Reduced in vivo toxicity of doxorubicin by encapsulation in cholesterol-containing self-assembled nanoparticles

Laura Gonzalez-Fajardo; Lalit H Mahajan; Dennis Ndaya; Derek Hargrove; José E Manautou; Bruce T Liang; Ming-Hui Chen; Rajeswari M Kasi; Xiuling Lu

doi:10.1016/j.phrs.2016.03.006

Reduced in vivo toxicity of doxorubicin by encapsulation in cholesterol-containing self-assembled nanoparticles

Pharmacol Res. 2016 May:107:93-101. doi: 10.1016/j.phrs.2016.03.006. Epub 2016 Mar 11.

Authors

Laura Gonzalez-Fajardo¹, Lalit H Mahajan², Dennis Ndaya³, Derek Hargrove¹, José E Manautou¹, Bruce T Liang⁴, Ming-Hui Chen⁵, Rajeswari M Kasi⁶, Xiuling Lu⁷

Affiliations

¹ Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA.
² Polymer Program, Institute of Materials Science, University of Connecticut, Storrs, CT 06269, USA.
³ Department of Chemistry, University of Connecticut, Storrs, CT 06269, USA.
⁴ Pat and Jim Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington, CT 06030, USA.
⁵ Department of Statistics, University of Connecticut, Storrs, CT 06269, USA.
⁶ Polymer Program, Institute of Materials Science, University of Connecticut, Storrs, CT 06269, USA; Department of Chemistry, University of Connecticut, Storrs, CT 06269, USA.
⁷ Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA. Electronic address: [email protected].

PMID: 26976795
DOI: 10.1016/j.phrs.2016.03.006

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.

Keywords: Brush-copolymer nanoparticle; Cancer therapy; Doxorubicin; Toxicity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

A549 Cells
Alanine Transaminase / blood
Animals
Antineoplastic Agents* / adverse effects
Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacokinetics
Antineoplastic Agents* / therapeutic use
Cholesterol / chemistry*
Doxorubicin* / adverse effects
Doxorubicin* / chemistry
Doxorubicin* / pharmacokinetics
Doxorubicin* / therapeutic use
Liver / drug effects
Liver / pathology
Mice, SCID
Myocardium / pathology
Nanoparticles* / adverse effects
Nanoparticles* / chemistry
Nanoparticles* / therapeutic use
Neoplasms / blood
Neoplasms / drug therapy
Neoplasms / pathology
Spleen / drug effects
Spleen / pathology
Troponin I / blood
Tumor Burden / drug effects
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Troponin I
Doxorubicin
Cholesterol
Alanine Transaminase