Combinatorial synthesis of chemically diverse core-shell nanoparticles for intracellular delivery
Combinatorial synthesis of chemically diverse core-shell nanoparticles for intracellular delivery
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DOI：
10.1073/pnas.1106379108
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发表时间：
2011-08-09
影响因子：
11.1
通讯作者：
Anderson, Daniel G.
中科院分区：
文献类型：
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作者：
Siegwart, Daniel J.;Whitehead, Kathryn A.;Anderson, Daniel G.
与装配线类似，我们采用模块化设计对 1,536 种具有阳离子核和可变壳的结构不同的纳米颗粒进行高通量研究。这使得能够阐明复杂性、内化和交付趋势，而这些趋势只能通过评估大型图书馆来了解。使用机器人自动化，环氧化物官能化嵌段聚合物与多种胺库组合交联，然后测量分子量、直径、RNA 络合、细胞内化以及体外 siRNA 和 pDNA 递送。分析揭示了结构-功能关系和有益的设计指南，包括更高的反应性嵌段重量分数、环氧化物和胺之间的化学计量当量以及薄亲水壳。交联剂最好具有叔二甲胺或哌嗪基团和潜在的缓冲能力。共价胆固醇附着允许在体内转染至小鼠的肝细胞。调节核和壳化学性质的能力可以使这些材料在其他应用中发挥作用。
Analogous to an assembly line, we employed a modular design for the high-throughput study of 1,536 structurally distinct nanoparticles with cationic cores and variable shells. This enabled elucidation of complexation, internalization, and delivery trends that could only be learned through evaluation of a large library. Using robotic automation, epoxide-functionalized block polymers were combinatorially cross-linked with a diverse library of amines, followed by measurement of molecular weight, diameter, RNA complexation, cellular internalization, and in vitro siRNA and pDNA delivery. Analysis revealed structure-function relationships and beneficial design guidelines, including a higher reactive block weight fraction, stoichiometric equivalence between epoxides and amines, and thin hydrophilic shells. Cross-linkers optimally possessed tertiary dimethylamine or piperazine groups and potential buffering capacity. Covalent cholesterol attachment allowed for transfection in vivo to liver hepatocytes in mice. The ability to tune the chemical nature of the core and shell may afford utility of these materials in additional applications.