子：
3.8
作者：
Fu, K;Harrell, R;Langer, R
通讯作者：
Langer, R
影响因子：
3.9
作者：
Zhang, Xue-Qing;Intra, Janjira;Salem, Aliasger K.
通讯作者：
Salem, Aliasger K.