Poly(2-oxazoline) block copolymer based formulations of taxanes: effect of copolymer and drug structure, concentration, and environmental factors
Poly(2-oxazoline) block copolymer based formulations of taxanes: effect of copolymer and drug structure, concentration, and environmental factors
复制标题
DOI：
10.1002/pat.3556
复制
发表时间：
2015-07-01
影响因子：
3.4
通讯作者：
Kabanov, Alexander V.
中科院分区：
文献类型：
--
作者：
Seo, Youngee;Schulz, Anita;Kabanov, Alexander V.
目前许多紫杉烷的纳米配方受到低载药能力和不利的物理化学特性（如大颗粒尺寸（bbb100纳米）和/或低尺寸均匀性）的阻碍。我们之前已经报道了基于聚（2-恶唑啉）聚合物胶束的紫杉烷纳米配方，该配方显示出极高的紫杉烷负载能力（bbb40 %w/w）和小于50nm的粒径。以前的工作是基于聚（2-丁基-2-恶唑啉）作为疏水嵌段和聚（2-甲基-2-恶唑啉）作为亲水嵌段的三嵌段共聚物。本文探讨了各种配方参数的影响，如：(1)药物和聚合物结构；（ii）药物和聚合物的浓度；（三）水介质的组成对所得配方的增溶行为和理化性质的影响。此外，体外抗肿瘤活性也有报道。尽管疏水性、极性或在疏水性核心中添加芳香残基有许多变化，但具有聚（2-丁基-2-恶唑啉）嵌段的三嵌段共聚物仍然是具有最高载药能力的聚合物。值得注意的是，该配方易于扩展，具有不受影响的封装效率、负载能力和物理化学性质。紫杉烷制剂在水、盐水和葡萄糖溶液中储存1-2周后是稳定的，并且可以在不影响制剂性质的情况下进行冻干和再分散。此外，稀释后胶束仍保持稳定。负载药物的聚（2-恶唑啉）胶束对多种癌细胞具有高毒性。总之，这些结果强调了聚（2-恶唑啉）胶束作为紫杉烷和其他可能的疏水性药物的配方赋形剂的潜力。版权所有：John Wiley & Sons， Ltd
Many current nanoformulations of taxanes are hampered by low drug-loading capacity and unfavorable physicochemical characteristics such as large particles size (>100nm) and/or low size uniformity. We have previously reported on taxane nanoformulations, based on poly(2-oxazoline) polymeric micelles that display an extremely high taxane loading capacity (>40%w/w) and particle size below 50nm. Previous work was based on a triblock copolymer having poly(2-butyl-2-oxazoline) as the hydrophobic block and poly(2-methyl-2-oxazoline) as the hydrophilic blocks. This paper explores the effects of various formulation parameters such as (i) the drug and polymer structure; (ii) the drug and polymer concentration; and (iii) the composition of aqueous medium on the solubilization behavior and physicochemical properties of the resulting formulations. In addition, in vitro anticancer activity is reported. Despite numerous variations of the hydrophobicity, polarity or addition of aromatic residues in the hydrophobic core, the triblock copolymer with the poly(2-butyl-2-oxazoline) block remains the polymer with the highest drug-loading capacity. Notably, the formulation was easily scalable with uncompromised encapsulation efficacy, loading capacity, and physicochemical properties. The taxane formulations were stable upon storage (water, saline, and dextrose solution) for 1-2weeks and could be lyophilized and re-dispersed without compromising the formulation properties. Furthermore, the micelles remained stable upon dilution. The drug-loaded poly(2-oxazoline) micelles showed high toxicity against several cancer cell lines. Taken together, these results underscore the potential of poly(2-oxazoline) micelles as formulation excipient for taxanes and possibly other hydrophobic drugs. Copyright (c) 2015 John Wiley & Sons, Ltd.