title: Delivery as nanoparticles reduces imatinib mesylate-induced cardiotoxicity and improves anticancer activity.
abstract: Clinical effectiveness of imatinib mesylate in cancer treatment is compromised by its off-target cardiotoxicity. In the present study, we have developed physically stable imatinib mesylate-loaded poly(lactide-co-glycolide) nanoparticles (INPs) that could sustainably release the drug, and studied its efficacy by in vitro anticancer and in vivo cardiotoxicity assays. MTT (methylthiazolyldiphenyl-tetrazolium bromide) assay revealed that INPs are more cytotoxic to MCF-7 breast cancer cells compared to the equivalent concentration of free imatinib mesylate. Wistar rats orally administered with 50 mg/kg INPs for 28 days showed no significant cardiotoxicity or associated changes. Whereas, increased alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels, and reduced white blood cell, red blood cell, and hemoglobin content were observed in the animals administered with free drug. While the histological sections from hearts of animals that received INPs did not show any significant cardiotoxic symptoms, loss of normal architecture and increased cytoplasmic vacuolization were observed in the heart sections of animals administered with free imatinib mesylate. Based on these results, we conclude that nano-encapsulation of imatinib mesylate increases its efficacy against cancer cells, with almost no cardiotoxicity.
authors.affiliation: AgroBioPlant Group, Centre for the Research and Technology of Agro-Environment and Biological Sciences (CITAB), University of Minho, Braga, Portugal.
authors.forename: Gregory
authors.initials: G
authors.lastname: Marslin
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal ; ICVS/3B's - PT Government Associate Laboratory, Braga/ Guimarães, Portugal.
authors.forename: Ann Mary
authors.initials: AM
authors.lastname: Revina
authors.affiliation: Department of Translational Pharmacology, Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy.
authors.forename: Vinoth Kumar Megraj
authors.initials: VK
authors.lastname: Khandelwal
authors.affiliation: Department of Pharmaceutics, PSG College of Pharmacy, Coimbatore, Tamil Nadu, India.
authors.forename: Krishnamoorthy
authors.initials: K
authors.lastname: Balakumar
authors.affiliation: Department of Pharmaceutics, Vels University, Chennai, Tamil Nadu, India.
authors.forename: Jose
authors.initials: J
authors.lastname: Prakash
authors.affiliation: AgroBioPlant Group, Centre for the Research and Technology of Agro-Environment and Biological Sciences (CITAB), University of Minho, Braga, Portugal.
authors.forename: Gregory
authors.initials: G
authors.lastname: Franklin
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal ; ICVS/3B's - PT Government Associate Laboratory, Braga/ Guimarães, Portugal ; Regenerative Medicine Program, Department of Biomedical Sciences and Medicine, University of Algarve, Faro, Portugal.
authors.forename: Caroline J
authors.initials: CJ
authors.lastname: Sheeba
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D054715:Cardiotoxins / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D000068877:Imatinib Mesylate / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D061986:MCF-7 Cells; D053758:Nanoparticles / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000970:Antineoplastic Agents; D054715:Cardiotoxins; D000068877:Imatinib Mesylate
keywords: cardiotoxicity; cytotoxicity; hematology; imatinib nanoparticles