RESUMEN
In this study, we explored the feasibility of biotin-mediated modified polymeric micelles for pancreatic cancer targeted photodynamic therapy. Poly (ethylene glycol)-distearoyl phosphatidyl ethanolamine (mPEG2000-DSPE) served as the drug-loaded material, biotin-poly(ethylene glycol)-distearoyl phosphatidyl ethanolamine (Biotin-PEG3400-DSPE) as the functional material and the polymeric micelles were prepared by a thin-film hydration method. The targeting capability of micelles was investigated by cell uptake assay in vitro and fluorescence imaging in vivo and the amounts of Biotin-PEG-DSPE were optimized accordingly. Hypocrellin B (HB), a novel photosensitizer was then encapsulated in biotinylated polymeric micelles and the anti-tumor efficacy was evaluated systemically in vitro and in vivo. The results showed that micelles with 5 mol % Biotin-PEG-DSPE demonstrated the best targeting capability than those with 20 mol % or 0.5 mol % of corresponding materials. This formulation has a small particle size [mean diameter of (36.74 ± 2.16) nm] with a homogeneous distribution and high encapsulation efficiency (80.06 ± 0.19) %. The following pharmacodynamics assays showed that the biotinylated micelles significantly enhanced the cytotoxicity of HB against tumor cells in vitro and inhibited tumor growth in vivo, suggesting a promising potential of this formulation for treatment of pancreatic cancer, especially those poorly permeable, or insensitive to radiotherapy and chemotherapy.
Asunto(s)
Antineoplásicos/química , Biotina , Micelas , Neoplasias Pancreáticas/tratamiento farmacológico , Fotoquimioterapia , Animales , Portadores de Fármacos/química , Ensayos de Selección de Medicamentos Antitumorales , HumanosRESUMEN
Inspired by the knowledge that most antibodies recognize a conformational epitope because of the epitope's specific three-dimensional shape rather than its linear structure, we combined scaffold-based peptide design and surface molecular imprinting to fabricate a novel nanocarrier harboring stable binding sites that captures a membrane protein. In this study, a disulfide-linked α-helix-containing peptide, apamin, was used to mimic the extracellular, structured N-terminal part of the protein p32 and then serve as an imprinting template for generating a sub-40â nm-sized polymeric nanoparticle that potently binds to the target protein, recognizes p32-positive tumor cells, and successfully mediates targeted photodynamic therapy inâ vivo. This could provide a promising alternative for currently used peptide-modified nanocarriers and may have a broad impact on the development of polymeric nanoparticle-based therapies for a wide range of human diseases.
Asunto(s)
Epítopos/química , Impresión Molecular , Nanopartículas/química , Oligopéptidos/química , Secuencia de Aminoácidos , Animales , Apamina/química , Apamina/metabolismo , Línea Celular Tumoral , Modelos Animales de Enfermedad , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Epítopos/administración & dosificación , Humanos , Ratones Desnudos , Datos de Secuencia Molecular , Nanopartículas/administración & dosificación , Nanopartículas/metabolismo , Neoplasias/tratamiento farmacológico , Oligopéptidos/administración & dosificación , Tamaño de la Partícula , Fotoquimioterapia , Estructura Secundaria de Proteína , Trasplante HeterólogoRESUMEN
In oncology, there is a growing need for simpler, more selective methods to deliver drug therapies directly to the tumor site. For combination therapies, simultaneous targeted delivery of multiple drugs would represent a significant improvement. In contrast to previous work that took a de novo approach, we constructed a novel two-in-one liposomal system (TWOLips) from two single drug-loaded liposomes. Our results demonstrated that TWOLips could be prepared by a simple process, through silica coating of one liposome and incubation with the second liposome. TWOLips had a mean diameter of 100 nm, relatively high drug loading rates (96.8%±0.9% for doxorubicin and 78.4%±1.2% for combretastatin), and high storage stability. TWOLips modification by adding a targeting moiety, an all D-amino acid peptide derived from a natural vascular endothelial growth factor, resulted in strong, selective binding to vascular endothelial growth factor receptor 2, a tumorigenesis marker, in vitro and in vivo. TWOLips significantly inhibited tumor growth and angiogenesis and enhanced survival in mice with A375 melanoma xenografts. The TWOLips system had a low potential risk of toxicity. Since the stepwise assembly could be carried further (additional drug-loaded liposomes), TWOLips shows potential as a treatment for many cancers, especially those that require multiple drugs.