RESUMO
Proteins often possess highly specific biological activities that make them potential therapeutics, but their physical and chemical instabilities during formulation, storage, and delivery have limited their medical use. Therefore, engineering of nanosized vehicles to stabilize protein therapeutics and to allow for targeted treatment of complex diseases, such as cancer, is of considerable interest. A micelle-like nanoparticle (NP) was designed for both, tumor targeting and stimulus-triggered release of the apoptotic protein cytochrome c (Cyt c). This system is composed of a Cyt c NP stabilized by a folate-receptor targeting amphiphilic copolymer (FA-PEG-PLGA) attached to Cyt c through a redox-sensitive bond. FA-PEG-PLGA-S-S-Cyt c NPs exhibited excellent stability under extracellular physiological conditions, whereas once in the intracellular reducing environment, Cyt c was released from the conjugate. Under the same conditions, the folate-decorated NP reduced folate receptor positive HeLa cell viability to 20%, while the same complex without FA only reduced it to 80%. Confocal microscopy showed that the FA-PEG-PLGA-S-S-Cyt c NPs were internalized by HeLa cells and were capable of endosomal escape. The specificity of the folate receptor-mediated internalization was confirmed by the lack of uptake by two folate receptor deficient cell lines: A549 and NIH-3T3. Finally, the potential as antitumor therapy of our folate-decorated Cyt c-based NPs was confirmed with an in vivo brain tumor model. In conclusion, we were able to create a stable, selective, and smart nanosized Cyt c delivery system.
Assuntos
Citocromos c/metabolismo , Nanopartículas/química , Nanopartículas/metabolismo , Células A549 , Animais , Apoptose , Citocromos c/química , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Glioma/metabolismo , Células HeLa , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Micelas , Células NIH 3T3 , Polímeros/químicaRESUMO
The title compound, C20H42O3S2Si, crystallized with two independent mol-ecules (A and B) in the asymmetric unit. They consist of syn,anti,anti-stereo-tetrads with a 1,3-di-thiane motif and a primary alcohol protected as the triisopropyl silyl ether. The 1,3-di-thiane ring adopts a chair conformation, while the rest of each mol-ecule displays a common zigzag conformation. There is an intra-molecular O-Hâ¯O hydrogen bond in each mol-ecule. In the crystal, the A and B mol-ecules are linked via O-Hâ¯O hydrogen bonds, forming -A-B-A--B-- chains along [010]. The absolute structure was determined by resonant scattering (anomalous scattering) [Flack parameter = 0.035â (8)].