Albumin-bound nanoparticle (nab) paclitaxel exhibits enhanced paclitaxel tissue distribution and tumor penetration.
Albumin-bound nanoparticle (nab) paclitaxel exhibits enhanced paclitaxel tissue distribution and tumor penetration.
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DOI：
10.1007/s00280-015-2833-5
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发表时间：
2015-10
影响因子：
3
通讯作者：
Chopra R
中科院分区：
文献类型：
--
作者：
Chen N;Brachmann C;Liu X;Pierce DW;Dey J;Kerwin WS;Li Y;Zhou S;Hou S;Carleton M;Klinghoffer RA;Palmisano M;Chopra R
与传统 Cremophor EL (CrEL)-紫杉醇相比，白蛋白结合型紫杉醇在多种肿瘤类型中表现出更好的临床疗效。本研究探讨了白蛋白结合型紫杉醇和 CrEL-紫杉醇之间药物分布的差异及其潜在机制。通过跨人内皮细胞单层的血管通透性测定来分析紫杉醇的摄取和转胞吞作用。通过局部注射肿瘤异种移植物和定量图像分析来评估紫杉醇在肿瘤内的组织渗透。使用药代动力学模型和模拟评估紫杉醇在实体瘤患者中的分布情况。实时成像表明，白蛋白和紫杉醇存在于内皮细胞的点状结构中，并且可以在非常接近的位置观察到，表明存在共转运。白蛋白、白蛋白结合型紫杉醇和紫杉醇的摄取和转运受到临床相关 CrEL 浓度的抑制。此外，在局部显微注射后，白蛋白结合型紫杉醇在异种移植肿瘤内的更广泛区域内引起比CrEL-或二甲亚砜-紫杉醇更大的有丝分裂停滞，这表明紫杉醇在肿瘤内的渗透和白蛋白的吸收增强。实体瘤患者中紫杉醇分布的建模表明，白蛋白结合型紫杉醇比 CrEL-紫杉醇更依赖于转运蛋白介导的药物分布至组织的途径。预计白蛋白结合型紫杉醇通过转运蛋白介导的途径递送至组织的剂量百分比是恒定的，但随着CrEL-紫杉醇剂量的增加而减少。与 CrEL-紫杉醇相比，白蛋白结合型紫杉醇表现出更有效的跨内皮细胞转运，在异种移植肿瘤中具有更大的渗透性和细胞毒性诱导作用，并且由于载体介导的转运而增强了患者的血管外分布。这些观察结果与白蛋白结合型紫杉醇独特的临床疗效和毒性特征一致。本文的在线版本 (doi:10.1007/s00280-015-2833-5) 包含补充材料，可供授权用户使用。
nab-paclitaxel demonstrates improved clinical efficacy compared with conventional Cremophor EL (CrEL)-paclitaxel in multiple tumor types. This study explored the distinctions in drug distribution between nab-paclitaxel and CrEL-paclitaxel and the underlying mechanisms. Uptake and transcytosis of paclitaxel were analyzed by vascular permeability assay across human endothelial cell monolayers. The tissue penetration of paclitaxel within tumors was evaluated by local injections into tumor xenografts and quantitative image analysis. The distribution profile of paclitaxel in solid-tumor patients was assessed using pharmacokinetic modeling and simulation. Live imaging demonstrated that albumin and paclitaxel were present in punctae in endothelial cells and could be observed in very close proximity, suggesting cotransport. Uptake and transport of albumin, nab-paclitaxel and paclitaxel were inhibited by clinically relevant CrEL concentrations. Further, nab-paclitaxel causes greater mitotic arrest in wider area within xenografted tumors than CrEL- or dimethyl sulfoxide-paclitaxel following local microinjection, demonstrating enhanced paclitaxel penetration and uptake by albumin within tumors. Modeling of paclitaxel distribution in patients with solid tumors indicated that nab-paclitaxel is more dependent upon transporter-mediated pathways for drug distribution into tissues than CrEL-paclitaxel. The percent dose delivered to tissue via transporter-mediated pathways is predicted to be constant with nab-paclitaxel but decrease with increasing CrEL-paclitaxel dose. Compared with CrEL-paclitaxel, nab-paclitaxel demonstrated more efficient transport across endothelial cells, greater penetration and cytotoxic induction in xenograft tumors, and enhanced extravascular distribution in patients that are attributed to carrier-mediated transport. These observations are consistent with the distinct clinical efficacy and toxicity profile of nab-paclitaxel. The online version of this article (doi:10.1007/s00280-015-2833-5) contains supplementary material, which is available to authorized users.