RESUMO
The increasing use of drug combinations to treat disease states, such as cancer, calls for improved delivery systems that are able to deliver multiple agents. Herein, we report a series of novel Janus dendrimers with potential for use in combination therapy. Different generations (first and second) of PEG-based dendrons containing two different "model drugs", benzyl alcohol (BA) and 3-phenylpropionic acid (PPA), were synthesized. BA and PPA were attached via two different linkers (carbonate and ester, respectively) to promote differential drug release. The four dendrons were coupled together via (3 + 2) cycloaddition chemistries to afford four Janus dendrimers, which contained varying amounts and different ratios of BA and PPA, namely, (BA)(2)-G1-G1-(PPA)(2), (BA)(4)-G2-G1-(PPA)(2), (BA)(2)-G1-G2-(PPA)(4), and (BA)(4)-G2-G2-(PPA)(4). Release studies in plasma showed that the dendrimers provided sequential release of the two model drugs, with BA being released faster than PPA from all of the dendrons. The different dendrimers allowed delivery of increasing amounts (0.15-0.30 mM) and in exact molecular ratios (1:2; 2:1; 1:2; 2:2) of the two model drug compounds. The dendrimers were noncytotoxic (100% viability at 1 mg/mL) toward human umbilical vein endothelial cells (HUVEC) and nontoxic toward red blood cells, as confirmed by hemolysis studies. These studies demonstrate that these Janus PEG-based dendrimers offer great potential for the delivery of drugs via combination therapy.
Assuntos
Álcool Benzílico/metabolismo , Dendrímeros/química , Dendrímeros/síntese química , Portadores de Fármacos , Fenilpropionatos/metabolismo , Polietilenoglicóis/química , Materiais Biocompatíveis , Células Cultivadas , Preparações de Ação Retardada , Combinação de Medicamentos , Eritrócitos/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Polímeros/químicaRESUMO
Dopamine has previously been shown to inhibit angiogenesis in vitro and in vivo, but its clinical applications in this context are severely limited by its short half-life. Here we report the synthesis of a polyglutamic acid-dopamine conjugate and show that conjugation significantly extends (from 1 to 24 h) dopamine's antiangiogenic activity in vitro and in vivo. These findings form the basis for the development of a new class of agents for the treatment of angiogenesis-dependent diseases.
Assuntos
Inibidores da Angiogênese/síntese química , Dopamina/síntese química , Ácido Poliglutâmico/química , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Animais , Permeabilidade Capilar/efeitos dos fármacos , Movimento Celular , Dopamina/química , Dopamina/farmacologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/fisiologia , Feminino , Humanos , Técnicas In Vitro , Camundongos , Camundongos Endogâmicos BALB C , Microvasos/efeitos dos fármacos , Microvasos/fisiologia , Neovascularização Fisiológica/efeitos dos fármacos , Relação Estrutura-Atividade , Veias Umbilicais/citologia , Fator A de Crescimento do Endotélio Vascular/farmacologiaRESUMO
We developed a family of polymer-drug conjugates carrying the combination of the anticancer agent epirubicin (EPI) and nitric oxide (NO). EPI-PEG-(NO)8, carrying the highest content of NO, displayed greater activity in Caco-2 cells while it decreased toxicity against endothelium cells and cardiomyocytes with respect to free EPI. FACS and confocal microscopy confirmed conjugates internalization. Light scattering showed formation of micelle whose size correlated with internalization rate. EPI-PEG-(NO)8 showed increased bioavailability in mice compared to free EPI.
