Poly(2-oxazoline) based micelles with high capacity for 3rd generation taxoids: preparation, in vitro and in vivo evaluation.
Poly(2-oxazoline) based micelles with high capacity for 3rd generation taxoids: preparation, in vitro and in vivo evaluation.
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DOI：
10.1016/j.jconrel.2015.02.024
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发表时间：
2015-06-28
期刊：
影响因子：
--
通讯作者：
Luxenhofer R
中科院分区：
文献类型：
--
作者：
He Z;Schulz A;Wan X;Seitz J;Bludau H;Alakhova DY;Darr DB;Perou CM;Jordan R;Ojima I;Kabanov AV;Luxenhofer R
临床上和商业上成功的紫杉烷，紫杉醇和多西他赛具有两个主要缺点，即它们非常低的水溶性和产生耐药性的风险。在这里，我们提出了一种方法，以一种非常简单的方式克服这两个缺点。我们配制了第三代紫杉烷，能够避免常见的耐药机制与双两亲性聚（2-恶唑啉）（POx），一种安全和高效的聚合物，用于配制极其疏水的药物。我们发现，无论药物的化学结构如何，不同的第三代紫杉烷都具有优异的增溶作用，基本上定量载药量和最终药物与聚合物的比例约为1。流体动力学直径小于100 nm的小的高负载胶束非常适合肠胃外给药。此外，具有紫杉烷SB-T-1214的选定制剂在多药耐药乳腺癌细胞系LCC 6-MDR中的体外活性比紫杉醇高约一到两个数量级。相反，在野生型LCC 6中，没有观察到差异。使用q4 d x 4给药方案，我们还发现POx/SB-T-1214显著抑制LCC 6-MDR正交各向异性肿瘤的生长，优于商业紫杉醇药物Taxol和Cremophor EL配制的SB-T-1214。
The clinically and commercially successful taxanes, paclitaxel and docetaxel suffer from two major drawbacks, namely their very low aqueous solubility and the risk of developing resistance. Here, we present a method that overcomes both drawbacks in a very simple manner. We formulated 3rd generation taxoids, able to avoid common drug resistance mechanisms with doubly amphiphilic poly(2-oxazoline)s (POx), a safe and highly efficient polymer for the formulation of extremely hydrophobic drugs. We found excellent solubilization of different 3rd generation taxoids irrespective of the drug's chemical structures with essentially quantitative drug loading and final drug to polymer ratios around unity. The small, highly loaded micelles with a hydrodynamic diameter of less than 100 nm are excellently suited for parenteral administration. Moreover, a selected formulation with the taxoid SB-T-1214 is about one to two orders of magnitude more active in vitro than paclitaxel in the multidrug resistant breast cancer cell line LCC6-MDR. In contrast, in wild-type LCC6, no difference was observed. Using a q4d x 4 dosing regimen, we also found that POx/SB-T-1214 significantly inhibits the growth of LCC6-MDR orthotropic tumors, outperforming commercial paclitaxel drug Taxol and Cremophor EL formulated SB-T-1214.
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DOI：
10.1016/j.jconrel.2011.04.010
发表时间：
2011-07-15
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Luxenhofer R;Sahay G;Schulz A;Alakhova D;Bronich TK;Jordan R;Kabanov AV
通讯作者：
Kabanov AV
影响因子：
10.8
作者：
Gaertner, Florian C.;Luxenhofer, Robert;Essler, Markus
通讯作者：
Essler, Markus
影响因子：
8.8
作者：
Leonessa, F;Green, D;Licht, T;Wright, A;WingateLegette, K;Lippman, J;Gottesman, MM;Clarke, R
通讯作者：
Clarke, R
影响因子：
120.1
作者：
Galsky, Matthew D.;Dritselis, Argyris;Oh, William K.
通讯作者：
Oh, William K.
DOI：
10.1073/pnas.1212826109
发表时间：
2012-12-04
影响因子：
11.1
作者：
Huang, Mia L.;Ehre, David;Ward, Michael D.
通讯作者：
Ward, Michael D.