In vivo evaluation of polymeric micellar paclitaxel formulation: toxicity and efficacy
In vivo evaluation of polymeric micellar paclitaxel formulation: toxicity and efficacy
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DOI：
10.1016/s0168-3659(01)00275-9
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发表时间：
2001-05-14
影响因子：
10.8
通讯作者：
Seo, MH
中科院分区：
文献类型：
--
作者：
Kim, SC;Kim, DW;Seo, MH
尽管紫杉醇（Taxol）的当前临床制剂具有针对多种肿瘤的有希望的临床活性，但其具有显著的毒副作用，其中一些毒副作用与其在Cremophor EL和无水乙醇的1：1（v/v）混合物中的制剂有关。与紫杉醇的静脉内给药相关的问题之一是其在水中的低溶解度。我们的研究旨在评价含有紫杉醇（Genexol（R））的可生物降解聚合物胶束系统（Genexol（R）-PM）与Taxol（R）相比的药代动力学、组织分布、毒性和功效。通过使用低分子量、无毒和可生物降解的两亲性二嵌段共聚物、单甲氧基聚（乙二醇）-嵌段-聚（D，L-丙交酯）（mPEG-PDLLA）和紫杉醇（Genexol（R），Samyang Genex Co.，韩国首尔）。在人癌细胞系模型中，Genexol（R）-PM和Taxol（R）对人卵巢癌细胞系OVCAR-3和人乳腺癌细胞系MCF 7显示出相当的体外细胞毒性。Genexol（R）-PM和Taxol（R）在裸鼠中的最大耐受剂量（MTD）分别测定为60和20 mg/kg。Genexol（R）-PM在Sprague-Dawley大鼠中的半数致死剂量（LD 50）为205.4 mg/kg（雄性）和221.6 mg/kg（雌性），而Taxol（R）为8.3 mg/kg（雄性）和8.8 mg/kg（雌性）。在鼠B16黑素瘤诱导的雌性SPF C57 BL/6小鼠中以50 mg/kg的剂量静脉内施用Genexol-PM后，血浆浓度-时间曲线下面积（AUC）与20 mg/kg剂量的Taxol相似，但施用Genexol-PM后紫杉醇的生物分布显示在包括肝、脾、肾、肺、心脏和肿瘤相比，紫杉醇（R）。通过移植到裸（nu/nu）无胸腺小鼠中的SKOV-3人卵巢癌和移植到Tac：Cr：（NCr）-nu无胸腺小鼠中的MX-I人乳腺癌的肿瘤体积的减小来测量Genexol（R）-PM的体内抗肿瘤功效显著大于Taxol（R）的体内抗肿瘤功效。细胞毒性、MTD、LD 50和抗肿瘤疗效的结果表明，Genexol（R）-PM可能比目前使用Taxol（R）的化疗具有很大的优势。(C)2001 Elsevier Science B. V.保留所有权利。
Although the current clinical formulation of paclitaxel (Taxol(R)) has a promising clinical activity against a wide variety of tumors, it has significant toxic side effects, some of which are associated with its formulation in a 1:1 (v/v) mixture of Cremophor EL and dehydrated alcohol. One of the problems associated with the intravenous administration of paclitaxel is its low solubility in water. Our study was designed to evaluate the pharmacokinetics, tissue distribution, toxicity and efficacy of a paclitaxel (Genexol(R))-containing biodegradable polymeric micellar system (Genexol(R)-PM) in comparison to Taxol(R). Genexol(R)-PM was newly developed by using a low molecular weight, nontoxic and biodegradable amphiphilic diblock copolymer, monomethoxy poly(ethylene glycol)-block-poly(D,L-lactide) (mPEG-PDLLA) and paclitaxel (Genexol(R), Samyang Genex Co., Seoul, Korea). In a human cancer cell line model, Genexol(R)-PM and Taxol(R) showed comparable in vitro cytotoxicity against human ovarian cancer cell line OVCAR-3 and human breast cancer cell line MCF7. The maximum tolerated dose (MTD) of Genexol(R)-PM and Taxol(R) in nude mice was determined to be 60 and 20 mg/kg, respectively. The median lethal dose (LD50) in Sprague-Dawley rats was 205.4 mg/kg (male) and 221.6 mg/kg (female) for Genexol(R)-PM, while 8.3 mg/kg (male) and 8.8 mg/kg (female) for Taxol(R). After intravenous administration of Genexol(R)-PM in murine B16 melanoma-induced female SPF C57BL/6 mice at a dose of 50 mg/kg, the area under the plasma concentration-time curve (AUC) was similar to Taxol(R) at a dose of 20 mg/kg, but biodistribution of paclitaxel after administration of Genexol(R)-PM showed 2 to 3-fold higher levels in tissues including liver, spleen, kidneys, lungs, heart and tumor as compared to Taxol(R). The in vivo antitumor efficacy of Genexol(R)-PM as measured by reduction in tumor volume of SKOV-3 human ovarian cancer implanted in nude (nu/nu) athymic mice and MX-I human breast cancer implanted in Tac:Cr:(NCr)-nu athymic mice was significantly greater than that of Taxol(R). The results of cytotoxicity, MTD, LD50 and antitumor efficacy suggest that Genexol(R)-PM may have a great advantage over present-day chemotherapy with Taxol(R). (C) 2001 Elsevier Science B.V. All rights reserved.