Mitochondria-Specific Nano-Emulsified Therapy for Myocardial Protection Against Doxorubicin-Induced Cardiotoxicity
The quinonoid anthracycline, doxorubicin (Adriamycin), is a widely used potent antineoplastic agent, showing the broadest spectrum of antineoplastic activity against various types of solid carcinomas, hematological malignancies, and soft tissue sarcomas. Unfortunately, the clinical use of doxorubicin is associated with cumulative dose-limiting cardiac toxicity, manifested as cardiomyopathy and congestive heart failure, in which mitochondrial damage is primarily implicated. Free radical formation at and inside mitochondria, in particular the rise of reactive oxygen species (ROS), has long been hypothesized as the common mechanism by which doxorubicin causes this severe cardiotoxicity. Concomitant with newly gained insights into the central role of mitochondria in programmed cell death (apoptosis), irreversible destabilization of mitochondrial membrane permeability transition (mMPT), and disruption of mitochondrial Ca2+ homeostasis have been strongly implicated in triggering myocardial apoptosis, due to accumulated doxorubicin dosing.
Hence, our current protocols show the development of mitochondria-targeted nanoemulsions (NEs), based on previous work using nano-vesicle surface modification with mitochondriotropic triphenylphosphonium (TPP) ligands, which have successfully been demonstrated to target drug and DNA-loaded liposomes to mitochondria in living mammalian cells. Our mitochondria-specific TPP-coated therapeutic NEs are prepared using tocopherol oxygen scavengers and are highly loaded with mitochondria-stabilizing therapeutics, namely, cyclosporine A (CsA). Our targeted nano-formulation, proposed as injectable adjuvant therapy, is capable of reaching target affected mitochondria in sufficient therapeutic concentration, in order to revert or at least limit oxidative and non-oxidative doxorubicin-induced mitochondrial damage, manifested in affected cardiac muscle tissues, Based on several encouraging studies using in vitro model rat cardiac muscle, H9C2 cardiomyocytes, and vascular media tunica media, A10, cell cultures, our proof-of principal mitochondriotropic nano-therapy demonstrates strong potential to improve not only the cardiac safety profile, through concurrent rescue administration of targeted nano-encapsulated FDA-approved cyclosporine A (CSA), but also dosing range of the currently available potent adriamycin/doxorubicin-based chemotherapy regimens.
Key wordsAnthracycline Mitochondrial damage Mitochondriotropic Cyclosporine A Cardiomyocytes Chaotropic effect Apoptosis
- 2.Allen A (1992) The cardiotoxicity of chemotherapeutic drugs. Semin Oncol 19:529–542Google Scholar
- 3.Doroshow JH (1983) Effect of anthracycline antibiotics on oxygen radical formation in rat heart. Cancer Res 43:460–472Google Scholar
- 4.DiPiro JT, Talbert RL (2002) Pharmacotherapy: a pathophysiologic approach, 5th edn. McGraw-Hill, LondonGoogle Scholar
- 6.Doroshow JH (1983) Anthracycline antibiotic-stimulated superoxide, hydrogen peroxide, and hydroxyl radical production by NADH dehydrogenase. Cancer Res 43:4543–4551Google Scholar
- 9.Zhou S, Starkov A, Froberg MK, Leino RL, Wallace KB (2001) Cumulative and irreversible cardiac mitochondrial dysfunction induced by doxorubicin. Cancer Res 61:771–777Google Scholar
- 13.Boddapati SV, Tongcharoensirikul P, Hanson RN, D’Souza GG, Torchilin VP, Weissig V (2005) Mitochondriotropic liposomes. J Liposome Res 15:49–58Google Scholar