Multifunctional Peptide-Amphiphile End-Capped Mesoporous Silica Nanoparticles for Tumor Targeting Drug Delivery

A tumor targeting redox-responsive drug delivery system (DDS) with bioactive surface was constructed by immobilizing peptide-based amphiphile C12-CGRKKRRQRRRPPQRGDS (defined as ADDA-TCPP) onto the mesoporous silica nanoparticles (MSNs) as an end-capping nanovalve, which consists of two main segments: a hydrophobic alkyl chain ADDA and a hydrophilic amino acid sequence containing a Tat_48-60 peptide sequence with a thiol terminal group and an RGDS targeting ligand, via a disulfide linkage for redox-triggered intracellular drug delivery. A series of characterizations confirmed that the nanosystem had been successfully fabricated. The antitumor drug doxorubicin (DOX) was selected as a model drug and efficiently trapped in the pores of MSNs, and an in vitro release experiment demonstrated that the mesopores of the resulting DOX-loaded MSNs (DOX@MSN-ss-ADDA-TCPP) could be sealed tightly with ADDA-TCPP self-assemblies through hydrophobic interactions between the alkyl chains; the resulting DDS exhibited "zero premature release" of DOX in the physical environment. However, a burst drug release was triggered by a high concentration of glutathione (GSH) in simulated cellular cytosol. Moreover, detailed investigations confirmed that incorporation of RGDS peptide facilitated the active targeting delivery of DOX to α_vβ₃ integrin overexpressed tumor cells, and Tat_48-60 modification on MSNs could enhance intracellular drug delivery, exhibiting an obvious toxicity to tumor cells. The multifunctional nanosystem constructed here can realize the controlled drug release and serve as a platform for designing multifunctional nanocarriers using diversified bioactive peptide-based amphiphile.