title: Reduced in vivo toxicity of doxorubicin by encapsulation in cholesterol-containing self-assembled nanoparticles.
abstract: We previously reported the development of an amphiphilic brush-like block copolymer composed of polynorbornene-cholesterol/polyethylene glycol (P(NBCh9-b-NBPEG)) that self-assembles in aqueous media to form long circulating nanostructures capable of encapsulating doxorubicin (DOX-NPs). Biodistribution studies showed that this formulation preferentially accumulates in tumor tissue with markedly reduced accumulation in the heart and other major organs. The aim of the current study was to evaluate the in vivo efficacy and toxicity of DOX containing self-assembled polymer nanoparticles in a mouse xenograft tumor model and compare its effects with the hydrochloride non-encapsulated form (free DOX). DOX-NPs significantly reduced the growth of tumors without inducing any apparent toxicity. Conversely, mice treated with free DOX exhibited significant weight loss, early toxic cardiomyopathy, acute toxic hepatopathy, reduced hematopoiesis and fatal toxicity. The improved safety profile of the polymeric DOX-NPs can be explained by the low circulating concentration of non-nanoparticle-associated drug as well as the reduced accumulation of DOX in non-target organs. These findings support the use of P(NBCh9-b-NBPEG) nanoparticles as delivery platforms for hydrophobic anticancer drugs intended to reduce the toxicity of conventional treatments.
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Gonzalez-Fajardo
authors.affiliation: Polymer Program, Institute of Materials Science, University of Connecticut, Storrs, CT 06269, USA.
authors.forename: Lalit H
authors.initials: LH
authors.lastname: Mahajan
authors.affiliation: Department of Chemistry, University of Connecticut, Storrs, CT 06269, USA.
authors.forename: Dennis
authors.initials: D
authors.lastname: Ndaya
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA.
authors.forename: Derek
authors.initials: D
authors.lastname: Hargrove
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA.
authors.forename: José E
authors.initials: JE
authors.lastname: Manautou
authors.affiliation: Pat and Jim Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington, CT 06030, USA.
authors.forename: Bruce T
authors.initials: BT
authors.lastname: Liang
authors.affiliation: Department of Statistics, University of Connecticut, Storrs, CT 06269, USA.
authors.forename: Ming-Hui
authors.initials: MH
authors.lastname: Chen
authors.affiliation: Polymer Program, Institute of Materials Science, University of Connecticut, Storrs, CT 06269, USA; Department of Chemistry, University of Connecticut, Storrs, CT 06269, USA.
authors.forename: Rajeswari M
authors.initials: RM
authors.lastname: Kasi
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA. Electronic address: xiuling.lu@uconn.edu.
authors.forename: Xiuling
authors.initials: X
authors.lastname: Lu
mesh_terms: D000072283:A549 Cells; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D002784:Cholesterol / Q000737:chemistry*; D004317:Doxorubicin / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D008099:Liver / Q000187:drug effects / Q000473:pathology; D016513:Mice, SCID; D009206:Myocardium / Q000473:pathology; D053758:Nanoparticles / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D019210:Troponin I / Q000097:blood; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D019210:Troponin I; D004317:Doxorubicin; D002784:Cholesterol; D000410:Alanine Transaminase
keywords: Brush-copolymer nanoparticle; Cancer therapy; Doxorubicin; Toxicity