title: Correlating preclinical animal studies and human clinical trials of a multifunctional, polymeric nanoparticle.
abstract: 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.
authors: Cerulean Pharma, Cambridge, MA 02139.
authors: Scott
authors: S
authors: Eliasof
authors: Douglas
authors: D
authors: Lazarus
authors: Christian G
authors: CG
authors: Peters
authors: Roy I
authors: RI
authors: Case
authors: Roderic O
authors: RO
authors: Cole
authors: Jungyeon
authors: J
authors: Hwang
authors: Thomas
authors: T
authors: Schluep
authors: Joseph
authors: J
authors: Chao
authors: James
authors: J
authors: Lin
authors: Yun
authors: Y
authors: Yen
authors: Han
authors: H
authors: Han
authors: Devin T
authors: DT
authors: Wiley
authors: Jonathan E
authors: JE
authors: Zuckerman
authors: Mark E
authors: ME
authors: Davis
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D019540:Area Under Curve; D002166:Camptothecin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002986:Clinical Trials as Topic; D003505:Cyclodextrins / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004285:Dogs; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D058726:Nanoconjugates / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D051381:Rats; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000378:metabolism; D057170:Translational Research, Biomedical
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D003505:Cyclodextrins; C542292:IT-101; D058726:Nanoconjugates; D002166:Camptothecin
keywords: Nanoparticles; clinical translation; interspecies scaling; nanomedicine; pharmacodynamics
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