Lu Dan, Wientjes M Guillaume, Lu Ze, Au Jessie L-S
Division of Pharmaceutics, College of Pharmacy, Ohio State University, Columbus, OH 43210, USA.
J Pharmacol Exp Ther. 2007 Jul;322(1):80-8. doi: 10.1124/jpet.107.121632. Epub 2007 Apr 9.
We have shown that high epithelial cell density is a major barrier to the distribution of protein-bound drugs in solid tumors, and tumor priming (expansion of interstitial space using an apoptosis-inducing pretreatment) can promote drug delivery. This study evaluated the optimal conditions of paclitaxel tumor priming (time window, particle size) and its effects on the delivery and efficacy of nanomedicines. Paclitaxel tumor priming was applied to mice bearing human xenograft tumors. The kinetics of paclitaxel-induced apoptosis was evaluated to identify the time window of tumor priming. The effects of tumor priming on the tumor delivery and interstitial dispersion of fluorescence-labeled nanoparticles of various sizes, the perfusion of tumor and normal tissues, the delivery of doxorubicin HCl liposomes to tumor and host tissues, and the antitumor activity and host toxicity were studied. Tumor priming by a single i.v. injection of paclitaxel induced apoptosis, expanded the interstitial space, vessel diameter and blood-perfused area, and promoted the delivery and interstitial dispersion of nanoparticles (100- and 200-nm diameter, administered 48 h after paclitaxel) in a tumor-selective manner. Tumor priming also enhanced the tumor delivery and antitumor activity of doxorubicin HCl liposomes (85 nm) without affecting the delivery to noncancerous host tissues or enhancing host toxicity. Tumor priming represents a potentially useful means to promote tumor-selective delivery and efficacy of nanomedicines. The current study will have significant impact on enhancing delivery and efficacy of nanomedicines and dosing regimen optimization of combination chemotherapy in the clinical setting.
我们已经表明，高上皮细胞密度是实体瘤中蛋白结合药物分布的主要障碍，而肿瘤预处理（使用诱导凋亡的预处理来扩大间质空间）可促进药物递送。本研究评估了紫杉醇肿瘤预处理的最佳条件（时间窗、粒径）及其对纳米药物递送和疗效的影响。将紫杉醇肿瘤预处理应用于荷人源异种移植瘤的小鼠。评估紫杉醇诱导凋亡的动力学以确定肿瘤预处理的时间窗。研究了肿瘤预处理对不同大小荧光标记纳米颗粒的肿瘤递送和间质扩散、肿瘤和正常组织的灌注、盐酸阿霉素脂质体向肿瘤和宿主组织的递送以及抗肿瘤活性和宿主毒性的影响。单次静脉注射紫杉醇进行肿瘤预处理可诱导凋亡，扩大间质空间、血管直径和血液灌注区域，并以肿瘤选择性方式促进纳米颗粒（直径100和200 nm，在紫杉醇注射后48小时给药）的递送和间质扩散。肿瘤预处理还增强了盐酸阿霉素脂质体（85 nm）的肿瘤递送和抗肿瘤活性，而不影响其向非癌宿主组织的递送或增强宿主毒性。肿瘤预处理是促进纳米药物肿瘤选择性递送和疗效的一种潜在有用手段。当前研究将对增强纳米药物的递送和疗效以及临床环境中联合化疗的给药方案优化产生重大影响。
