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Targeting brain lipid metabolism is a promising strategy to regulate the energy balance and fight metabolic diseases such as obesity. The development of stable platforms for selective delivery of drugs, particularly to the hypothalamus, is a challenge but a possible solution for these metabolic diseases. Attenuating fatty acid oxidation in the hypothalamus via CPT1A inhibition leads to satiety, but this target is difficult to reach in vivo with the current drugs. We propose using an advanced crosslinked polymeric micelle-type nanomedicine that can stably load the CPT1A inhibitor C75-CoA for in vivo control of the energy balance. Central administration of the nanomedicine induced a rapid attenuation of food intake and body weight in mice via regulation of appetite-related neuropeptides and neuronal activation of specific hypothalamic regions driving changes in the liver and adipose tissue. This nanomedicine targeting brain lipid metabolism was successful in the modulation of food intake and peripheral metabolism in mice. info:eu-repo/semantics/publishedVersion

Carnitine palmitoyltransferase 1A (CPT1A) is a central player in lipid metabolism, catalyzing the first step to fatty acid oxidation (FAO). Inhibiting CPT1A, especially in the brain, can have several pharmacological benefits, such as in treating obesity and brain cancer. C75-CoA is a strong competitive inhibitor of CPT1A. However, due to its negatively charged nature, it has low cellular permeability. Herein, we report the use of poly-ion complex (PIC) micelles to deliver the specific CPT1A inhibitors (±)-, (+)-, and (-)-C75-CoA into U87MG glioma cells and GT1-7 neurons. PIC micelles were formed through charge-neutralization of the cargo with the cationic side chain of PEG-poly{N-[N'-(2-aminoethyl)-2-aminoethyl]aspartamide} (PEG-PAsp(DET)), forming particles with 55 to 65 nm diameter. Upon short-term incubation with cells, the micelle-encapsulated CPT1A inhibitors resulted in up to 5-fold reduction of ATP synthesis compared to the free drug, without an apparent decline in cell viability. Micelle treatment showed a discernible decrease in 14C-palmitate oxidation into CO2 and acid-soluble metabolites, confirming that the substantial lowering of ATP production has resulted from FAO inhibition. Micelle treatment also diminished IC50 by 2 to 4-fold over the free drug-treated U87MG after long-term incubation. To measure the cellular uptake of these CoA-adduct loaded PIC micelles, we synthesized a fluorescent CoA derivative and prepared Fluor-CoA micelles which showed efficient internalization in the cell lines, both in 2D and 3D culture models, especially in neurons where uptake reached up to 3-fold over the free dye. Our results starkly demonstrate that the PIC micelles are a promising delivery platform for anionic inhibitors of CPT1A in glioma cells and neurons, laying the groundwork for future research or clinical applications.