Ponatinib (Pon) is
a multi-tyrosine kinase inhibitor that demonstrated
high efficiency for treating cancer. However, severe side effects
caused by Pon off-targeting effects prevent its extensive use. Using
our understanding into the mechanisms by which Pon is transported
by bovine serum albumin in the blood, we have successfully encapsulated
Pon into a biomimetic nanoparticle (NP). This lipid NP (i.e., “leukosomes”)
incorporates membrane proteins purified from activated leukocytes
that enable immune evasion, and enhanced targeting of inflamed endothelium
NPs have been characterized for their size, charge, and encapsulation
efficiency. Membrane proteins enriched on the NP surface enabled modulation
of Pon release. These NP formulations showed promising dose–response
results on two different murine osteosarcoma cell lines, F420 and
RF379. Our results indicate that our fabrication method is reproducible,
nonuser-dependent, efficient in loading Pon, and applicable toward
repurposing numerous therapeutic agents previously shelved due to
toxicity profiles.
The pro‐inflammatory microenvironment that contributes to atherosclerotic plaque progression is sustained by M1 macrophages. Metabolic reprogramming toward heightened glycolysis accompanies M1 macrophage polarization, with approaches aimed at lessening glycolytic metabolism in macrophages standing to impact disease progression. The objective is to decrease the inflammatory response in atherosclerotic lesions by inducing favorable metabolic phenotypes in macrophages using an innovative mitochondrial transplantation strategy. The hypothesis is that delivery of mitochondria, functionalized with a dextran and triphenylphosphonium (Dextran‐TPP) polymer conjugate for enhanced cellular transplantation, to atherosclerotic plaques properly regulates M1 macrophage bioenergetics, attenuating inflammatory processes and preventing plaque progression. Dextran‐TPP mitochondria transplantation to M1 macrophages has profound effects on cell bioenergetics, resulting in increased oxygen consumption rate and reduced glycolytic flux that coincides with a decreased inflammatory response. Upon intravenous delivery to ApoE−/− mice fed a high fat diet, Dextran‐TPP mitochondria accumulate in aortic plaques and co‐localize with macrophages. Importantly, Dextran‐TPP mitochondria treatment reduces the plaque burden in ApoE−/− mice, improving cholesterol levels, and ameliorating hepatic steatosis and inflammation. Findings highlight Dextran‐TPP mitochondria as a novel biological particle for the treatment of atherosclerosis, underlining the potential for macrophage metabolic regulation as a therapy in other diseases.
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