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Published on: February 5, 2019
Ligand-directed oral lipidic nanoplatform enables sustained ferroptosis and immune reprogramming via multivalent
Laxman Subedi1,2, In Ho Im3,4, Arjun Dhwoj Bamjan1
1Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, Biomedical and Healthcare Research Institute, Mokpo National University, Jeonnam 58554, Republic of Korea.
Abstract:
Rationale: Ferroptosis-induced tumor cell death and immune activation represent promising strategies for overcoming therapeutic resistance in triple-negative breast cancer (TNBC). However, clinical application remains limited by poor oral absorption, transient immune activation, and systemic toxicity. Methods: We developed an orally administrable nanoplatform (MCT-NE#9) co-delivering docetaxel (DTX) and atorvastatin (ATV), designed to enhance intestinal uptake via bile acid and vitamin transporters. Pharmacokinetic, in vitro, and in vivo studies were conducted to evaluate drug absorption, sustained ferroptosis, and immune modulation. Results: MCT-NE#9 markedly improved oral bioavailability (659% for ATV, 851% for DTX) and sustained intratumoral drug levels under a low-dose metronomic regimen. Mechanistically, it induced sustained ferroptosis by promoting iron accumulation, lipid peroxidation, and GPX4 suppression, while remodeling the tumor immune microenvironment. Treatment increased M1 macrophages and antigen-presenting cells and reduced TGFβ1, regulatory T cells, and M2 macrophages. In vivo, oral MCT-NE#9 suppressed tumor growth by 50.4%, with enhanced efficacy (70.3% inhibition) when combined with anti-CD47 therapy. Conclusion: MCT-NE#9 enables a synergistic, low-toxicity chemo-immunotherapeutic strategy by sustaining ferroptosis and reprogramming the immune microenvironment via transporter-targeted oral delivery. This ligand-directed nanoplatform offers a clinically translatable approach for effective TNBC treatment.
Insights
A novel oral nanoplatform (MCT-NE#9) co-delivering docetaxel and atorvastatin enhances ferroptosis and reshapes the tumor immune microenvironment for triple-negative breast cancer (TNBC) treatment with reduced toxicity.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Therapy
Background:
- Ferroptosis induction and immune activation are key strategies against triple-negative breast cancer (TNBC).
- Clinical translation of ferroptosis inducers is hindered by poor oral absorption, transient immune responses, and systemic toxicity.
- Targeted drug delivery is crucial for enhancing efficacy and minimizing side effects in TNBC treatment.
Purpose of the Study:
- To develop an orally administrable nanoplatform (MCT-NE#9) for co-delivering docetaxel (DTX) and atorvastatin (ATV).
- To enhance intestinal drug uptake via bile acid and vitamin transporters for sustained ferroptosis and immune modulation in TNBC.
- To evaluate the therapeutic efficacy and safety of MCT-NE#9 in preclinical TNBC models.
Main Methods:
- Development of MCT-NE#9 nanoplatform for oral delivery of DTX and ATV, utilizing transporter-mediated intestinal uptake.
- Pharmacokinetic studies to assess oral bioavailability and intratumoral drug distribution.
- In vitro and in vivo experiments to evaluate ferroptosis induction, immune microenvironment modulation, and tumor growth inhibition.
- Combination therapy assessment with anti-CD47 immunotherapy.
Main Results:
- MCT-NE#9 significantly improved oral bioavailability of ATV (659%) and DTX (851%).
- Sustained ferroptosis was induced via iron accumulation, lipid peroxidation, and GPX4 suppression, alongside immune reprogramming (M1 macrophage increase, Treg/M2 decrease).
- Oral MCT-NE#9 achieved 50.4% tumor growth suppression, with 70.3% inhibition when combined with anti-CD47 therapy.
Conclusions:
- MCT-NE#9 facilitates a synergistic, low-toxicity chemo-immunotherapeutic strategy for TNBC by sustaining ferroptosis and reprogramming the tumor immune microenvironment.
- Transporter-targeted oral delivery enhances drug bioavailability and therapeutic outcomes.
- This ligand-directed nanoplatform presents a clinically translatable approach for effective TNBC treatment.
