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Published on: December 1, 2016
Antiangiogenic Therapeutic mRNA Delivery Using Lung-Selective Polymeric Nanomedicine for Lung Cancer Treatment
Ngoc Duy Le1, Bao Loc Nguyen1, Basavaraj Rudragouda Patil1
1College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea.
Abstract:
Therapeutic antibodies that block vascular endothelial growth factor (VEGF) show clinical benefits in treating nonsmall cell lung cancers (NSCLCs) by inhibiting tumor angiogenesis. Nonetheless, the therapeutic effects of systemically administered anti-VEGF antibodies are often hindered in NSCLCs because of their limited distribution in the lungs and their adverse effects on normal tissues. These challenges can be overcome by delivering therapeutic antibodies in their mRNA form to lung endothelial cells, a primary target of VEGF-mediated pulmonary angiogenesis, to suppress the NSCLCs. In this study, we synthesized derivatives of poly(β-amino esters) (PBAEs) and prepared nanoparticles to encapsulate the synthetic mRNA encoding bevacizumab, an anti-VEGF antibody used in the clinic. Optimization of nanoparticle formulations resulted in a selective lung transfection after intravenous administration. Notably, the optimized PBAE nanoparticles were distributed in lung endothelial cells, resulting in the secretion of bevacizumab. We analyzed the protein corona on the lung- and spleen-targeting nanoparticles using proteomics and found distinctive features potentially contributing to their organ-selectivity. Lastly, bevacizumab mRNA delivered by the lung-targeting PBAE nanoparticles more significantly inhibited tumor proliferation and angiogenesis than recombinant bevacizumab protein in orthotopic NSCLC mouse models, supporting the therapeutic potential of bevacizumab mRNA therapy and its selective delivery through lung-targeting nanoparticles. Our proof-of-principle results highlight the clinical benefits of nanoparticle-mediated mRNA therapy in anticancer antibody treatment in preclinical models.
Insights
Novel nanoparticles deliver anti-VEGF antibody mRNA directly to lung cells, enhancing cancer treatment. This targeted mRNA therapy shows greater efficacy than traditional protein delivery for nonsmall cell lung cancer.
Area of Science:
- Biotechnology
- Nanomedicine
- Oncology
Background:
- Vascular Endothelial Growth Factor (VEGF) inhibitors improve nonsmall cell lung cancer (NSCLC) treatment by blocking tumor angiogenesis.
- Systemic delivery of anti-VEGF antibodies faces challenges including poor lung distribution and off-target effects.
- Messenger RNA (mRNA) delivery offers a potential alternative for targeted antibody production within lung endothelial cells.
Purpose of the Study:
- To develop and optimize poly(β-amino esters) (PBAEs) nanoparticles for selective lung delivery of bevacizumab mRNA.
- To evaluate the efficacy of nanoparticle-mediated bevacizumab mRNA delivery in preclinical models of NSCLC.
- To investigate the organ-selectivity of these nanoparticles through proteomic analysis of their protein corona.
Main Methods:
- Synthesis of PBAE derivatives and encapsulation of bevacizumab mRNA into nanoparticles.
- Intravenous administration of optimized nanoparticles in orthotopic NSCLC mouse models.
- Analysis of nanoparticle biodistribution, protein corona composition (proteomics), and therapeutic efficacy (tumor proliferation, angiogenesis).
Main Results:
- Optimized PBAE nanoparticles demonstrated selective lung transfection and distribution in lung endothelial cells after intravenous administration.
- Proteomic analysis revealed distinct protein corona features on lung- and spleen-targeting nanoparticles, suggesting organ-selectivity.
- Bevacizumab mRNA delivered via lung-targeting nanoparticles significantly inhibited tumor proliferation and angiogenesis compared to recombinant bevacizumab protein.
Conclusions:
- Nanoparticle-mediated delivery of therapeutic antibody mRNA represents a promising strategy for enhanced anticancer therapy.
- Selective lung delivery of bevacizumab mRNA using PBAE nanoparticles overcomes limitations of traditional antibody treatments for NSCLC.
- This approach holds significant potential for improving the efficacy and safety of antibody-based cancer therapies.
