RESUMEN
The dissolution rate is the rate-limiting step for Biopharmaceutics Classification System (BCS) class II drugs to enhance their in vivo pharmacokinetic behaviors. There are some factors affecting the dissolution rate, such as polymorphism, particle size, and crystal habit. In this study, to improve the dissolution rate and enhance the in vivo pharmacokinetics of sorafenib tosylate (Sor-Tos), a BCS class II drug, two crystal habits of Sor-Tos were prepared. A plate-shaped crystal habit (ST-A) and a needle-shaped crystal habit (ST-B) were harvested by recrystallization from acetone (ACN) and n-butanol (BuOH), respectively. The surface chemistry of the two crystal habits was determined by powder X-ray diffraction (PXRD) data, molecular modeling, and face indexation analysis, and confirmed by X-ray photoelectron spectroscopy (XPS) data. The results showed that ST-B had a larger hydrophilic surface than ST-A, and subsequently a higher dissolution rate and a substantial enhancement of the in vivo pharmacokinetic performance of ST-B.
Asunto(s)
Solubilidad/efectos de los fármacos , Sorafenib/química , Acetona/química , Biofarmacia/métodos , Química Farmacéutica/métodos , Cristalización/métodos , Interacciones Hidrofóbicas e Hidrofílicas , Tamaño de la Partícula , Polvos/química , Difracción de Rayos X/métodosRESUMEN
The malignancy of colorectal cancer (CRC) is connected with inflammation and tumor-associated macrophages (TAMs), but effective therapeutics for CRC are limited. To integrate therapeutic targeting with tumor microenvironment (TME) reprogramming, here we develop biocompatible, non-covalent channel-type nanoparticles (CNPs) that are fabricated through host-guest complexation and self-assemble of mannose-modified γ-cyclodextrin (M-γ-CD) with Regorafenib (RG), RG@M-γ-CD CNPs. In addition to its carrier role, M-γ-CD serves as a targeting device and participates in TME regulation. RG@M-γ-CD CNPs attenuate inflammation and inhibit TAM activation by targeting macrophages. They also improve RG's anti-tumor effect by potentiating kinase suppression. In vivo application shows that the channel-type formulation optimizes the pharmacokinetics and bio-distribution of RG. In colitis-associated cancer and CT26 mouse models, RG@M-γ-CD is proven to be a targeted, safe and effective anti-tumor nanomedicine that suppresses tumor cell proliferation, lesions neovascularization, and remodels TME. These findings indicate RG@M-γ-CD CNPs as a potential strategy for CRC treatment.
Asunto(s)
Neoplasias Colorrectales/tratamiento farmacológico , Nanopartículas/administración & dosificación , Neoplasias Experimentales/tratamiento farmacológico , Compuestos de Fenilurea/administración & dosificación , Piridinas/administración & dosificación , gamma-Ciclodextrinas/administración & dosificación , Animales , Línea Celular , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células HT29 , Humanos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Manosa/química , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Nanopartículas/química , Neoplasias Experimentales/genética , Neoplasias Experimentales/metabolismo , Compuestos de Fenilurea/química , Piridinas/química , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/genética , gamma-Ciclodextrinas/químicaRESUMEN
Puerarin (PUE) is a Chinese traditional medicine known to enhance glucose uptake into the insulin cells to downregulate the blood glucose levels in the treatment of type II diabetes. Nevertheless, the bioavailability of pristine PUE is limited due to its poor solubility and low intestinal permeability. In this work, we demonstrate that the solubility of PUE can be significantly enhanced via its co-crystallization with L-Proline (PRO). Two crystalline phases, namely, the solvate-free form [PUE][PRO] (I) and the solvated form [PUE]2[PRO]âEtOHâ(H2O)2 (II) are isolated. These two phases are characterized by single-crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), Fourier-transformed infrared (FT-IR) spectra, nuclear magnetic resonance (NMR), and thermogravimetric analysis in association with differential scanning calorimetry (TGA-DSC). The solubility and dissolution rate of both I and II in water, gastrointestinal tract at pH 1.2, and phosphate buffer at pH 6.8 indicates a nearly doubled increase as compared to the pristine PUE. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay of pristine PUE, I and II against murine colon cancer cell lines CT-26 and human kidney cell lines HEK-293 indicated that neither compound exhibits obvious cytotoxicity after 24 h. This work showcases that the readily available and biocompatible PRO can be a promising adjuvant to enhance the physicochemical properties of PUE toward orally administered drug formulation with improved pharmacokinetics.
Asunto(s)
Química Farmacéutica , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Isoflavonas/química , Prolina/química , Animales , Disponibilidad Biológica , Cristalización , Cristalografía por Rayos X , Diabetes Mellitus Tipo 2/patología , Células HEK293 , Humanos , Isoflavonas/uso terapéutico , Medicina Tradicional China , Ratones , Polvos/química , Prolina/uso terapéutico , Solubilidad/efectos de los fármacos , Espectroscopía Infrarroja por Transformada de Fourier , Difracción de Rayos XRESUMEN
Studies on neutrophil-based nanotherapeutic engineering have shown great potentials in treating infection and inflammation disorders. Conventional neutrophil labeling methods are time-consuming and often result in undesired contamination and activation since neutrophils are terminal-differentiated cells with a half-life span of only 7â h. A simple, fast, and biocompatible strategy to construct engineered neutrophils is highly desirable but remains difficult to achieve. In this study, we present an AIEgen-lipid conjugate, which can efficiently label harvested neutrophils in 30â s with no washing step required. This fast labeling method does not affect the activation and transmigration property of neutrophils, which has been successfully used to monitor neutrophil behaviors such as the chemotaxis process and migrating function towards inflammation sites both inâ vitro and inâ vivo, offering a tantalizing prospect for neutrophil-based nanotherapeutics studies.
Asunto(s)
Lípidos/química , Neutrófilos/metabolismo , Animales , Quimiotaxis , Membrana Dobles de Lípidos/química , Lisofosfatidilcolinas/química , Ratones , Nanopartículas/química , Neutrófilos/química , Neutrófilos/inmunología , Imagen Óptica , Especies de Nitrógeno Reactivo/metabolismo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Bacteria hiding in host phagocytes are difficult to kill, which can cause phagocyte disorders resulting in local and systemic tissue damage. Effective accumulation of activatable photosensitizers (PSs) in phagocytes to realize selective imaging and on-demand photodynamic ablation of bacteria is of great scientific and practical interests for precise bacteria diagnosis and treatment. Herein, HClO-activatable theranostic nanoprobes, DTF-FFP NPs, for image-guided bacterial ablation in phagocytes are introduced. DTF-FFP NPs are prepared by nanoprecipitation of an HClO-responsive near-infrared molecule FFP and an efficient PS DTF with aggregation-induced emission characteristic using an amphiphilic polymer Pluronic F127 as the encapsulation matrix. As an energy acceptor, FFP can quench both fluorescence and production of reactive oxygen species (ROS) of DTF, thus eliminating the phototoxicity of DTF-FFP NPs in normal cells and tissues. Once delivered to the infection sites, DTF-FFP NPs light up with red fluorescence and efficiently generate ROS owing to the degradation of FFP by the stimulated release of HClO in phagocytes. The selective activation of fluorescence and photosensitization is successfully confirmed by both in vitro and in vivo results, demonstrating the effectiveness and theranostic potential of DTF-FFP NPs in precise bacterial therapy.