Bromberg Lev
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
J Control Release. 2008 Jun 4;128(2):99-112. doi: 10.1016/j.jconrel.2008.01.018. Epub 2008 Feb 11.
Oral administration of anticancer agents is preferred by patients for its convenience and potential for use in outpatient and palliative setting. In addition, oral administration facilitates a prolonged exposure to the cytotoxic agents. Enhancement of bioavailability of emerging cytotoxic agents is a pre-requisite for successful development of oral modes of cancer treatment. Over the last decade, our studies have focused specifically on the utilization of large (MW>10(5)) and non-degradable polymers in oral chemotherapy. A family of block-graft copolymers of the poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO) Pluronic(R) polyethers and poly(acrylic acid) (PAA) bound by carbon-carbon bonds emerged, wherein both polymeric components are generally recognized as safe. Animal studies with Pluronic-PAA copolymers demonstrated that these molecules are excreted when administered orally and do not absorb into the systemic circulation. The Pluronic-PAA copolymers are surface-active and self-assemble, at physiological pH, into intra- and intermolecular micelles with hydrophobic cores of dehydrated PPO and multilayered coronas of hydrophilic PEO and partially ionized PAA segments. These micelles efficiently solubilize hydrophobic drugs such as paclitaxel and steroids and protect molecules such as camptothecins from the hydrolytic reactions. High surface activity of the Pluronic-PAA copolymers in water results in interactions with cell membranes and suppression of the membrane pumps such as P-glycoprotein. The ionizable carboxyls in the micellar corona facilitate mucoadhesion that enhances the residence time of the micelles and solubilized drugs in the gastrointestinal tract. Large payloads of the Pluronic-PAA micelles with weakly basic and water-soluble drugs such as doxorubicin and its analogs, mitomycin C, mitoxantrone, fluorouracil, and cyclophosphamide are achieved through electrostatic interactions with the micellar corona. Mechanical and physical properties of the Pluronic-PAA powders, blends, and micelles allow for formulation procedures where an active is simply dispersed into an aqueous Pluronic-PAA micellar formulation followed by optional lyophilization and processing into a ready dosage form. We review a number of in vivo and in vitro experiments demonstrating that that the oral administration of the cytotoxics formulated with the Pluronic-PAA copolymer micelles results in enhanced drug bioavailability.
由于口服抗癌药物方便且可用于门诊和姑息治疗，患者更倾向于选择口服给药方式。此外，口服给药有助于延长细胞毒性药物的暴露时间。提高新型细胞毒性药物的生物利用度是成功开发口服癌症治疗模式的先决条件。在过去十年中，我们的研究特别关注在口服化疗中使用大分子（分子量>10⁵）且不可降解的聚合物。一类由聚环氧乙烷（PEO）和聚环氧丙烷（PPO）的Pluronic®聚醚与通过碳 - 碳键结合的聚丙烯酸（PAA）组成的嵌段接枝共聚物应运而生，其中两种聚合物成分通常被认为是安全的。对Pluronic - PAA共聚物进行的动物研究表明，这些分子口服给药后会排出体外，不会吸收进入体循环。Pluronic - PAA共聚物具有表面活性，在生理pH值下会自组装成分子内和分子间的胶束，其疏水核心由脱水的PPO组成，亲水的PEO和部分离子化的PAA链段形成多层冠层。这些胶束能有效增溶疏水性药物，如紫杉醇和类固醇，并保护喜树碱等分子免受水解反应的影响。Pluronic - PAA共聚物在水中具有高表面活性，会与细胞膜相互作用并抑制膜泵，如P - 糖蛋白。胶束冠层中可电离的羧基有助于黏膜黏附，从而延长胶束和增溶药物在胃肠道中的停留时间。通过与胶束冠层的静电相互作用，可在Pluronic - PAA胶束中负载大量弱碱性和水溶性药物，如阿霉素及其类似物、丝裂霉素C、米托蒽醌、氟尿嘧啶和环磷酰胺。Pluronic - PAA粉末、混合物和胶束的机械和物理性质使得制剂制备过程变得简单，即将活性成分简单分散到水性Pluronic - PAA胶束制剂中，然后进行可选的冻干处理，制成即用剂型。我们回顾了大量体内和体外实验，这些实验表明用Pluronic - PAA共聚物胶束配制的细胞毒性药物口服给药可提高药物的生物利用度。
