RESUMEN
The high vulnerability of mRNA necessitates the manufacture of delivery vehicles to afford adequate protection in the biological milieu. Here, mRNA was complexed with a mixture of cRGD-poly(ethylene glycol) (PEG)-polylysine (PLys) (thiol) and poly(N-isopropylacrylamide) (PNIPAM)-PLys(thiol). The ionic complex core consisting of opposite-charged PLys and mRNA was crosslinked though redox-responsive disulfide linkage, thereby avoiding structural disassembly for exposure of mRNA to harsh biological environments. Furthermore, PNIPAM contributed to prolonged survival in systemic circulation by presenting a spatial barrier in impeding accessibility of nucleases, e.g., RNase, due to the thermo-responsive hydrophilic-hydrophobic transition behavior upon incubation at physiological temperature enabling translocation of PNIPAM from shell to intermediate barrier. Ultimately, the cRGD ligand attached to the formulation demonstrated improved tumor accumulation and potent gene expression, as manifested by virtue of facilitated cellular uptake and intracellular trafficking. These results indicate promise for the utility of mRNA as a therapeutic tool for disease treatment.
Asunto(s)
Sistemas de Liberación de Medicamentos , Nanopartículas , Polímeros , ARN Mensajero/administración & dosificación , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Composición de Medicamentos , Humanos , Ligandos , Nanopartículas/química , Neoplasias/metabolismo , Neoplasias/patología , Polietilenglicoles/química , Polilisina/química , Polímeros/síntesis química , Polímeros/química , ARN Mensajero/químicaRESUMEN
A facile poly(ethylene glycol) (PEG) detachment scheme was utilized to control the PEGylation degree of the polymeric micelles. The performance of cyclic Arg-Gly-Asp (cRGD) as a targeted moiety was studied on a class of polymeric micelles with various PEGylation degrees, revealing that the specific cRGD-mediated cell affinity, thus the cellular uptake and implicated privileges including the ligand-specified favorable intracellular trafficking and consequent favorable biofunctions, was prominent for the polymeric micelles with high PEGylation degree. These results endow important information and implications for the design and development of targeted nanomedicine, particularly the delivery of vulnerable biological compounds.