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Curr Drug Deliv ; 12(1): 98-107, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25860966

RESUMEN

Synthetic analogues of the peptide hormone calcitonin have been used in medicine as biologic drug therapies for decades, to treat pathological conditions of excessive bone turnover, such as osteoporosis, where more bones are removed than replaced during bone remodeling. Osteoporosis and other chronic skeletal diseases, including inflammatory arthritis, exact a substantial and growing toll on aging populations worldwide however they respond poor to synthetic biologic drug therapy, due in part to the rapid half-life of elimination, which for calcitonin is 43 minutes. To address those shortcomings, we have developed and synthesized bone-targeting variants of calcitonin as a targeted drug delivery strategy, by conjugation to bisphosphonate drug bone-seeking functional groups in highly specific reaction conditions. To evaluate their in vivo efficacy, bisphosphonate-mediated bone targeting with PEGylated (polyethylene glycol conjugated) and non-PEGylated salmon calcitonin analogues were synthesized and dose escalation was performed in female rats developing Osteoporosis. The bone-targeting calcitonin analogues were also tested in a separate cohort of male rats developing adjuvant-induced arthritis. Ovariectomized female rats developing Osteoporosis were administered daily sub-cutaneous injection of analogues equivalent to 5, 10 and 20 IU/kg of calcitonin for 3 months. Adjuvant arthritis was developed in male rats by administering Mycobacterium butyricum through tail base injection. Daily sub-cutaneous injection of analogues equivalent to 20 IU/kg of calcitonin was administered and the rats were measured for visible signs of inflammation to a 21 day endpoint. In both studies, the effect of drug intervention upon bone volume and bone mineral density (BMD) was assessed by measuring the trabecular bone volume percentage and BMD at the proximal tibial metaphysis using in vivo micro-computed tomography. With dose escalation studies, only bone targeting analogue dosed groups showed a trend towards increased BMD and bone volume at 4, 8 and 12 weeks. Significant preservation of bone volume and BMD as evidenced by nonsignificant (P<0.05) loss of bone volume and BMD at the end of 3 month study endpoint was seen in animals dosed with 20 IU/kg of calcitonin compounds. Similarly, in case of adjuvant-induced arthritis rats, there was a significant increase (P<0.05) in bone volume and BMD in calcitonin-bisphosphonate and calcitonin-PEG-bisphosphonate treated groups at 21 days compared to the baseline values. Improved efficacy in terms of preserving bone volume and BMD in Osteoporosis, and in rats developing adjuvant-induced arthritis, by these analogues suggests their potential as new drug candidates for further evaluation to determine their usefulness in bone diseases characterized by excessive bone resorption.


Asunto(s)
Artritis Experimental/tratamiento farmacológico , Conservadores de la Densidad Ósea/administración & dosificación , Calcitonina/administración & dosificación , Difosfonatos/administración & dosificación , Osteoporosis Posmenopáusica/tratamiento farmacológico , Animales , Articulación del Tobillo/diagnóstico por imagen , Articulación del Tobillo/efectos de los fármacos , Articulación del Tobillo/fisiopatología , Artritis Experimental/diagnóstico por imagen , Artritis Experimental/microbiología , Artritis Experimental/fisiopatología , Densidad Ósea/efectos de los fármacos , Conservadores de la Densidad Ósea/química , Remodelación Ósea/efectos de los fármacos , Calcitonina/química , Química Farmacéutica , Difosfonatos/química , Portadores de Fármacos , Femenino , Humanos , Inyecciones Subcutáneas , Masculino , Mycobacterium , Osteoporosis Posmenopáusica/diagnóstico por imagen , Osteoporosis Posmenopáusica/etiología , Osteoporosis Posmenopáusica/fisiopatología , Ovariectomía , Polietilenglicoles/química , Ratas Sprague-Dawley , Tecnología Farmacéutica/métodos , Tibia/diagnóstico por imagen , Tibia/efectos de los fármacos , Tibia/fisiopatología , Factores de Tiempo , Microtomografía por Rayos X
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