Department of Pharmaceutics and Pharmaceutical Chemistry/CCCD, University of Utah, Salt Lake City, UT 84112, USA.
J Control Release. 2013 Feb 28;166(1):66-74. doi: 10.1016/j.jconrel.2012.12.009. Epub 2012 Dec 20.
The performance and safety of current antineoplastic agents, particularly water-insoluble drugs, are still far from satisfactory. For example, the currently widely used Cremophor EL®-based paclitaxel (PTX) formulation exhibits pharmacokinetic concerns and severe side effects. Thus, the concept of a biodegradable polymeric drug-delivery system, which can significantly improve therapeutic efficacy and reduce side effects is advocated. The present work aims to develop a new-generation of long-circulating, biodegradable carriers for effective delivery of PTX. First, a multiblock backbone biodegradable N-(2-hydroxypropyl)methacrylamide(HPMA) copolymer-PTX conjugate (mP-PTX) with molecular weight (Mw) of 335 kDa was synthesized by RAFT (reversible addition-fragmentation chain transfer) copolymerization, followed by chain extension. In vitro studies on human ovarian carcinoma A2780 cells were carried out to investigate the cytotoxicity of free PTX, HPMA copolymer-PTX conjugate with Mw of 48 kDa (P-PTX), and mP-PTX. The experiments demonstrated that mP-PTX has a similar cytotoxic effect against A2780 cells as free PTX and P-PTX. To further compare the behavior of this new biodegradable conjugate (mP-PTX) with free PTX and P-PTX in vivo evaluation was performed using female nu/nu mice bearing orthotopic A2780 ovarian tumors. Pharmacokinetics study showed that high Mw mP-PTX was cleared more slowly from the blood than commercial PTX formulation and low Mw P-PTX. SPECT/CT imaging and biodistribution studies demonstrated biodegradability as well as elimination of mP-PTX from the body. The tumors in the mP-PTX treated group grew more slowly than those treated with saline, free PTX, and P-PTX (single dose at 20 mg PTX/kg equivalent). Moreover, mice treated with mP-PTX had no obvious ascites and body-weight loss. Histological analysis indicated that mP-PTX had no toxicity in liver and spleen, but induced massive cell death in the tumor. In summary, this biodegradable drug delivery system has a great potential to improve performance and safety of current antineoplastic agents.
当前的抗肿瘤药物，特别是那些水溶性差的药物，其疗效和安全性仍远不能令人满意。例如，目前广泛使用的基于 Cremophor EL®的紫杉醇（PTX）制剂表现出药代动力学问题和严重的副作用。因此，倡导使用可生物降解的聚合物药物递送系统的概念，该系统可以显著提高治疗效果并降低副作用。本工作旨在开发新一代长循环、可生物降解的载体，以有效递送 PTX。首先，通过 RAFT（可逆加成-断裂链转移）共聚合成了分子量（Mw）为 335 kDa 的多嵌段可生物降解 N-（2-羟丙基）甲基丙烯酰胺（HPMA）共聚物-PTX 缀合物（mP-PTX），然后进行了链延伸。在人卵巢癌细胞 A2780 上进行了体外研究，以研究游离 PTX、Mw 为 48 kDa 的 HPMA 共聚物-PTX 缀合物（P-PTX）和 mP-PTX 的细胞毒性。实验表明，mP-PTX 对 A2780 细胞的细胞毒性与游离 PTX 和 P-PTX 相似。为了进一步比较这种新型可生物降解缀合物（mP-PTX）与游离 PTX 和 P-PTX 的体内行为，使用荷有原位 A2780 卵巢肿瘤的雌性 nu/nu 小鼠进行了体内评价。药代动力学研究表明，高 Mw mP-PTX 从血液中的清除速度比商业 PTX 制剂和低 Mw P-PTX 慢。SPECT/CT 成像和生物分布研究表明 mP-PTX 具有生物降解性，并从体内消除。与生理盐水、游离 PTX 和 P-PTX（单剂量 20mg PTX/kg 等效）相比，mP-PTX 治疗组的肿瘤生长较慢。此外，用 mP-PTX 治疗的小鼠没有明显的腹水和体重减轻。组织学分析表明，mP-PTX 对肝脏和脾脏没有毒性，但在肿瘤中诱导大量细胞死亡。总之，这种可生物降解的药物递送系统具有提高当前抗肿瘤药物疗效和安全性的巨大潜力。
