Daunorubicin

Small extracellular vesicles (sEVs) critically orchestrate inter-tissue and inter-organ communications and may play essential roles in heart-tumor interaction. However, whether cancer-secreted sEVs affect the progression of doxorubicin-induced cardiotoxicity (DOXIC) via orchestrating the tumor cell-cardiomyocyte crosstalk has not yet been explored. Herein, we reveal that Doxorubicin (DOX)-treated breast cancer cells secrete sEVs (D-BCC-sEVs) that exacerbate DOX-induced ferroptosis of human iPSC-derived cardiomyocytes (hiCMs). miRNA expression profiling and experimental validations reveal that miR-338-3p is upregulated in D-BCC-sEVs and mediate its detrimental effects. Incubation of hiCMs with D-BCC-sEVs or overexpression of miR-338-3p alone intensifies DOX-induced ferroptosis. N6-methyladenosine (m6A) is revealed to mediate the upregulation of miR-338-3p in D-BCCs. D-BCCs-enriched miR-338-3p is packaged in sEVs and transferred into hiCMs in a RBMX-dependent manner, miR-338-3p further targets anti-ferroptotic genes CP, SLC7A11, and GPX4 to facilitate their degradation. Therapeutically, dual-functional decoying sEVs encapsulated with miR-338-3p inhibitor mitigate DOXIC in an orthotopic breast cancer mouse model. Clinically, plasma sEVs isolated from patients experiencing DOXIC enhance DOX-induced ferroptosis in hiCM, which is rescued by miR-338-3p inhibitor. Our findings uncovered for the first time that DOX-treated BCCs exacerbated DOXIC through releasing pro-ferroptotic miR-338-3p-enriched sEVs. Therefore, targeting sEVs-mediated tumor/cardiomyocyte pathological communication may offer a novel approach for the management of DOXIC.

Despite the significant antitumor potential of doxorubicin and its widespread use in the treatment of various oncological diseases, its application is associated with side effects, among which the most common are cardiotoxicity, hepatotoxicity, nephrotoxicity, neurotoxicity, and gonadotoxicity. In contemporary times, innovative strategies to overcome the toxicity of doxorubicin and improve the effectiveness of therapies are intensively researched. The aim of this review is to discuss different approaches to alleviate the common toxic effects of doxorubicin, with an emphasis on oxidative stress. In particular, the review analyzes the significance of pharmaceutical nanotechnology for reducing doxorubicin toxicity while maintaining its antitumor effect (e.g., encapsulation of doxorubicin in passively and/or actively targeted nanoparticles to tumor tissue and cells). Other strategies commented in the review are the simultaneous delivery of doxorubicin with antioxidants and the administration of its derivatives with lower toxicity.

Doxorubicin (Dox) is a potent anthracycline antitumor drug whose clinical utility is significantly restricted by its dose-dependent, cumulative cardiotoxicity, driven by increased oxidative stress, impaired antioxidant defenses, and apoptosis-mediated cardiomyocyte loss. Methylene blue (MB), a phenothiazine derivative with well-documented redox-modulating properties, is being explored as a viable cardioprotective agent due to its antioxidant and anti-apoptotic effects. This study evaluated the protective role of MB against Dox-induced cardiotoxicity in rats by examining its impact on oxidative stress markers (Kelch-like ECH-associated protein 1; KEAP1, nuclear factor erythroid 2-related factor 2; NRF2, Glutathione peroxidase 4; GPX-4, 8-hydroxy-2'-deoxyguanosine; 8-OHdG), neurohormonal indicators (noradrenaline), cardiac injury biomarkers (troponin I), and apoptotic mediators (p53, Caspase-3). Forty male albino rats were divided equally into four groups: control, Dox (15 mg/kg, i.p.), MB alone (4 mg/kg/day, p.o. for 7 days), and Dox plus MB. Dox administration significantly increased serum troponin I and noradrenaline levels, elevated cardiac KEAP1 and 8-OHdG, and reduced NFE2L2, NRF2, and GPX-4 expression. It also upregulated p53 and Caspase-3 and caused marked myocardial degeneration, necrosis, and inflammatory infiltration. MB co-treatment significantly reduced troponin I and noradrenaline levels, restored KEAP1/NFE2L2 (NRF2)/GPX-4 pathway balance, decreased oxidative DNA damage, and attenuated p53 and Caspase-3 activation, preserving myocardial architecture with minimal inflammatory changes. These findings demonstrate that MB confers potent cardioprotection against Dox-induced cardiac injury by enhancing antioxidant defenses, limiting oxidative DNA damage, suppressing apoptosis, and normalizing neurohormonal imbalance, suggesting its promise as an adjunctive strategy to mitigate anthracycline-associated cardiotoxicity.

Hypoxia is a key feature of solid tumors, contributing to therapeutic resistance and poor prognosis. Targeting hypoxic environments presents an opportunity to enhance drug delivery selectivity and improve treatment outcomes. Among nanocarriers, mesoporous silica nanoparticles (MSNs) have demonstrated great potential for drug delivery; however, achieving precise control over drug release remains a challenge. In this work, we develop an enzyme-responsive MSN system for targeted drug delivery in hypoxic tumors. MSNs were loaded with the chemotherapeutic drug doxorubicin (Dox) and capped with an azobenzene (Azo) gatekeeper. The bulky Azo group acts as a responsive molecular gate that remains closed under normoxic conditions but undergoes enzymatic cleavage by azoreductases, which are overexpressed in hypoxic tumor microenvironment. This cleavage triggers the uncapping of the pores, inducing the release of Dox specifically in the hypoxic region, minimizing premature drug leakage and off-target toxicity. In vitro studies with A549 cells (which overexpress azoreductase) and THP-1 cells (with low expression of azoreductases) under normoxic and hypoxic conditions, demonstrated a significant increase in Dox release and cytotoxicity in the A549 cells compared with the THP-1, which was more pronounced under hypoxia. These findings highlight the potential of enzyme-responsive MSNs as a promising strategy for selective drug delivery in hypoxic tumors.