RESUMO
This study aimed to design an effective formulation for enhancing the tumor-targeted delivery of sorafenib. Three sorafenib-loaded liposomal formulations including uncoated liposome (SF-Lip), hyaluronic acid-coated liposome (HA-SF-Lip), and PEGylated hyaluronic acid-coated liposome (PEG-HA-SF-Lip) were developed with narrow size distribution and high encapsulation efficiency. The cellular uptake and cytotoxicity of HA-SF-Lip and PEG-HA-SF-Lip were greater than those of SF-Lip in MDA-MB-231 cells overexpressing CD44, whereas there were no significant differences in MCF-7 cells with low CD44 expression, indicating the CD44-mediated cellular uptake of coated liposomes. In comparison with sorafenib solution, PEG-HA-SF-Lip increased the systemic exposure and plasma half-life in rats by 3-fold and 2-fold, respectively. Consistently, PEG-HA-SF-Lip was the most effective for tumor growth inhibition through CD44 targeting in the MDA-MB-231 tumor xenograft mouse model. Taken together, the present study suggests that PEG-HA-SF-Lip might be effective for the tumor-targeted delivery of sorafenib with enhanced systemic exposure and longer blood circulation.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Ácido Hialurônico/química , Lipossomos/química , Polietilenoglicóis/química , Sorafenibe/farmacologia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Sobrevivência Celular , Feminino , Hemólise/efeitos dos fármacos , Humanos , Camundongos , Ratos , Ratos Sprague-Dawley , Sorafenibe/administração & dosagem , Sorafenibe/química , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Endocrine-cerebro-osteodysplasia (ECO) syndrome is a genetic disorder associated with congenital defects of the endocrine, cerebral, and skeletal systems in humans. ECO syndrome is caused by mutations of the intestinal cell kinase (ICK) gene, which encodes a mitogen-activated protein (MAP) kinase-related kinase that plays a critical role in controlling the length of primary cilia. Lack of ICK function disrupts transduction of sonic hedgehog (SHH) signaling, which is important for development and homeostasis in humans and mice. Craniofacial structure abnormalities, such as cleft palate, are one of the most common defects observed in ECO syndrome patients, but the role of ICK in palatal development has not been studied. METHODS: Using Ick-mutant mice, we investigated the mechanisms by which ICK function loss causes cleft palate and examined pharmacological rescue of the congenital defects. FINDINGS: SHH signaling was compromised with abnormally elongated primary cilia in the developing palate of Ick-mutant mice. Cell proliferation was significantly decreased, resulting in failure of palatal outgrowth, although palatal adhesion and fusion occurred normally. We thus attempted to rescue the congenital palatal defects of Ick mutants by pharmacological activation of SHH signaling. Treatment of Ick-mutant mice with an agonist for Smoothened (SAG) rescued several congenital defects, including cleft palate. INTERPRETATIONS: The recovery of congenital defects by pharmacological intervention in the mouse models for ECO syndrome highlights prenatal SHH signaling modulation as a potential therapeutic measure to overcome congenital defects of ciliopathies.
Assuntos
Doenças do Sistema Nervoso Central/congênito , Doenças do Sistema Nervoso Central/metabolismo , Doenças do Sistema Endócrino/congênito , Doenças do Sistema Endócrino/metabolismo , Proteínas Hedgehog/metabolismo , Transdução de Sinais , Receptor Smoothened/agonistas , Animais , Proliferação de Células , Doenças do Sistema Nervoso Central/genética , Cílios/metabolismo , Fissura Palatina/patologia , Modelos Animais de Doenças , Embrião de Mamíferos/anormalidades , Embrião de Mamíferos/patologia , Doenças do Sistema Endócrino/genética , Regulação da Expressão Gênica no Desenvolvimento , Camundongos Knockout , Modelos Biológicos , Mutação/genética , Palato/anormalidades , Palato/embriologia , Palato/ultraestrutura , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/metabolismoRESUMO
Precise modulation of polymer brush in its thickness and grafting density can cause unexpected cell behaviors and regulated bioactivities. Herein, a nanoscale poly(dimethylsiloxane) (PDMS) brush was employed to use as a controllable material for cell adhesion. Facile fabrication of ultrathin monolayer PDMS nanobrush on an underlying substrate facilitated regaining cell adhesion through long-range cell attractive forces such as the van der Waals forces. We showed that cell adhesion is diminished by increasing the number of nanobrush layers, causing a gradual decrease of the effectiveness of the long-range force. The result demonstrates that ultrathin PDMS nanobrush can either promote or inhibit cell adhesion, which is required for various biomedical fields such as tissue-engineering, anti-fouling coating, and implantable biomaterials and sensors.