RESUMEN
Polymeric drug carriers are widely used for providing temporal and/or spatial control of drug delivery, with corticosteroids being one class of drugs that have benefitted from their use for the treatment of inflammatory-mediated conditions. However, these polymer-based systems often have limited drug-loading capacity, suboptimal release kinetics, and/or promote adverse inflammatory responses. This manuscript investigates and describes a strategy for achieving controlled delivery of corticosteroids, based on a discovery that low molecular weight corticosteroid dimers can be processed into drug delivery implant materials using a broad range of established fabrication methods, without the use of polymers or excipients. These implants undergo surface erosion, achieving tightly controlled and reproducible drug release kinetics in vitro. As an example, when used as ocular implants in rats, a dexamethasone dimer implant is shown to effectively inhibit inflammation induced by lipopolysaccharide. In a rabbit model, dexamethasone dimer intravitreal implants demonstrate predictable pharmacokinetics and significantly extend drug release duration and efficacy (>6 months) compared to a leading commercial polymeric dexamethasone-releasing implant.
Asunto(s)
Corticoesteroides/administración & dosificación , Preparaciones de Acción Retardada/administración & dosificación , Dexametasona/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Corticoesteroides/química , Corticoesteroides/farmacocinética , Animales , Células Cultivadas , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/farmacocinética , Dexametasona/química , Dexametasona/farmacocinética , Dimerización , Modelos Animales de Enfermedad , Implantes de Medicamentos , Liberación de Fármacos , Polímeros/química , Conejos , Ratas , Uveítis/metabolismo , Uveítis/prevención & controlRESUMEN
Here we systematically examined the effect of nanoparticle size (10-100 nm) and surface chemistry (i.e., poly(ethylene glycol)) on passive targeting of tumors in vivo. We found that the physical and chemical properties of the nanoparticles influenced their pharmacokinetic behavior, which ultimately determined their tumor accumulation capacity. Interestingly, the permeation of nanoparticles within the tumor is highly dependent on the overall size of the nanoparticle, where larger nanoparticles appear to stay near the vasculature while smaller nanoparticles rapidly diffuse throughout the tumor matrix. Our results provide design parameters for engineering nanoparticles for optimized tumor targeting of contrast agents and therapeutics.