Hierarchical integration of degradable mesoporous silica nanoreservoirs and supramolecular dendrimer complex as a general-purpose tumor-targeted biomimetic nanoplatform for gene/small-molecule anticancer drug co-delivery.

Biomacromolecule therapeutic systems are intrinsically susceptible to degradation and denaturation. Nanoformulations are promising delivery vehicles for therapeutic biomacromolecules (antibodies, genes and so on). However, their applications in these areas still face many challenges including in vivo stability, premature leakage and accurate tumor recognition. In this study, a generally applicable new strategy for tumor-targeted delivery of biomacromolecules was developed through the hierarchical integration of degradable large-pore dendritic mesoporous silica nanoparticles (dMSNs) and cyclodextrin-modified polyamidoamine (PAMAM-CD) dendrimers. The orifice rim of the dMSNs was modified with ROS-responsive nitrophenyl-benzyl-carbonate (NBC) groups while disulfide-bonded azido ligands were subsequently grafted onto the inner channel walls via heterogeneous functionalization. The PAMAM-CD was then interred into the dendritic pores via click reactions and supramolecularly loaded with archetypal hydrophobic small-molecule anticancer model drug (SN-38) and therapeutic model gene (Bcl-2 siRNA), after which dMSNs were eventually coated with a 4T1 cancer cell membrane (CCM). Experimental evidence demonstrated that the synthesized nanocarriers could efficiently deliver therapeutic cargos to target cancer cells and release them in the tumor cytosol in a cascade-responsive manner. This biomimetic nanoplatform presents a novel strategy to efficiently deliver biomolecular therapeutics in a tumor-targeted manner.

Antibacterial and osteogenesis performances of LL37-loaded titania nanopores in vitro and in vivo.

Background: Many studies have shown that the size of nanotube (NT) can significantly affect the behavior of osteoblasts on titanium-based materials. But the weak bonding strength between NT and substrate greatly limits their application. Purpose: The objective of this study was to compare the stability of NT and nanopore (NP) coatings, and further prepare antibacterial titanium-based materials by loading LL37 peptide in NP structures. Methods: The adhesion strength of NT and NP layers was investigated using a scratch tester. The proliferation and differentiation of MC3T3-E1 cells on different substrates were evaluated in vitro by CCK8, alkaline phosphatase activity, mineralization and polymerase chain reaction assays. The antibacterial rates of NP and NP/LL37 were also measured by spread plate method. Moreover, the osteogenesis around NP and NP/LL373 in vivo was further evaluated using uninfected and infected models. Results: Scratch test proved that the NP layers had stronger bonding strength with the substrates due to their continuous pore structures and thicker pipe walls than the independent NT structures. In vitro, cell results showed that MC3T3-E1 cells on NP substrates had better early adhesion, spreading and osteogenic differentiation than those of NT group. In addition, based on the drug reservoir characteristics of porous materials, the NP substrates were also used to load antibacterial LL37 peptide. After loading LL37, the antibacterial and osteogenic induction abilities of NP were further improved, thus significantly promoting osteogenesis in both uninfected and infected models. Conclusion: We determined that the NP layers had stronger bonding strength than NT structures, and the corresponding NP materials might be more suitable than NT for preparing drug-device combined titanium implants for bone injury treatment.

Stability and osteogenic potential evaluation of micro-patterned titania mesoporous-nanotube structures.

Background: Although titanium dioxide nanotubes (TNTs) had great potential to promote osteogenesis, their weak bonding strength with titanium substrates greatly limited their clinical application. Purpose: The objective of this study was to maintain porosity and improve the stability of TNT coatings by preparing some micro-patterned mesoporous/nanotube (MP/TNT) structures via a photolithography-assisted anodization technology. Methods: The adhesion strength of different coatings was studied by ultrasonic cleaning machine and scratch tester. The early adhesion, spreading, proliferation and differentiation of MC3T3-E1 cells on different substrates were investigated in vitro by fluorescent staining, CCK8, alkaline phosphatase activity, mineralization and polymerase chain reaction assays, respectively. Results: Results of ultrasonic and scratch assays showed that the stability of TNTs (especially 125 nm) was significantly improved after being patterned with MP structures. In vitro cell assays further demonstrated that the insertion of MP structure into 125 nm TNT coating, which was denoted as MP125, could effectively improve the early adhesion, spreading and proliferation of surface MC3T3-E1 cells without damaging their osteogenic differentiation. Conclusion: We determined that the MP/TNT patterned samples (especially MP125) have excellent stability and osteogenesis properties, and may have better clinical application prospects.

Sustained Release of Zoledronic Acid from Mesoporous TiO2-Layered Implant Enhances Implant Osseointegration in Osteoporotic Condition.

Implant surface modification that provides local sustained release of osteoinductive therapeutic agents enhances implant stability. We designed a mesoporous TiO2-layered titanium implant (MLT) by modified anodization technique that allowed local sustained release of zoledronic acid up to 21 days. Mesoporous layer has pore size 15 nm, depth ∼30 µm, volume 0.32 cm3/g, surface area 112.3 m2/g, surface roughness 20 nm and water contact angle 18.3°. Zoledronic acid-loaded MLT (MLT-Z) was biocompatible, showed anabolic effect on bone forming osteoblasts and catabolic effect on bone resorbing osteoclasts. MLT or MLT-Z implants were implanted in osteoporotic rat-tail vertebrae. Smooth implant in healthy rats were used as a positive control. Histomorphometric analysis showed that bone implant contact of smooth implant in osteoporotic rats was reduced by 4.1-fold compared to healthy rats and MLT-Z rescued the effect by 53%. Similar effect was observed in implant fixation, mechanical stability, BV/TV ratio, Tb.N, Tb.Th and OI% among the groups. Histological and µ-CT images strongly supported the above-mentioned findings. In conclusion, a novel surface-fabricated MLT-Z gives local sustained drug release, robustly enhances implant osseointegration and stability in osteoporotic condition, suggesting it as a promising implant model for patients with compromised bone quality.

Gallium and silicon synergistically promote osseointegration of dental implant in patients with osteoporosis.

Over the last few decades, a wide variety of dental implants have been successfully placed in jaw bones to restore tooth function. But major challenges still remain in patients with osteoporosis involving compromised osseointegration, and the therapeutic methods is far from optimism. Gallium can directly inhibit bone osteolysis, prevent bone calcium release and augment bone mass, which makes Ga unique among the potential antiresorptive drugs. Silicon, as an indispensable modulator in bone formation, presents its bone anabolic effects, while reduces, at least doesn't increase, bone resorption. We hypothesize that the combination of bone anabolic effects of Si and antiresorptive effects of Ga will result in synergistic effects on the improvement of osteointegration under osteoporotic condition. In our strategy, in order to maximize the efficacy while minimize the side effects of ions, a novel titania mesoporous layer fabricated by electrochemical anodization on the surface of titanium implant will be employed as a promising local drug delivery system. The synergistic effects of Ga and Si on improving osseointegration will be verified by animal experiments, and be furthered by clinical trials. Our hypothesis could help to create an option to improve success rate of dental implants in osteoporotic patients.

pH dependent silver nanoparticles releasing titanium implant: A novel therapeutic approach to control peri-implant infection.

Peri-implant infection control is crucial for implant fixation and durability. Antimicrobial administration approaches to control peri-implant infection are far from satisfactory. During bacterial infection, pH level around the peri-implant surface decreases as low as pH 5.5. This change of pH can be used as a switch to control antimicrobial drug release from the implant surface. Silver nanoparticles (AgNPs) have broad-spectrum antimicrobial properties. In this study, we aimed to design a pH-dependent AgNPs releasing titania nanotube arrays (TNT) implant for peri-implant infection control. The nanotube arrays were fabricated on the surface of titanium implant as containers; AgNPs were grafted on TNT implant surface via a low pH-sensitive acetal linker (TNT-AL-AgNPs). SEM, TEM, AFM, FTIR as well as XPS data showed that AgNPs have been successfully linked to TNT via acetal linker without affecting the physicochemical characteristics of TNT. The pH 5.5 enhanced AgNPs release from TNT-AL-AgNPs implant compared with pH 7.4. AgNPs released at pH 5.5 robustly increased antimicrobial activities against gram-positive and gram-negative bacteria compared with AgNPs released at pH 7.4. TNT-AL-AgNPs implant enhanced osteoblast proliferation, differentiation, and did not affect osteoblast morphology in vitro. In conclusion, incorporation of AgNPs in TNT via acetal linker maintained the surface characteristics of TNT. TNT-AL-AgNPs implant was biocompatible to osteoblasts and showed osteoinductive properties. AgNPs were released from TNT-AL-AgNPs implant in high dose at pH 5.5, and this release showed strong antimicrobial properties in vitro. Therefore, this novel design of low pH-triggered AgNPs releasing TNT-AL-AgNPs could be an infection-triggered antimicrobial releasing implant model to control peri-implant infection.