RESUMO
The use of lanthanide-based contrast agents for magnetic resonance imaging has become an integral component of this important diagnostic modality. These inert chelates typically possess high thermodynamic stability constants that serve as a predictor for in vivo stability and low toxicity. Recently, a new class of contrast agents was reported having a significantly lower degree of thermodynamic stability while exhibiting biodistribution profiles indicative of high stability under biological conditions. These observations are suggestive that the nature of contrast agent stability is also dependent upon the kinetics of complex dissociation, a feature of potential importance when contemplating the design of new chelates for in vivo use. We present a study of the kinetics of acid-catalyzed dissociation, thermodynamic stability, serum stability, and biodistribution of a series of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-tetraamide complexes that have been substituted with peripheral hydroxyl groups. The data indicate that these nontraditional contrast agents exhibit in vivo stability comparable to that of agents with much higher log K (ML) values, demonstrating the important contribution of kinetic inertness.
Assuntos
Amidas/química , Compostos Heterocíclicos com 1 Anel/química , Radical Hidroxila/química , Elementos da Série dos Lantanídeos/química , Compostos Organometálicos/síntese química , Compostos Organometálicos/farmacocinética , Animais , Meios de Contraste/síntese química , Meios de Contraste/química , Meios de Contraste/farmacocinética , Radical Hidroxila/sangue , Íons/química , Cinética , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Conformação Molecular , Compostos Organometálicos/sangue , Potenciometria , Prótons , Ratos , Estereoisomerismo , Termodinâmica , Distribuição TecidualRESUMO
The synthesis and biodistribution of three triazine dendrimers differing in PEGylation are described. Dendrimers 1, 2, and 3 are derived from a common intermediate, dendrimer 4, and vary in molecular mass from 11 to 73 kDa as a result of PEGylation with multiple (theoretically, 16) PEG groups of 0.6, 2, and 5 kDa, respectively. As expected, elimination half-lives increased with an increase in molecular mass. In light of other results, however, molecular mass proves not to be the primary determinant of elimination half-lives. Instead, these times can be more readily predicted from the number of PEG groups on the dendrimer: the size of the PEG chain contributes to a lesser extent. Tumor uptake is observed for all the three dendrimers in mice bearing prostate cancer xenografts.
Assuntos
Dendrímeros/química , Dendrímeros/farmacocinética , Neoplasias/patologia , Polietilenoglicóis/química , Triazinas/química , Animais , Linhagem Celular Tumoral , Dendrímeros/síntese química , Dendrímeros/metabolismo , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Peso Molecular , Baço/efeitos dos fármacos , Baço/metabolismo , Distribuição Tecidual , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A hybrid compound (DO3A-BP) featuring a radiometal bifunctional chelator (1,4,7,10-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid, DOTA) and an osteoclast-targeting moiety (bisphosphonate) was designed and synthesized. The (111)In-labeled complex of DO3A-BP showed significantly elevated uptake in osteoclasts compared to the undifferentiated adherent bone marrow derived cells. Biodistribution studies revealed a favorable tissue distribution profile in normal mice with high bone uptake and long retention, and low or negligible accumulation in non-target organs.