Biodistribution of paclitaxel and poly(L-glutamic acid)-paclitaxel conjugate in mice with ovarian OCa-1 tumor
Biodistribution of paclitaxel and poly(L-glutamic acid)-paclitaxel conjugate in mice with ovarian OCa-1 tumor
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DOI：
10.1007/s002800000168
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发表时间：
2000-11-01
影响因子：
3
通讯作者：
Wallace, S
中科院分区：
文献类型：
--
作者：
Li, C;Newman, RA;Wallace, S
目的：聚(L-谷氨酸)-紫杉醇(PG-TXL)是紫杉醇(TXL)与聚(L-谷氨酸)通过酯键偶联而成的水溶性紫杉醇结合物。在临床前研究中，PG-TXL对多种实体肿瘤显示出显著的抗肿瘤活性。为了阐明PG-TXL的组织分布与抗肿瘤作用的关系，我们对PG-TXL和TXL的生物分布进行了研究和比较。方法：C3Hf/Kam雌性OCA-1荷瘤小鼠分别注射等量的[H-3]TXL或PG-[H-3]TXL，剂量为20 mg/kg。分别于给药后不同时间处死小鼠，取血、脾、肝、肾、肺、心、肌肉、脑、脂肪、肿瘤等组织标本进行放射性计数。此外。用高效液相色谱法分析PG[H-3]TXL在脾、肝、肾和肿瘤组织中释放的游离[H-3]TXL浓度。分别于注射PG-[H-3]TXL后1天和6天处死小鼠，摄取全身放射自显影，研究PG-TXL在肿瘤内的分布。结果：当[H-3]TXL与聚合物偶联时，PG-[H-3]TXL的生物分布模式与[H-3]TXL不同。根据组织浓度-时间曲线下面积(AUC)值，当给予PG-TXL时，肿瘤对[H-3]TXL的暴露是在Cremophor EL/酒精载体中配制的TXL的5倍。此外，PG-[H-3]TXL在肿瘤组织中释放的游离紫杉醇浓度在给药后5、48和144h保持相对稳定，分别为489、949和552 ng/g肿瘤组织。注射PG-[H-3]TXL的小鼠放射自显影图像显示，给药后第1天，放射性主要位于肿瘤的外围，到第6天，放射性已均匀扩散到肿瘤中心。在144小时的研究期间，网状内皮系统较丰富的组织(即肝、肾、脾、肺)的[H-3]TXL浓度高于RE系统较少或缺乏的组织(即肌肉、大鼠、脑)。[H-3]TXL和PG[H-3]TXL主要通过肝胆途径排泄，每种药物的一小部分(分别为5%和8.7%)在48h内排入尿液。结论：[H-3]TXL作为大分子结合物给药后，肿瘤组织的分布增强，游离TXL释放并在肿瘤内维持较长时间。因此，在临床前研究中观察到的PG-TXL的抗肿瘤活性可能部分归因于促进肿瘤对PG-TXL的摄取。
Purpose: Poly(L-glutamic acid)-paclitaxel (PG-TXL) is a water-soluble paclitaxel (TXL) conjugate made by conjugating TXL to poly(L-glutamic; acid) via ester bonds. In preclinical studies, PG-TXL has shown significant antitumor activity against a variety of solid tumors. To elucidate the relationship between tissue distribution and antitumor efficacy of PG-TXL, we studied and compared the biodistribution of PG-TXL and TXL. Methods: Female C3Hf/Kam mice bearing syngeneic ovarian OCa-1 tumors were injected with either [H-3]TXL or PG-[H-3]TXL at an equivalent TXL dose of 20 mg/kg. Mice were killed at various times after drug injection, and samples of blood, spleen, liver, kidney, lung, heart, muscle, brain, fat, and tumor were removed and the radioactivity counted. In addition. concentrations of free [H-3]TXL released from PG[H-3]TXL in the spleen, liver, kidney, and tumor were analyzed by using high-performance liquid chromatography (HPLC). Whole-body autoradiographs of mice killed 1 day and 6 days after administration of PG-[H-3]TXL were obtained to study the intratumoral distribution of PG-TXL. Results: When [H-3]TXL was conjugated to polymer, the biodistribution pattern of PG-[H-3]TXL differed from that of [H-3]TXL. Based on area under the tissue concentration-time curve (AUC) values, tumor exposure to [H-3]TXL was five times greater when administered as PG-TXL than as TXL formulated in Cremophor EL/alcohol vehicle. Furthermore, concentrations of free paclitaxel released from PG-[H-3]TXL remained relatively constant in tumor tissue, being 489, 949 and 552 ng/g tumor tissue at 5, 48 and 144 h after dosing, respectively. Autoradiographic images of mice injected with PG-[H-3]TXL revealed that radioactivity was primarily located in the periphery of the tumor on day 1 after drug administration and was homogeneously diffused into the center of the tumor by day 6. Over the 144-h study period, [H-3]TXL concentrations, predominantly as the inactive conjugate, were higher in tissues with a more abundant reticular endothelial system (i.e, liver, kidney, spleen, lung) than in tissues with less abundant or lacking RE systems (i.e. muscle, rat, brain). Both [H-3]TXL and PG [H-3]TXL were excreted primarily through the hepatobiliary route, with a small fraction of each drug (5% and 8.7%, respectively) excreted into the urine within 48 h. Conclusions: This study indicates that the distribution to tumor tissue was enhanced when [H-3]TXL was administered as a macromolecular conjugate, and that free TXL was released and maintained within the tumor for a prolonged period. Thus, the antitumor activity of PG-TXL observed in preclinical studies may be attributed in part to enhanced tumor uptake of PG-TXL.