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Targeted niosomes protect the heart from doxorubicin-induced injury: evidence from oxidative stress, pyroptosis, and
Singaravel Vijayapoopathi1, Kalaiyarasi Kasirajan2, Malathi Sampath3
1Saveetha Institute of Basic Medical Sciences (SIBMS), Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, Tamil Nadu 602105 India.
Abstract:
Doxorubicin (DOX) is a frontline chemotherapeutic agent whose clinical utility is significantly limited by dose-dependent and often irreversible cardiotoxicity. Niosomal drug delivery systems, owing to their biocompatibility and tumour-targeting potential, often a promising strategy to enhance therapeutic efficacy while mitigating systemic toxicity. In this study, we developed epidermal growth factor receptor (EGFR)-targeted, centuximab-conjugated niosomes co-loaded with DOX and vitexin (NIODVC) and evaluated their cardioprotective efficacy in 4T1 breast tumor-bearing BALB/c mice. Non-targeted niosomes (NIODV) facilitated tumor-specific delivery but were associated with cardiac injury. In contrast, centuximab-modified NIODVC improved formulation stability, enhanced therapeutic effectiveness, and reduced off-target cardiotoxicity. Cardioprotection was supported by normalization of hematological indices, restoration of serum biochemical and oxidative stress markers, preservation of antioxidant competence, and maintenance of myocardial histoarchitecture. Molecular analysis demonstrated upregulation of antioxidant genes (Nrf2, Ho-1, Nqo1, Sod1, Sod2) and suppression of the pro-oxidant gene p67phox. NIODVC also reduced expression of pyroptosis-related mediators (Nlrp3, Caspase-1, Gsdmd, Il-1β, Il-18) and favorably modulated apoptotic balance by increasing Bcl2 and reducing Bax expression relative to NIODV. Notably, intratumoural administration provided grater cardioprotection than intravenous delivery. Taken together, these findings suggest that NIODVC represents a multifunctional nanocarrier capable of enhancing anticancer efficacy while mitigating DOX-induced cardiac injury, Supports its potential for safer breast cancer chemotherapy.
Insights
EGFR-targeted niosomes co-loaded with doxorubicin and vitexin (NIODVC) effectively treat breast cancer while protecting the heart from doxorubicin-induced cardiotoxicity. Intratumoral delivery enhanced these cardioprotective effects.
Area of Science:
- Nanomedicine
- Pharmacology
- Oncology
Background:
- Doxorubicin (DOX) is a vital chemotherapy drug, but its use is limited by cardiotoxicity.
- Niosomal drug delivery systems offer potential for targeted delivery and reduced systemic toxicity.
- EGFR-targeted niosomes show promise for enhancing cancer therapy efficacy and safety.
Purpose of the Study:
- To develop and evaluate EGFR-targeted, centuximab-conjugated niosomes co-loaded with DOX and vitexin (NIODVC).
- To assess the cardioprotective efficacy of NIODVC in a 4T1 breast tumor mouse model.
- To compare the therapeutic and cardioprotective effects of targeted vs. non-targeted niosomes.
Main Methods:
- Development of EGFR-targeted niosomes (NIODVC) co-loaded with DOX and vitexin.
- Evaluation in 4T1 breast tumor-bearing BALB/c mice.
- Assessment of cardiac function, oxidative stress markers, antioxidant gene expression, pyroptosis, and apoptosis.
- Comparison of intravenous and intratumoral administration routes.
Main Results:
- NIODVC demonstrated improved formulation stability, enhanced anti-tumor efficacy, and reduced cardiotoxicity compared to non-targeted niosomes (NIODV).
- NIODVC normalized hematological indices, restored biochemical and oxidative stress markers, and preserved myocardial histoarchitecture.
- Molecular analysis revealed upregulation of antioxidant genes, suppression of pro-oxidant genes, reduced pyroptosis mediators, and a favorable apoptotic balance.
- Intratumoral administration of NIODVC provided superior cardioprotection.
Conclusions:
- EGFR-targeted niosomes (NIODVC) represent a promising nanocarrier for safer breast cancer chemotherapy.
- NIODVC enhances anticancer efficacy while mitigating DOX-induced cardiotoxicity.
- Targeted delivery and intratumoral administration are key strategies for maximizing therapeutic benefits and minimizing cardiac side effects.
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