RESUMEN
Glioma, as one of the most common primary intracranial tumors, is in an urgent need for specific targeting agents. Multi-branched RGD ligand is a promising alternative for liposome functionalization which combines the benefits of high affinity with αvß3 receptors and proper branching structure in response to the receptor clustering. Herein, we designed and synthesized single branched, double branched and triple branched RGD ligand (1RGD-Chol, 2RGD-Chol and 3RGD-Chol) respectively, which were then modified on the liposomes to prepare six different kinds of liposomes (including 1RGD-Lip, 2RGD-Lip, 3RGD-Lip, 2 × 1RGD-Lip, 3 × 1RGD-Lip and unmodified Lip). Subsequently, a series of assays were conducted. The results exhibited that the liposome decorated with 3RGD-Chol ligand possessed superior cellular internalization ability in C6 cells and bEnd.3 cells, suggesting the strongest ability of 3RGD-Lip to target the blood-brain barrier (BBB) and glioma cells. Besides, both the cytotoxicity and pro-apoptotic assays revealed that PTX-3RGD-Lip had the strongest ability to inhibit the survival of C6 cells. Moreover, the enrichment of liposomes at tumor site was 3RGD-Lip > 3 × 1RGD-Lip ≈ 2RGD-Lip ≈ 2 × 1RGD-Lip > 1RGD-Lip > Lip according to the in vivo imaging of C6-bearing mice, which was consistent with the result of in vitro targeting experiments. To sum up, the targeting efficiency of liposomes can be strongly promoted by improving the amount of targeting molecules, whereas the branching structure and spatial distance of RGD residues also accounted for the affinity between liposomes and αvß3 receptors. Collectively, PTX-3RGD-Lip would be a prospective strategy in glioma treatment.
Asunto(s)
Neoplasias Encefálicas , Glioma , Animales , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos/métodos , Glioma/tratamiento farmacológico , Glioma/patología , Ligandos , Liposomas/química , Ratones , Oligopéptidos/química , Estudios ProspectivosRESUMEN
A series of liposome ligands (Bio-Chol, Bio-Bio-Chol, tri-Bio-Chol and tetra-Bio-Chol) modified by different branched biotins that can recognize the SMVT receptors over-expressed in breast cancer cells were synthesized. And four liposomes (Bio-Lip, Bio-Bio-Lip, tri-Bio-Lip and tetra-Bio-Lip) modified by above mentioned ligands as well as the unmodified liposome (Lip) were prepared to study the targeting ability for breast cancer. The cytotoxicity study and apoptosis assay of paclitaxel-loaded liposomes showed that tri-Bio-Lip had the strongest anti-proliferative effect on breast cancer cells. The cellular uptake studies on mice breast cancer cells (4T1) and human breast cancer cells (MCF-7) indicated tri-Bio-Lip possessed the strongest internalization ability, which was 5.21 times of Lip, 2.60 times of Bio-Lip, 1.67 times of Bio-Bio-Lip and 1.17 times of tetra-Bio-Lip, respectively. Moreover, the 4T1 tumor-bearing BALB/c mice were used to evaluate the in vivo targeting ability. The data showed the enrichment of liposomes at tumor sites were tri-Bio-Lip > tetra-Bio-Lip > Bio-Bio-Lip > Bio-Lip > Lip, which were consistent with the results of in vitro targeting studies. In conclusion, increasing the density of targeting molecules on the surface of liposomes can effectively enhance the breast cancer targeting ability, and the branching structure and spatial distance of biotin residues may also have an important influence on the affinity to SMVT receptors. Therefore, tri-Bio-Lip could be a promising drug delivery system for targeting breast cancer.
Asunto(s)
Antineoplásicos/farmacología , Biotina/química , Neoplasias de la Mama/tratamiento farmacológico , Colesterol/farmacología , Diseño de Fármacos , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Colesterol/síntesis química , Colesterol/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Ligandos , Liposomas/química , Células MCF-7 , Ratones , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-ActividadRESUMEN
The first example of transition-metal-catalyzed C-H activations of 2-phenylisatogens with alkynes and sulfonyl azides has been developed using N-oxide as the directing group. Ru(ii)-Catalyzed C-H alkenylation/cyclization and Ir(iii)-catalyzed direct C-H sulfamidation proceeded with good yields and excellent functional group tolerance. Importantly, these two transformations provided straightforward routes for the synthesis of indol-3-one derivatives and sulfamidated 2-phenylisatogens respectively, which might be of considerable bioactivities.