Desai Neil, Trieu Vuong, Yao Zhiwen, Louie Leslie, Ci Sherry, Yang Andrew, Tao Chunlin, De Tapas, Beals Bridget, Dykes Donald, Noker Patricia, Yao Rosie, Labao Elizabeth, Hawkins Michael, Soon-Shiong Patrick
American BioScience, Inc., Santa Monica, California 90403, USA.
Clin Cancer Res. 2006 Feb 15;12(4):1317-24. doi: 10.1158/1078-0432.CCR-05-1634.
ABI-007, an albumin-bound, 130-nm particle form of paclitaxel, was developed to avoid Cremophor/ethanol-associated toxicities in Cremophor-based paclitaxel (Taxol) and to exploit albumin receptor-mediated endothelial transport. We studied the antitumor activity, intratumoral paclitaxel accumulation, and endothelial transport for ABI-007 and Cremophor-based paclitaxel. Antitumor activity and mortality were assessed in nude mice bearing human tumor xenografts [lung (H522), breast (MX-1), ovarian (SK-OV-3), prostate (PC-3), and colon (HT29)] treated with ABI-007 or Cremophor-based paclitaxel. Intratumoral paclitaxel concentrations (MX-1-tumored mice) were compared for radiolabeled ABI-007 and Cremophor-based paclitaxel. In vitro endothelial transcytosis and Cremophor inhibition of paclitaxel binding to cells and albumin was compared for ABI-007 and Cremophor-based paclitaxel. Both ABI-007 and Cremophor-based paclitaxel caused tumor regression and prolonged survival; the order of sensitivity was lung > breast congruent with ovary > prostate > colon. The LD(50) and maximum tolerated dose for ABI-007 and Cremophor-based paclitaxel were 47 and 30 mg/kg/d and 30 and 13.4 mg/kg/d, respectively. At equitoxic dose, the ABI-007-treated groups showed more complete regressions, longer time to recurrence, longer doubling time, and prolonged survival. At equal dose, tumor paclitaxel area under the curve was 33% higher for ABI-007 versus Cremophor-based paclitaxel, indicating more effective intratumoral accumulation of ABI-007. Endothelial binding and transcytosis of paclitaxel were markedly higher for ABI-007 versus Cremophor-based paclitaxel, and this difference was abrogated by a known inhibitor of endothelial gp60 receptor/caveolar transport. In addition, Cremophor was found to inhibit binding of paclitaxel to endothelial cells and albumin. Enhanced endothelial cell binding and transcytosis for ABI-007 and inhibition by Cremophor in Cremophor-based paclitaxel may account in part for the greater efficacy and intratumor delivery of ABI-007.
ABI-007是一种与白蛋白结合的130纳米颗粒形式的紫杉醇，其研发目的是避免基于聚氧乙烯蓖麻油的紫杉醇（泰素）中与聚氧乙烯蓖麻油/乙醇相关的毒性，并利用白蛋白受体介导的内皮转运。我们研究了ABI-007和基于聚氧乙烯蓖麻油的紫杉醇的抗肿瘤活性、瘤内紫杉醇蓄积以及内皮转运。在用ABI-007或基于聚氧乙烯蓖麻油的紫杉醇治疗的荷人肿瘤异种移植瘤（肺癌（H522）、乳腺癌（MX-1）、卵巢癌（SK-OV-3）、前列腺癌（PC-3）和结肠癌（HT29））的裸鼠中评估了抗肿瘤活性和死亡率。比较了放射性标记的ABI-007和基于聚氧乙烯蓖麻油的紫杉醇在瘤内的紫杉醇浓度（MX-1荷瘤小鼠）。比较了ABI-007和基于聚氧乙烯蓖麻油的紫杉醇在体外的内皮转胞吞作用以及聚氧乙烯蓖麻油对紫杉醇与细胞和白蛋白结合的抑制作用。ABI-007和基于聚氧乙烯蓖麻油的紫杉醇均导致肿瘤消退并延长生存期；敏感性顺序为肺癌＞乳腺癌≈卵巢癌＞前列腺癌＞结肠癌。ABI-007和基于聚氧乙烯蓖麻油的紫杉醇的半数致死量（LD50）和最大耐受剂量分别为47和30毫克/千克/天以及30和13.4毫克/千克/天。在等效毒性剂量下，ABI-007治疗组显示出更完全的消退、更长的复发时间、更长的倍增时间以及更长的生存期。在等剂量下，ABI-007的肿瘤紫杉醇曲线下面积比基于聚氧乙烯蓖麻油的紫杉醇高33%，表明ABI-007在瘤内的蓄积更有效。与基于聚氧乙烯蓖麻油的紫杉醇相比，ABI-007的紫杉醇在内皮结合和转胞吞作用明显更高，并且这种差异被一种已知的内皮gp60受体/小窝转运抑制剂消除。此外，发现聚氧乙烯蓖麻油可抑制紫杉醇与内皮细胞和白蛋白的结合。ABI-007增强的内皮细胞结合和转胞吞作用以及聚氧乙烯蓖麻油对基于聚氧乙烯蓖麻油的紫杉醇的抑制作用可能部分解释了ABI-007更高的疗效和瘤内递送。
