RESUMEN
The possibility to affect bone formation by using crushed versus solid hydrogels as carriers for bone morphogenetic protein 2 (BMP-2) was studied. Hydrogels, based on chemical crosslinking between hyaluronic acid and poly(vinyl alcohol) derivatives, were loaded with BMP-2 and hydroxyapatite. Crushed and solid forms of the gels were analyzed both in vitro via a release study using ¹²5I radioactive labeling of BMP-2, and in vivo in a subcutaneous ectopic bone model in rats. Dramatically different morphologies were observed for the ectopic bone formed in vivo in the two types of gels, even though virtually identical release profiles were observed in vitro. Solid hydrogels induced formation of a dense bone shell around non-degraded hydrogel, while crushed hydrogels demonstrated a uniform bone formation throughout the entire sample. These results suggest that by crushing the hydrogel, the construct's three-dimensional network becomes disrupted. This could expose unreacted functional groups, making the fragment's surfaces reactive and enable limited chemical fusion between the crushed hydrogel fragments, leading to similar in vitro release profiles. However, in vivo these interactions could be broken by enzymatic activity, creating a macroporous structure that allows easier cell infiltration, thus, facilitating bone formation.
Asunto(s)
Proteína Morfogenética Ósea 2/farmacología , Ácido Hialurónico/farmacología , Hidrogel de Polietilenoglicol-Dimetacrilato/farmacología , Osteogénesis/efectos de los fármacos , Animales , Densidad Ósea/efectos de los fármacos , Proteína Morfogenética Ósea 2/farmacocinética , Coristoma/inducido químicamente , Coristoma/patología , Implantes de Medicamentos/química , Implantes de Medicamentos/farmacocinética , Implantes de Medicamentos/farmacología , Ácido Hialurónico/química , Ácido Hialurónico/farmacocinética , Hidrogel de Polietilenoglicol-Dimetacrilato/química , Hidrogel de Polietilenoglicol-Dimetacrilato/farmacocinética , Masculino , Tamaño de los Órganos/efectos de los fármacos , Porosidad , Ratas , Ratas Sprague-Dawley , Enfermedades de la Piel/inducido químicamente , Enfermedades de la Piel/patología , Propiedades de SuperficieRESUMEN
New analogues of the previously described 3-aryl pyridone KOR agonists have been synthesised by parallel synthetic methods, both in solution- and with solid-phase chemistry, making use of the well known and versatile Mitsunobu, Suzuki and Buchwald reactions. Opioid receptor binding data for the compounds produced is reported.
Asunto(s)
Piridonas/síntesis química , Piridonas/farmacología , Receptores Opioides kappa/agonistas , Alquilación , Fenómenos Químicos , Química Física , Indicadores y Reactivos , Biblioteca de Péptidos , Receptores Opioides delta/química , Receptores Opioides delta/metabolismo , Receptores Opioides kappa/química , Receptores Opioides mu/química , Receptores Opioides mu/metabolismo , Soluciones , Relación Estructura-ActividadRESUMEN
A new series of 3-aryl pyridone based kappa opioid receptor agonists was designed and synthesised, based on an understanding of the classical kappa opioid receptor pharmacophore. The most potent of the new compounds were comparable to U-69,593 in receptor affinity, selectivity and functional agonist effect at the cloned human kappa opioid receptor.