Using Flash Nanoprecipitation To Produce Highly Potent and Stable Cellax Nanoparticles from Amphiphilic Polymers Derived from Carboxymethyl Cellulose, Polyethylene Glycol, and Cabazitaxel
Using Flash Nanoprecipitation To Produce Highly Potent and Stable Cellax Nanoparticles from Amphiphilic Polymers Derived from Carboxymethyl Cellulose, Polyethylene Glycol, and Cabazitaxel
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DOI：
10.1021/acs.molpharmaceut.7b00670
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发表时间：
2017-11-01
影响因子：
4.9
通讯作者：
Sokoll, Kenneth K.
中科院分区：
文献类型：
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作者：
Bteich, Joseph;McManus, Simon A.;Sokoll, Kenneth K.
我们报告了闪光纳米沉淀法(FNP)作为一种生产Cellax纳米颗粒的有效和可扩展的方法的使用。由聚乙二醇化的羧甲基纤维素和疏水性抗癌药物组成的Cellax聚合物结合物，如卡巴紫杉醇(Cellax-CBZ)，已被证明对包括前列腺癌在内的几个肿瘤靶点具有很高的效力。FNP是一种通过快速混合生成纳米颗粒的可靠方法，已被用于将几种疏水药物与嵌段共聚物稳定剂一起包裹，但从未被用于从无规共聚物(如Cellax-CBZ)形成纳米颗粒。为了评估使用FNP生产Cellax纳米颗粒的潜力，我们测试了浓度、混合速度、溶剂比例和随后的稀释等参数，目标纳米颗粒的尺寸范围为60 nm。在优化的溶剂条件下，形成的颗粒经过随后的重排形成直径为60 nm的纳米颗粒，与Cellax-CBZ聚合物的浓度无关。这种颗粒内松弛，没有颗粒间的关联，指向聚合物主干上疏水/亲水结构域的微妙平衡。这些颗粒随着时间的推移是稳定的，随机的两亲性不会导致颗粒间的吸引，这将损害注射所需的稳定性和相应的窄尺寸分布。这些偶联物的两亲性使它们可以加工成纳米颗粒，用于持续药物释放和提高肿瘤选择性。对体外培养的PC3前列腺癌细胞株的血浆稳定性和细胞毒性进行了评价。这些参数在评估纳米颗粒安全性和评估潜在疗效时分别是重要的。优化的处方显示，血浆稳定性与长循环纳米粒一致，细胞毒性与游离CBZ相当。这项研究表明，FNP是一种开发Cellax纳米颗粒的很有前途的技术。
We report the use of flash nanoprecipitation (FNP) as an efficient and scalable means of producing Cellax nano particles. Cellax polymeric conjugates consisting of carboxymethyl cellulose functionalized with PEG and hydrophobic anticancer drugs, such as cabazitaxel (coined Cellax-CBZ), have been shown to have high potency against several oncology targets, including prostate cancer. FNP, a robust method used to create nanoparticles through rapid mixing, has been used to encapsulate several hydrophobic drugs with block copolymer stabilizers, but has never been used to form nanoparticles from random copolymers, such as Cellax-CBZ. To assess the potential of using FNP to produce Cellax nanoparticles, parameters such as concentration, mixing rate, solvent ratios, and subsequent dilution were tested with a target nanoparticle size range of 60 nm. Under optimized solvent conditions, particles were formed that underwent a subsequent rearrangement to form nanoparticles of 60 nm diameter, independent of Cellax-CBZ polymer concentration. This intraparticle relaxation, without interparticle association, points to a delicate balance of hydrophobic/hydrophilic domains on the polymer backbone. These particles were stable over time, and the random amphiphilicity did not lead to interparticle attractions, which would compromise the stability and corresponding narrow size distribution required for parenteral injection. The amphiphilic nature of these conjugates allows them to be processed into nanoparticles for sustained drug release and improved tumor selectivity. Preferred candidates were evaluated for plasma stability and cytotoxicity against the PC3 prostate cancer cell line in vitro. These parameters are important when assessing nanoparticle safety and for estimating potential efficacy, respectively. The optimal formulations showed plasma stability profiles consistent with long circulating nanoparticles, and cytotoxicity comparable to that of free CBZ. This study demonstrates that FNP is a promising technology for development of Cellax nanoparticles.