Effects of block copolymer properties on nanocarrier protection from in vivo clearance.
Effects of block copolymer properties on nanocarrier protection from in vivo clearance.
复制标题
块共聚物特性对纳米载体保护免受体内清除的影响。
DOI：
10.1016/j.jconrel.2012.06.020
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发表时间：
2012-08-20
期刊：
影响因子：
--
通讯作者：
Prud'homme RK
中科院分区：
文献类型：
--
作者：
D'Addio SM;Saad W;Ansell SM;Squiers JJ;Adamson DH;Herrera-Alonso M;Wohl AR;Hoye TR;Macosko CW;Mayer LD;Vauthier C;Prud'homme RK
免疫系统对药物纳米载体的清除必须最小化，以实现对病理组织的靶向递送。人们对寻找能够预测体内清除结果的体外试验非常感兴趣。在这项工作中，我们在快速沉淀过程中通过嵌段共聚物定向组装产生具有密集PEG层的纳米载体。纳米载体的嵌段共聚物由疏水嵌段的聚苯乙烯（PS）、聚-ε-己内酯（PCL）、聚- d、l -丙交酯（PLA）或聚-丙交酯-共聚物（PLGA）和亲水嵌段的聚乙二醇（PEG）组成，分子量为1.5 kg/mol至9 kg/mol。我们在Foxn1nu小鼠体内评估了含有紫杉醇前药的纳米载体，以确定其相对清除率。根据嵌段共聚物的不同，4小时后纳米载体的循环量从初始剂量的10%到85%不等。体外补体活化试验是为了将纳米载体表面的保护与补体结合、活化和体内循环联系起来。本文提出了优化嵌段共聚物结构的指导方针，以最大限度地提高通过快速沉淀和定向组装形成的纳米载体的循环，涉及亲水和疏水嵌段的相对尺寸、锚定嵌段的疏水性、PEG嵌段的绝对尺寸和聚合物结晶度。体外实验结果区分了循环不良的PEG5k-PCL9k和循环较好的纳米载体，但不能按循环时间对循环较好的纳米载体进行排序。对单分散200 nm乳胶球上聚乙二醇表面堆积的分析表明，疏水性PCL、PS和PLA块的大小与聚乙二醇团的大小有关，可能与循环间隙有关。对下一步的体外测定提出了建议。
Drug nanocarrier clearance by the immune system must be minimized to achieve targeted delivery to pathological tissues. There is considerable interest in finding in vitro tests that can predict in vivo clearance outcomes. In this work, we produce nanocarriers with dense PEG layers resulting from block copolymer-directed assembly during rapid precipitation. Nanocarriers are formed using block copolymers with hydrophobic blocks of polystyrene (PS), poly-ε-caprolactone (PCL), poly-D,L-lactide (PLA), or poly-lactide-co-glycolide (PLGA), and hydrophilic blocks of polyethylene glycol (PEG) with molecular weights from 1.5 kg/mol to 9 kg/mol. Nanocarriers with paclitaxel prodrugs are evaluated in vivo in Foxn1nu mice to determine relative rates of clearance. The amount of nanocarrier in circulation after 4 h varies from 10% to 85% of initial dose, depending on the block copolymer. In vitro complement activation assays are conducted in an effort to correlate the protection of the nanocarrier surface from complement binding and activation and in vivo circulation. Guidelines for optimizing block copolymer structure to maximize circulation of nanocarriers formed by rapid precipitation and directed assembly are proposed, relating to the relative size of the hydrophilic and hydrophobic block, the hydrophobicity of the anchoring block, the absolute size of the PEG block, and polymer crystallinity. The in vitro results distinguish between the poorly circulating PEG5k-PCL9k and the better circulating nanocarriers, but could not rank the better circulating nanocarriers in order of circulation time. Analysis of PEG surface packing on monodisperse 200 nm latex spheres indicates that the sizes of the hydrophobic PCL, PS, and PLA blocks are correlated with the PEG blob size, and possibly the clearance from circulation. Suggestions for next step in vitro measurements are made.
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