RESUMO
Here we report the 18F labeling of a prostate specific membrane antigen (PSMA) ligand via a strain promoted oxa-dibenzocyclooctyne (ODIBO)- or bicyclo[6.1.0]nonyne (BCN)-azide reaction. Although ODIBO reacts with azide 20 fold faster than BCN, in vivo PET imaging suggests that 18F-BCN-azide-PSMA demonstrated much higher tumor uptake and a much higher tumor to background contrast.
Assuntos
Alcinos/química , Antígenos de Superfície/metabolismo , Azidas/química , Compostos Bicíclicos com Pontes/metabolismo , Ciclo-Octanos/metabolismo , Glutamato Carboxipeptidase II/metabolismo , Hidrocarbonetos Fluorados/metabolismo , Compostos Radiofarmacêuticos/metabolismo , Animais , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/farmacologia , Ciclo-Octanos/síntese química , Ciclo-Octanos/química , Ciclo-Octanos/farmacologia , Dipeptídeos/metabolismo , Radioisótopos de Flúor , Compostos Heterocíclicos com 1 Anel/metabolismo , Humanos , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/química , Hidrocarbonetos Fluorados/farmacologia , Interações Hidrofóbicas e Hidrofílicas , Cinética , Ligantes , Masculino , Camundongos , Tomografia por Emissão de Pósitrons , Antígeno Prostático Específico , Neoplasias da Próstata/diagnóstico por imagem , Ligação Proteica , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
For drug delivery purposes, the ability to conveniently attach a targeting moiety that will deliver drugs to cells and then enable controlled release of the active molecule after localization is desirable. Toward this end, we designed and synthesized clickable and photocleavable lipid analogue 1 to maximize the efficiency of bioconjugation and triggered release. This compound contains a dibenzocyclooctyne group for bioorthogonal derivatization linked via a photocleavable 2-nitrobenzyl moiety at the headgroup of a synthetic lipid backbone for targeting to cell membranes. To assess delivery and release using this system, we report fluorescence-based assays for liposomal modification and photocleavage in solution as well as through surface immobilization to demonstrate successful liposome functionalization and photoinduced release. In addition, fluorophore delivery to and release from live cells was confirmed and characterized using fluorescence microscopy and flow cytometry analysis in which 1 was delivered to cells, derivatized, and photocleaved. Finally, drug delivery studies were performed using an azide-tagged analogue of camptothecin, a potent anticancer drug that is challenging to deliver due to poor solubility. In this case, the ester attachment of the azide tag acted as a caging group for release by intracellular esterases rather than through photocleavage. This resulted in a dose-dependent response in the presence of liposomes containing delivery agent 1, confirming the ability of this compound to stimulate delivery to the cytoplasm of cells.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Camptotecina/administração & dosagem , Preparações de Ação Retardada/química , Lipídeos/química , Lipossomos/química , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Azidas/química , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Células HeLa , Humanos , Luz , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Imagem Óptica , Processos Fotoquímicos , Saccharomyces cerevisiae/citologia , Saccharomyces cerevisiae/metabolismoRESUMO
The ability to rationally design and construct a platform technology to develop new platinum(IV) [Pt(IV)] prodrugs with functionalities for installation of targeting moieties, delivery systems, fluorescent reporters from a single precursor with the ability to release biologically active cisplatin by using well-defined chemistry is critical for discovering new platinum-based therapeutics. With limited numbers of possibilities considering the sensitivity of Pt(IV) centers, we used a strain-promoted azide-alkyne cycloaddition approach to provide a platform, in which new functionalities can easily be installed on cisplatin prodrugs from a single Pt(IV) precursor. The ability of this platform to be incorporated in nanodelivery vehicle and conjugation to fluorescent reporters were also investigated.