Enzyme-Responsive Intracellular-Controlled Release Using Silica Mesoporous Nanoparticles Capped with e-Poly-l-lysine

The synthesis and characterization of two new capped silica mesoporous nanoparticles for controlled delivery purposes are described. Capped hybrid systems consist of MCM-41 nanoparticles functionalized on the outer surface with polymer epsilon-poly-L-lysine by two different anchoring strategies. In both cases, nanoparticles were loaded with model dye molecule [Ru(bipy)(3)](2+). An anchoring strategy involved the random formation of urea bonds by the treatment of propyl isocyanate-functionalized MCM-41 nanoparticles with the lysine amino groups located on the epsilon-poly-L-lysine backbone (solid Ru-rLys-S1). The second strategy involved a specific attachment through the carboxyl terminus of the polypeptide with azidopropyl-functionalized MCM-41 nanoparticles (solid Ru-tLys-S1). Once synthesized, both nanoparticles showed a nearly zero cargo release in water due to the coverage of the nanoparticle surface by polymer epsilon-poly-L-lysine. In contrast, a remarkable payload delivery was observed in the presence of proteases due to the hydrolysis of the polymer's amide bonds. Once chemically characterized, studies of the viability and the lysosomal enzyme-controlled release of the dye in intracellular media were carried out. Finally, the possibility of using these materials as drug-delivery systems was tested by preparing the corresponding epsilon-poly-L-lysine capped mesoporous silica nanoparticles loaded with cytotoxic drug camptothecin (CPT), CPT-rLys-S1 and CPT-tLys-S1. Cellular uptake and cell-death induction were studied. The efficiency of both nanoparticles as new potential platforms for cancer treatment was demonstrated.We thank the Spanish Government (Project MAT2012-38429-C04, CTQ2007-64735-AR07 and SAF2010-15512) and the Generalitat Valenciana (Project PROMETEO/2009/016) for support. L.M. and A.A. thank the Generalitat Valenciana for their postdoctoral contract VALI+D and Santiago Grisolia PhD fellowship, respectively. N.M. thanks The Spanish Ministry of Science and Innovation for her FPI fellowship. C.T. thanks the Universitat Politecnica de Valencia for her PhD fellowship. M.O. thanks the CIPF for her postdoctoral fellowship. We thank the confocal microscopy service, Alberto Hernandez and EvaMaria LaFuente from CIPF for their technical support.Mondragón Martínez, L.; Mas Font, N.; Ferragud, V.; De La Torre, C.; Agostini, A.; Martínez Mañez, R.; Sancenón Galarza, F.... (2014). Enzyme-Responsive Intracellular-Controlled Release Using Silica Mesoporous Nanoparticles Capped with e-Poly-l-lysine. Chemistry - A European Journal. 20(18):5271-5281. https://doi.org/10.1002/chem.201400148527152812018Ge, Z., & Liu, S. (2013). 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