A new nanomedicine platform to deliver a carnitine palmitoyl-transferase 1 (CPT1) inhibitor into glioma cells and neurons

Obesity and glioblastoma multiforme (GB) are two unmet medical needs where effective therapies are lacking. Carnitine palmitoyl transferase 1 (CPT1), an enzyme catalyzing the rate-lim- iting step in fatty acid oxidation (FAO), is a viable target for both diseases. C75, a fatty acid synthase (FAS) inhibitor, forms an adduct with coenzyme A (CoA) to form C75-CoA, which is a strong com- petitive inhibitor to CPT1 that is selective in its target. However, it is polar and charged, having low cell membrane permeability, and therefore needing a delivery system for intracellular transport. (±)-C75-CoA and its enantio-separated forms (+)- and (−)-C75-CoA were used to form poly-ion com- plex (PIC) micelles with the cationic block co-polymer PEG-PAsp(DET). The drug and polymer were mixed in a 1:1 anion/cation ratio to give 50-70 nm micelles with a unimodal size profile and narrow polydispersity. Size was maintained upon introduction of physiological saline. Micellar (±)-, (+)-, and (−)-C75-CoA were all significantly more cytotoxic compared to the respective free drugs in U87MG. We examined whether C75-CoA inhibits FAO by measuring ATP concentrations in U87MG and GT1-7. ATP generation was found to be hampered after adding C75-CoA in both cell types, with micelle-treated cells producing significantly lower ATP than those treated with free drug, suggesting that the effective intracellular delivery of C75-CoA leads to a more pronounced FAO inhibition. A fluorescent CoA derivative, Fluor-CoA, also yielded monodisperse micelles sim- ilar to C75-CoA. Micellar internalization was significantly greater than that of the free dye. Uptake of both increased with time, with this effect is more pronounced in U87MG than GT1-7. The %Fluor- CoA+ cells were also expressively higher for the micelle across cell lines. From this data, it can be convincingly concluded that neuronal and glioma cellular uptake of micelles is superior to that of the free dye, validating the need for cellular delivery systems for anionic, CoA-type molecules. The micellar form neutralized the negative charge of the cargo, promoting transport into the cell. These outcomes strongly support the effectiveness of using a PIC micelle-type system to deliver anionic small molecules into glioma cells and neurons meant to inhibit enzymes such as CPT1, for future applications in diseases like obesity and cancer

An overview of nanomedicines for neuron targeting

Medical treatments of neuron-related disorders are limited due to the difficulty of targeting brain cells. Major drawbacks are the presence of the blood-brain barrier and the lack of specificity of the drugs for the diseased cells. Nanomedicine-based approaches provide promising opportunities for overcoming these limitations. Although many previous reviews are focused on brain targeting with nanomedicines in general, none of those are concerned explicitly on the neurons, while targeting neuronal cells in central nervous diseases is now one of the biggest challenges in nanomedicine and neuroscience. We review the most relevant advances in nanomedicine design and strategies for neuronal drug delivery that might successfully bridge the gap between laboratory and bedside treatment in neurology

Heterogeneous contributions of change in population distribution of body mass index to change in obesity and underweight NCD Risk Factor Collaboration (NCD-RisC)

From 1985 to 2016, the prevalence of underweight decreased, and that of obesity and severe obesity increased, in most regions, with significant variation in the magnitude of these changes across regions. We investigated how much change in mean body mass index (BMI) explains changes in the prevalence of underweight, obesity, and severe obesity in different regions using data from 2896 population-based studies with 187 million participants. Changes in the prevalence of underweight and total obesity, and to a lesser extent severe obesity, are largely driven by shifts in the distribution of BMI, with smaller contributions from changes in the shape of the distribution. In East and Southeast Asia and sub-Saharan Africa, the underweight tail of the BMI distribution was left behind as the distribution shifted. There is a need for policies that address all forms of malnutrition by making healthy foods accessible and affordable, while restricting unhealthy foods through fiscal and regulatory restrictions

Nanomedicine targeting brain lipid metabolism as a feasible approach for controlling energy balance

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 adminis- tration of the nanomedicine induced a rapid attenuation of food intake and body weight in mice via regu- lation 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

Poly-ion complex micelle effectively delivers CoA- conjugated CPT1A inhibitors to modulate lipid metabolism in brain cells

Carnitine palmitoyltransferase 1 (CPT1) is a central player in lipid metabolism, catalyzing the first committed step to fatty acid oxidation (FAO), and is an appealing target for several diseases. However, CoA-conjugated CPT1 inhibitors are negatively-charged and have low cell membrane permeability. Herein, we report the use of a poly-ion complex (PIC) micelles to deliver the specific CPT1 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 50-60-nm particles with a neutral surface charge. Upon short-term incubation with cells, the micelle-encapsulated CPT1 inhibitors resulted in 1.5 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 oxidation of 14C-palmitate into CO2 and acid-soluble FAO metabolites, confirming that the substantial lowering of ATP production was related to FAO inhibition. Micelle treatment also diminished IC50 by 2 to 4-fold over the free-drug-treated U87MG after long-term incubation. The resulting IC50 is comparable with etomoxir. We synthesized a fluorescent CoA derivative and encapsulated it in the PIC micelle to measure cellular uptake. The fluorescent micelle showed more efficient internalization in both cell types, especially in neurons where uptake reached up to 3-fold over the free dye. The results starkly demonstrate that the PIC micelle is a promising delivery system for anionic inhibitors of CPT1 in glioma cells and neurons, laying the groundwork for future research or clinical applications

Libro Digital Proyectos Posgrados 2015-30

MaestríaDoctoradoDoctor en Ingeniería Eléctrica y ElectrónicaDoctor en Ingeniería CivilDoctor en Ingeniería de Sistemas y ComputaciónDoctor en Ingeniería IndustrialDoctor en Ingeniería MecánicaMagister en Gobierno de Tecnología InformáticaMagister en Ingeniería AdministrativaMagister en Ingeniería AmbientalMagister en Ingeniería CivilMagister en Ingeniería de Sistemas y ComputaciónMagister en Ingeniería EléctricaMagister en Ingeniería ElectrónicaMagister en Ingeniería IndustrialMagister en Ingeniería Mecánic

Diminishing benefits of urban living for children and adolescents’ growth and development

Optimal growth and development in childhood and adolescence is crucial for lifelong health and well-being1–6. Here we used data from 2,325 population-based studies, with measurements of height and weight from 71 million participants, to report the height and body-mass index (BMI) of children and adolescents aged 5–19 years on the basis of rural and urban place of residence in 200 countries and territories from 1990 to 2020. In 1990, children and adolescents residing in cities were taller than their rural counterparts in all but a few high-income countries. By 2020, the urban height advantage became smaller in most countries, and in many high-income western countries it reversed into a small urban-based disadvantage. The exception was for boys in most countries in sub-Saharan Africa and in some countries in Oceania, south Asia and the region of central Asia, Middle East and north Africa. In these countries, successive cohorts of boys from rural places either did not gain height or possibly became shorter, and hence fell further behind their urban peers. The difference between the age-standardized mean BMI of children in urban and rural areas was <1.1 kg m–2 in the vast majority of countries. Within this small range, BMI increased slightly more in cities than in rural areas, except in south Asia, sub-Saharan Africa and some countries in central and eastern Europe. Our results show that in much of the world, the growth and developmental advantages of living in cities have diminished in the twenty-first century, whereas in much of sub-Saharan Africa they have amplified

Heterogeneous contributions of change in population distribution of body mass index to change in obesity and underweight

From 1985 to 2016, the prevalence of underweight decreased, and that of obesity and severe obesity increased, in most regions, with significant variation in the magnitude of these changes across regions. We investigated how much change in mean body mass index (BMI) explains changes in the prevalence of underweight, obesity, and severe obesity in different regions using data from 2896 population-based studies with 187 million participants. Changes in the prevalence of underweight and total obesity, and to a lesser extent severe obesity, are largely driven by shifts in the distribution of BMI, with smaller contributions from changes in the shape of the distribution. In East and Southeast Asia and sub-Saharan Africa, the underweight tail of the BMI distribution was left behind as the distribution shifted. There is a need for policies that address all forms of malnutrition by making healthy foods accessible and affordable, while restricting unhealthy foods through fiscal and regulatory restrictions