RESUMEN
Peptide amphiphiles (PAs) self-assemble nanostructures with potential applications in drug delivery and tissue engineering. Some PAs share environmentally responsive behavior with their peptide components. Here we report a new type of PAs biologically inspired from human tropoelastin. Above a lower critical solution temperature (LCST), elastin-like polypeptides (ELPs) undergo a reversible inverse phase transition. Similar to other PAs, elastin-like PAs (ELPAs) assemble micelles with fiber-like nanostructures. Similar to ELPs, ELPAs have inverse phase transition behavior. Here we demonstrate control over the ELPAs fiber length and cellular uptake. In addition, we observed that both peptide assembly and nanofiber phase separation are accompanied by a distinctive secondary structure attributed primarily to a type-1 ß turn. We also demonstrate increased solubility of hydrophobic paclitaxel (PAX) in the presence of ELPAs. Due to their biodegradability, biocompatibility, and environmental responsiveness, elastin-inspired biopolymers are an emerging platform for drug and cell delivery; furthermore, the discovery of ELPAs may provide a new and useful approach to engineer these materials into stimuli-responsive gels and drug carriers.
Asunto(s)
Materiales Biocompatibles/síntesis química , Portadores de Fármacos/síntesis química , Nanofibras/química , Péptidos/síntesis química , Tensoactivos/síntesis química , Materiales Biocompatibles/farmacología , Materiales Biomiméticos/química , Supervivencia Celular/efectos de los fármacos , Portadores de Fármacos/farmacología , Células HEK293 , Células HeLa , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Micelas , Microscopía de Fuerza Atómica , Nanofibras/ultraestructura , Paclitaxel/química , Paclitaxel/farmacología , Péptidos/farmacología , Transición de Fase , Fosfatidiletanolaminas/química , Estructura Secundaria de Proteína , Solubilidad , Tensoactivos/farmacología , Temperatura , Tropoelastina/química , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologíaRESUMEN
Nanoparticle technologies are significantly impacting the development of both therapeutic and diagnostic agents. At the intersection between treatment and diagnosis, interest has grown in combining both paradigms into clinically effective formulations. This concept, recently coined as theranostics, is highly relevant to agents that target molecular biomarkers of disease and is expected to contribute to personalized medicine. Here we review state-of-the-art nanoparticles from a therapeutic and a diagnostic perspective and discuss challenges in bringing these fields together. Major classes of nanoparticles include, drug conjugates and complexes, dendrimers, vesicles, micelles, core-shell particles, microbubbles, and carbon nanotubes. Most of these formulations have been described as carriers of either drugs or contrast agents. To observe these formulations and their interactions with disease, a variety of contrast agents have been used, including optically active small molecules, metals and metal oxides, ultrasonic contrast agents, and radionuclides. The opportunity to rapidly assess and adjust treatment to the needs of the individual offers potential advantages that will spur the development of theranostic agents.
Asunto(s)
Diagnóstico por Imagen/métodos , Portadores de Fármacos/uso terapéutico , Nanopartículas/uso terapéutico , Animales , Medios de Contraste/uso terapéutico , HumanosRESUMEN
Obesity is associated with increased cancer incidence and mortality. We have previously found that obesity in children is associated with a 50% increased recurrence of acute lymphoblastic leukemia (ALL) in high-risk patients. We have therefore developed novel in vivo and in vitro preclinical models to study the mechanism(s) of this association. Obesity increased relapse after monotherapy with vincristine (P = 0.03) in obese mice injected with syngeneic ALL cells. This occurred although the drug was dosed proportionally to body weight, equalizing blood and tissue drug levels. In coculture, 3T3-L1 adipocytes significantly impaired the antileukemia efficacy of vincristine, as well as three other chemotherapies (P < 0.05). Interestingly, this protection was independent of cell-cell contact, and it extended to human leukemia cell lines as well. Adipocytes prevented chemotherapy-induced apoptosis, and this was associated with increased expression of the two prosurvival signals Bcl-2 and Pim-2. These findings highlight the role of the adipocyte in fostering leukemia chemotherapy resistance, and may help explain the increased leukemia relapse rate in obese children and adults. Given the growing prevalence of obesity worldwide, these effects are likely to have increasing importance to cancer treatment.