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

• DOI: 10.18632/oncotarget.543
• Publication Date: 2015-09-16T21:49:41Z
• Authors: Dipankar Pramanik; Nathaniel R. Camp...; Samarjit Das; Sonal Gupta; Venugopal Chenna; Savita Bisht; Polina Sysa-Shah; Djahida Bedja; Collins Karikari; Charles Steenbergen; Kathleen L. Gabri...; Amarnath Maitra; Anirban Maitra
• Keywords: Male; 0301 basic medicine; Antibiotics, Antineoplastic; Curcumin; Mice, Nude; Prostatic Neoplasms; Glutathione; Xenograft Model Antitumor Assays; 3. Good health; Mice; Random Allocation; 03 medical and health sciences; Doxorubicin; Drug Resistance, Neoplasm; Cell Line, Tumor; Animals; Humans; Nanoparticles; Cardiomyopathies; Multiple Myeloma

Dipankar Pramanik 1,2,* , Nathaniel R. Campbell Samarjit Das 2 Sonal Gupta 1,2 Venugopal Chenna Savita Bisht 5 Polina Sysa-Shah 3 Djahida Bedja Collins Karikari Charles Steenbergen Kathleen L. Gabrielson Amarnath Maitra 6,π and Anirban 1,2,4 1 The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland Department Pathology, Molecular Comparative Pathobiology, 4 Oncology, Internal Medicine 3, Center Integrated Oncology Cologne-Bonn, Bonn, Germany 6 Senior Scientist, Indian National Science Academy, New Delhi, India. π Deceased * Constitutes equal contribution Received: June 19, 2012; Accepted: July 8, Published: 10, Keywords: curcumin, doxorubicin, multidrug resistance Correspondence: Maitra, email: // This manuscript is dedicated to (1943-2012), nanobiotechnology colleague, mentor extraordinary scientist. Abstract Acquired chemotherapy a major contributor treatment failure in oncology. For example, the efficacy common anticancer agent doxorubicin (DOX) limited by emergence (MDR) phenotype cancer cells. While dose escalation DOX can circumvent such degree, this precluded appearance cardiotoxicity, particularly debilitating condition children. In vitro studies have established ability natural phytochemical curcumin overcome MDR; however, its widespread clinical application restricted poor solubility low bioavailability. Building upon our recently developed polymer nanoparticle (NanoCurc or NC) that significantly enhances systemic bioavailability we synthesized doxorubicin-curcumin composite formulation called NanoDoxCurc (NDC) for overcoming resistance. Compared alone, NDC inhibited MDR caused striking growth inhibition both vivo several models DOX-resistant cancers (multiple myeloma, acute leukemia, prostate ovarian cancers, respectively). Notably, NDC-treated mice also demonstrated complete absence cardiac toxicity, as assessed echocardiography, any bone marrow suppression, even at cumulative dosages where free pegylated liposomal (Doxil®) resulted demonstrable attenuation function hematological toxicities. improvement safety profile was achieved through reduction DOX-induced intracellular oxidative stress, indicated total glutathione levels peroxidase activity tissue. A DOX-curcumin overcomes MDR-based chemoresistance cardiotoxicity holds promise providing lasting safe therapy.