Synthesis and evaluation of a backbone biodegradable multiblock HPMA copolymer nanocarrier for the systemic delivery of paclitaxel.
Synthesis and evaluation of a backbone biodegradable multiblock HPMA copolymer nanocarrier for the systemic delivery of paclitaxel.
复制标题
DOI：
10.1016/j.jconrel.2012.12.009
复制
发表时间：
2013-02-28
期刊：
影响因子：
--
通讯作者：
Kopeček J
中科院分区：
文献类型：
--
作者：
Zhang R;Luo K;Yang J;Sima M;Sun Y;Janát-Amsbury MM;Kopeček J
目前抗肿瘤药物的性能和安全性，特别是水不溶性药物，还远远不能令人满意。例如，目前广泛使用的基于cremoophor EL®的紫杉醇（PTX）配方存在药代动力学问题和严重的副作用。因此，提倡生物可降解高分子给药系统的概念，该系统可以显著提高治疗效果，减少副作用。目前的工作旨在开发新一代长循环、可生物降解的载体，以有效地递送PTX。首先，采用可逆加成-断裂链转移（RAFT）共聚法制备了分子量为335 kDa的多嵌段可降解N-（2-羟丙基）甲基丙烯酰胺（HPMA）共聚物-PTX共轭物（mP-PTX）。体外实验研究了游离PTX、分子量为48 kDa的HPMA共聚物-PTX偶联物（P-PTX）和mP-PTX对人卵巢癌A2780细胞的细胞毒性。实验表明，mP-PTX对A2780细胞具有与游离PTX和P-PTX相似的细胞毒作用。为了进一步比较这种新的生物可降解偶联物（mP-PTX）与游离PTX和P-PTX在体内的行为，我们用携带原位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从血液中清除的速度比商业PTX制剂和低Mw P-PTX慢。SPECT/CT成像和生物分布研究证明了mP-PTX的生物降解性以及从体内消除。mP-PTX治疗组的肿瘤生长速度比生理盐水、游离PTX和P-PTX治疗组（单剂量20mg PTX/kg当量）慢。此外，mP-PTX处理的小鼠没有明显的腹水和体重减轻。组织学分析表明，mP-PTX对肝脏和脾脏无毒性，但可诱导肿瘤细胞大量死亡。综上所述，这种可生物降解的给药系统在提高现有抗肿瘤药物的性能和安全性方面具有很大的潜力。
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.
登录
查看更多内容
影响因子：
5.5
作者：
Luo K;Yang J;Kopečková P;Kopeček J
通讯作者：
Kopeček J
影响因子：
10.8
作者：
Joshi, Nitin;Shanmugam, Thanigaivel;Banerjee, Rinti
通讯作者：
Banerjee, Rinti
影响因子：
3.5
作者：
Erez, Rotem;Segal, Ehud;Shabat, Doron
通讯作者：
Shabat, Doron
DOI：
10.1016/s0022-5223(03)00710-4
发表时间：
2003-11-01
影响因子：
6
作者：
Keresztes, RS;Port, JL;Altorki, NK
通讯作者：
Altorki, NK
影响因子：
10.8
作者：
Danhier, Fabienne;Lecouturier, Nathalie;Preat, Veronique
通讯作者：
Preat, Veronique