posted on 2024-03-07, 13:10authored byNgoc Duy Le, Bao Loc Nguyen, Basavaraj Rudragouda Patil, HeeSang Chun, SiYoon Kim, Thi Oanh Oanh Nguyen, Sunil Mishra, Sudarshan Tandukar, Jae-Hoon Chang, Dong Young Kim, Sung Giu Jin, Han-Gon Choi, Sae Kwang Ku, Jeonghwan Kim, Jong Oh Kim
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.