Oncotarget

Research Papers:

A composite polymer nanoparticle overcomes multidrug resistance and ameliorates doxorubicin-associated cardiomyopathy

Dipankar Pramanik, Nathaniel R Campbell, Samarjit Das, Sonal Gupta, Venugopal Chenna, Savita Bisht, Polina Sysa-shah, Djahida Bedja, Collins Karikari, Charles Steenbergen, Kathleen L. Gabrielson, Amarnath Maitra, Anirban Maitra _

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Abstract

Dipankar Pramanik1,2,*, Nathaniel R. Campbell1,2,*, Samarjit Das2, Sonal Gupta1,2, Venugopal Chenna1,2, Savita Bisht5, Polina Sysa-Shah3, Djahida Bedja3, Collins Karikari1,2, Charles Steenbergen2, Kathleen L. Gabrielson3, Amarnath Maitra6,π and Anirban Maitra1,2,4

1 The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland

2 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland

3 Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland

4 Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland

5 Department of Internal Medicine 3, Center of Integrated Oncology Cologne-Bonn, University of Bonn, Germany

6 Senior Scientist, Indian National Science Academy, New Delhi, India. π Deceased

* Constitutes equal contribution

Received: June 19, 2012; Accepted: July 8, 2012; Published: July 10, 2012;

Keywords: curcumin, doxorubicin, multidrug resistance

Correspondence:

Anirban Maitra, email:

This manuscript is dedicated to Amarnath Maitra (1943-2012), nanobiotechnology colleague, mentor and extraordinary scientist.

Abstract

Acquired chemotherapy resistance is a major contributor to treatment failure in oncology. For example, the efficacy of the common anticancer agent doxorubicin (DOX) is limited by the emergence of multidrug resistance (MDR) phenotype in cancer cells. While dose escalation of DOX can circumvent such resistance to a degree, this is precluded by the appearance of cardiotoxicity, a particularly debilitating condition in children. In vitro studies have established the ability of the natural phytochemical curcumin to overcome MDR; however, its widespread clinical application is restricted by poor solubility and low bioavailability. Building upon our recently developed polymer nanoparticle of curcumin (NanoCurc or NC) that significantly enhances the systemic bioavailability of curcumin, we synthesized a doxorubicin-curcumin composite nanoparticle formulation called NanoDoxCurc (NDC) for overcoming DOX resistance. Compared to DOX alone, NDC inhibited the MDR phenotype and caused striking growth inhibition both in vitro and in vivo in several models of DOX-resistant cancers (multiple myeloma, acute leukemia, prostate and ovarian cancers, respectively). Notably, NDC-treated mice also demonstrated complete absence of cardiac toxicity, as assessed by echocardiography, or any bone marrow suppression, even at cumulative dosages where free DOX and pegylated liposomal DOX (Doxil®) resulted in demonstrable attenuation of cardiac function and hematological toxicities. This improvement in safety profile was achieved through a reduction of DOX-induced intracellular oxidative stress, as indicated by total glutathione levels and glutathione peroxidase activity in cardiac tissue. A composite DOX-curcumin nanoparticle that overcomes both MDR-based DOX chemoresistance and DOX-induced cardiotoxicity holds promise for providing lasting and safe anticancer therapy.

Author Information

Dipankar Pramanik

Nathaniel R Campbell

Samarjit Das

Sonal Gupta

Venugopal Chenna

Savita Bisht

Polina Sysa-shah

Djahida Bedja

Collins Karikari

Charles Steenbergen

Kathleen L. Gabrielson

Amarnath Maitra

Anirban Maitra
Primary Contact  _


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