Mitochondria-Specific Nano-Emulsified Therapy for Myocardial Protection Against Doxorubicin-Induced Cardiotoxicity

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Abstract

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.