Multifunctional\nPeptide-Amphiphile End-Capped Mesoporous\nSilica Nanoparticles for Tumor Targeting Drug Delivery

Abstract

A tumor\ntargeting redox-responsive drug delivery system (DDS) with\nbioactive surface was constructed by immobilizing peptide-based amphiphile\nC12-CGR­KKRR­QRRR­PPQR­GDS (defined as ADDA-TCPP)\nonto the mesoporous silica nanoparticles (MSNs) as an end-capping\nnanovalve, which consists of two main segments: a hydrophobic alkyl\nchain ADDA and a hydrophilic amino acid sequence containing a Tat_48‑60 peptide sequence with a thiol terminal group and\nan RGDS targeting ligand, via a disulfide linkage for redox-triggered\nintracellular drug delivery. A series of characterizations confirmed\nthat the nanosystem had been successfully fabricated. The antitumor\ndrug doxorubicin (DOX) was selected as a model drug and efficiently\ntrapped in the pores of MSNs, and an in vitro release experiment demonstrated\nthat the mesopores of the resulting DOX-loaded MSNs (DOX@MSN-ss-ADDA-TCPP)\ncould be sealed tightly with ADDA-TCPP self-assemblies through hydrophobic\ninteractions between the alkyl chains; the resulting DDS exhibited\n“zero premature release” of DOX in the physical environment.\nHowever, a burst drug release was triggered by a high concentration\nof glutathione (GSH) in simulated cellular cytosol. Moreover, detailed\ninvestigations confirmed that incorporation of RGDS peptide facilitated\nthe active targeting delivery of DOX to α_vβ₃ integrin overexpressed tumor cells, and Tat_48‑60 modification on MSNs could enhance intracellular drug delivery,\nexhibiting an obvious toxicity to tumor cells. The multifunctional\nnanosystem constructed here can realize the controlled drug release\nand serve as a platform for designing multifunctional nanocarriers\nusing diversified bioactive peptide-based amphiphile.