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

Abstract

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 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 αβ integrin overexpressed tumor cells, and Tat 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.

Mesoporous Silica and Organosilica Nanoparticles: Physical Chemistry, Biosafety, Delivery Strategies, and Biomedical Applications

“…The Benzoic imine bond could be cleaved upon cellular internalization, and pH lowering, and then the disulfide would be accessible by the intracellular GSH for cleavage of doxorubicin cargo delivery . A recent study used large peptide‐based amphiphiles to cover the MSN surface via disulfide linkers, and the hindrance of the linkers prevented their cleavage at 2 µm of GSH, while the release was triggered at 10 × 10 −3 m . Another strategy aiming at hindering the accessibility of disulfides was developed by covalently attaching drugs within the silica mesopores via disulfide linkers .…”

High‐Drug‐Loading Mesoporous Silica Nanorods with Reduced Toxicity for Precise Cancer Therapy against Nasopharyngeal Carcinoma

“…However, due to inevitable side effects and remarkable toxicity of radiotherapy and chemotherapy, the clinical therapy of nasopharyngeal carcinome encounters the great difficulty. Receptor‐mediated targeting drug delivery nanosystem offered the opportunity to overcome these problems . Studies have reported that, FA (folic acid), an extremely effective targeting molecule, can bind specifically to folate receptors overexpressed in nasopharyngeal carcinoma cells and other tumor cells .…”

<p>A dual-functional HER2 aptamer-conjugated, pH-activated mesoporous silica nanocarrier-based drug delivery system provides in vitro synergistic cytotoxicity in HER2-positive breast cancer cells</p>

“…Drug-loading content (DLC) and drug-loading efficiency (DLE) were determined using equations (1) and 2: DLC=(weight of drug loaded in MSN/weight of MSN)×100% 1DLE=(weight of drug loaded in MSN/weight of feed drug)×100% 2Control MSN-BM/CD-NCApt@DOX was prepared in a similar manner using the scrambled NCApt sequence instead of HApt.…”

“…Conventional cancer chemotherapy encounters drastic limitations in terms of nonspecific delivery of antitumor drugs and severe side-effects. 1,2 A variety of smart drug-delivery systems with selective targeting and controlled release properties have been developed to minimize systemic cytotoxicity. 3 Mesoporous silica nanoparticles (MSN) have been widely used as drug release systems in recent decades due to their desirable properties, including good biocompatibility, high loading capacity and ease of functionalization.…”

“…To enhance the accuracy of drug delivery to tumors, controlled drug-delivery systems have been functionalized with a variety of tumor-specific targeting ligands-such as aptamers, [28][29][30] peptides, 1,[30][31][32] antibodies and growth factors 33 -to selectively target molecules and receptors that are overexpressed on the surface of tumor cells. Aptamers, single-stranded DNA or RNA oligonucleotides, 34,35 are a novel type of targeting agent that offer several advantages over other tumor-specific ligands.…”