Effect of obesity on biodistribution of nanoparticles

[EN] Nanoparticles have specific features (lipophilicity, surface charge, composition and size). Studies regarding the biological behavior of nanoparticles in diseases such diabetics and obesity are scarce. Here, we evaluated two nanoparticles: magnetic core mesoporous silica (MSN) (58 nm) and polycaprolactone (PCL) nanoparticle (280 nm) in obese mice. Changes in the biodistribution were observed, especially considering the mononuclear phagocyte system (MPS), and the visceral fat tissue. Nonetheless, our data corroborates the influence of size in the biodistribution in obese animals, supporting that smaller nanoparticles, may show a higher tissue deposition at spleen, due the associated splenomegaly and the complications arising from this state. Finally, our study demonstrated that, in obesity, probably due the low-grade inflammatory state associated with metabolic syndrome a difference in accumulation of nanoparticles was found, with profound impact in the tissue deposition of nanoparticles.The authors would like to thank the National Scientific and Technological Research Council (CNPQ) - no. 400018/2016-0 and the Rio de Janeiro State Research Foundation (FAPERJ) - E-26/102.940/2012 for funding. Authors also gratefully acknowledge the financial support from the Ministerio de Economía y Competitividad (Project MAT2012-38429-C04-01) and the Generalitat Valenciana (project PROMETEO/2009/016) for support.Felismino, CDJ.; Helal-Neto, E.; Portilho, F.; Rocha Pinto, S.; Sancenón Galarza, F.; Martínez-Máñez, R.; Ferreira, ADA.... (2018). Effect of obesity on biodistribution of nanoparticles. Journal of Controlled Release. 281:11-18. https://doi.org/10.1016/j.jconrel.2018.05.003S111828

Structural Insights for the Optimization of Dihydropyrimidin-2(1H)-one Based mPGES-1 Inhibitors

The recently crystallized structure of microsomal prostaglandin E2 synthase 1 (mPGES-1) in complex with the inhibitor LVJ (PDB code: 4BPM) offered new structural information for the optimization of the previously identified lead compound 1 (IC50 = 4.16 ± 0.47 μM), which contains the privileged dihydropyrimidin-2-one chemical core. Systematic optimization of 1, through accurate structure-based design, provided compound 4 with a 10-fold improved mPGES-1 inhibitory activity (IC50 = 0.41 ± 0.02 μM). Here we highlight the optimal scaffold decoration pattern of 4 and propose a three-dimensional model for the interaction with this complex trimeric membrane protein. The reported computational insights, together with the accessible one-pot synthetic procedure, stimulate for the generation of further potent dihydropyrimidine-based mPGES-1 inhibitors

Structure-Based Design of Microsomal Prostaglandin E2 Synthase-1 (mPGES-1) Inhibitors using a Virtual Fragment Growing Optimization Scheme

A small library of 2,3-dihydroxybenzamide- and N-(2,3-dihydroxyphenyl)-4-sulfonamide-based microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitors was identified following a step-by-step optimization of small aromatic fragments selected to interact in focused regions in the active site of mPGES-1. During the virtual optimization process, the 2,3-dihydroxybenzamide moiety was first selected as a backbone of the proposed new chemical entities; the identified compounds were then synthesized and biologically evaluated, identifying derivatives with very promising inhibitory activities in the micromolar range. Subsequent structure-guided replacement of the 2,3-dihydroxybenzamide by the N-(2,3-dihydroxyphenyl)sulfonamide moiety led to the identification of N-(2,3-dihydroxyphenyl)-4-biphenylsulfonamide (6), the most potent small molecule of the series (IC50=0.53±0.04 μm). The simple synthetic procedure and the possibility of enhancing the potency of this class of inhibitors through additional structural modifications pave the way for further development of new molecules with mPGES-1-inhibitory activity, with potential application as anti-inflammatory and anticancer agents