Copper-doxorubicin as a nanoparticle cargo retains efficacy with minimal toxicity

Azadeh Kheirolomoom, Lisa M. Mahakian, Chun Yen Lai, Heather A. Lindfors, Jai Woong Seo, Eric E. Paoli, Katherine D. Watson, Eric M. Haynam, Elizabeth S. Ingham, Li Xing, R. Holland Cheng, Alexander D. Borowsky, Robert D. Cardiff, Katherine W. Ferrara

Research output: Contribution to journalArticle

71 Scopus citations

Abstract

Repeated administration of chemotherapeutics is typically required for the effective treatment of highly aggressive tumors and often results in systemic toxicity. We have created a copper-doxorubicin complex within the core of liposomes and applied the resulting particle in multidose therapy. Copper and doxorubicin concentrations in the blood pool were similar at 24 h (∼40% of the injected dose), indicating stable circulation of the complex. Highly quenched doxorubicin fluorescence remained in the blood pool over tens of hours, with fluorescence increasing only with the combination of liposome disruption and copper trans-chelation. At 48 h after injection, doxorubicin fluorescence within the heart and skin was one-fifth and one-half, respectively, of fluorescence observed with ammonium sulfate-loaded doxorubicin liposomes. After 28 days of twice per week doxorubicin administration of 6 mg/kg, systemic toxicity (cardiac hypertrophy and weight and hair loss) was not detected with the copper-doxorubicin liposomes but was substantial with ammonium sulfate-loaded doxorubicin liposomes. We then incorporated two strategies designed to enhance efficacy, mTOR inhibition (rapamycin) to slow proliferation and therapeutic ultrasound to enhance accumulation and local diffusion. Tumor accumulation was ∼10% ID/g and was enhanced approximately 2-fold with the addition of therapeutic ultrasound. After the 28-day course of therapy, syngeneic tumors regressed to a premalignant phenotype of ∼(1 mm) 3 or could not be detected.

Original languageEnglish (US)
Pages (from-to)1948-1958
Number of pages11
JournalMolecular Pharmaceutics
Volume7
Issue number6
DOIs
StatePublished - Dec 6 2010

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Molecular Medicine
  • Drug Discovery

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    Kheirolomoom, A., Mahakian, L. M., Lai, C. Y., Lindfors, H. A., Seo, J. W., Paoli, E. E., Watson, K. D., Haynam, E. M., Ingham, E. S., Xing, L., Cheng, R. H., Borowsky, A. D., Cardiff, R. D., & Ferrara, K. W. (2010). Copper-doxorubicin as a nanoparticle cargo retains efficacy with minimal toxicity. Molecular Pharmaceutics, 7(6), 1948-1958. https://doi.org/10.1021/mp100245u