title: CRLX101 nanoparticles localize in human tumors and not in adjacent, nonneoplastic tissue after intravenous dosing.
abstract: Nanoparticle-based therapeutics are being used to treat patients with solid tumors. Whereas nanoparticles have been shown to preferentially accumulate in solid tumors of animal models, there is little evidence to prove that intact nanoparticles localize to solid tumors of humans when systemically administered. Here, tumor and adjacent, nonneoplastic tissue biopsies are obtained through endoscopic capture from patients with gastric, gastroesophageal, or esophageal cancer who are administered the nanoparticle CRLX101. Both the pre- and postdosing tissue samples adjacent to tumors show no definitive evidence of either the nanoparticle or its drug payload (camptothecin, CPT) contained within the nanoparticle. Similar results are obtained from the predosing tumor samples. However, in nine of nine patients that were evaluated, CPT is detected in the tumor tissue collected 24-48 h after CRLX101 administration. For five of these patients, evidence of the intact deposition of CRLX101 nanoparticles in the tumor tissue is obtained. Indications of CPT pharmacodynamics from tumor biomarkers such as carbonic anhydrase IX and topoisomerase I by immunohistochemistry show clear evidence of biological activity from the delivered CPT in the posttreatment tumors.
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125;
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Clark
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125;
authors.forename: Devin T
authors.initials: DT
authors.lastname: Wiley
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125; Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095;
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Zuckerman
authors.affiliation: Oak Crest Institute of Science, Pasadena, CA 91107;
authors.forename: Paul
authors.initials: P
authors.lastname: Webster
authors.affiliation: Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, CA 91010.
authors.forename: Joseph
authors.initials: J
authors.lastname: Chao
authors.affiliation: Division of Gastroenterology, City of Hope Comprehensive Cancer Center, Duarte, CA 91010;
authors.forename: James
authors.initials: J
authors.lastname: Lin
authors.affiliation: Graduate Institute for Cancer Biology and Drug Discovery, Taipei Medical University, Taipei 11031, Taiwan mdavis@cheme.caltech.edu yyen@tmu.edu.tw.
authors.forename: Yun
authors.initials: Y
authors.lastname: Yen
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125; mdavis@cheme.caltech.edu yyen@tmu.edu.tw.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Davis
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism; D002166:Camptothecin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000071231:Carbonic Anhydrase IX / Q000378:metabolism; D045744:Cell Line, Tumor; D003505:Cyclodextrins / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004724:Endoscopy; D004938:Esophageal Neoplasms / Q000473:pathology*; D006801:Humans; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage / Q000378:metabolism* / Q000627:therapeutic use; D013274:Stomach Neoplasms / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D014408:Biomarkers, Tumor; D003505:Cyclodextrins; C542292:IT-101; D000071231:Carbonic Anhydrase IX; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin
keywords: clinical trial; gastric cancer; nanomedicine; nanoparticles; tumor targeting