Cerulean Pharma, Cambridge, MA 02139.
Proc Natl Acad Sci U S A. 2013 Sep 10;110(37):15127-32. doi: 10.1073/pnas.1309566110. Epub 2013 Aug 26.
Nanoparticles are currently being investigated in a number of human clinical trials. As information on how nanoparticles function in humans is difficult to obtain, animal studies that can be correlative to human behavior are needed to provide guidance for human clinical trials. Here, we report correlative studies on animals and humans for CRLX101, a 20- to 30-nm-diameter, multifunctional, polymeric nanoparticle containing camptothecin (CPT). CRLX101 is currently in phase 2 clinical trials, and human data from several of the clinical investigations are compared with results from multispecies animal studies. The pharmacokinetics of polymer-conjugated CPT (indicative of the CRLX101 nanoparticles) in mice, rats, dogs, and humans reveal that the area under the curve scales linearly with milligrams of CPT per square meter for all species. Plasma concentrations of unconjugated CPT released from CRLX101 in animals and humans are consistent with each other after accounting for differences in serum albumin binding of CPT. Urinary excretion of polymer-conjugated CPT occurs primarily within the initial 24 h after dosing in animals and humans. The urinary excretion dynamics of polymer-conjugated and unconjugated CPT appear similar between animals and humans. CRLX101 accumulates into solid tumors and releases CPT over a period of several days to give inhibition of its target in animal xenograft models of cancer and in the tumors of humans. Taken in total, the evidence provided from animal models on the CRLX101 mechanism of action suggests that the behavior of CRLX101 in animals is translatable to humans.
纳米颗粒目前正在多项人体临床试验中进行研究。由于难以获取纳米颗粒在人体中作用的信息，因此需要进行能够与人类行为相关联的动物研究，为人体临床试验提供指导。在这里，我们报告了关于 CRLX101 的动物和人体的相关性研究，CRLX101 是一种 20 至 30 纳米直径的多功能聚合物纳米颗粒，包含喜树碱（CPT）。CRLX101 目前处于 2 期临床试验阶段，将来自该临床试验的几项人体数据与多物种动物研究的结果进行了比较。在小鼠、大鼠、狗和人中，聚合物结合的 CPT（表明 CRLX101 纳米颗粒）的药代动力学表明，所有物种的曲线下面积均与每平方米毫克 CPT 呈线性比例。考虑到 CPT 与血清白蛋白结合的差异，动物和人类中从 CRLX101 释放的未结合的 CPT 的血浆浓度是一致的。在动物和人类中，聚合物结合的 CPT 的尿排泄主要发生在给药后最初 24 小时内。聚合物结合的和未结合的 CPT 的尿排泄动力学在动物和人类之间似乎相似。CRLX101 积累到实体瘤中，并在数天内释放 CPT，从而抑制其在癌症动物异种移植模型和人类肿瘤中的靶标。总的来说，动物模型中提供的关于 CRLX101 作用机制的证据表明，CRLX101 在动物中的行为可以转化为人类。
