Liangliang Dai

Redox-responsive nanocarrier based on heparin end-capped mesoporous silica nanoparticles for targeted tumor therapy in vitro and in vivo.

This study reports a smart controlled drug release system based on mesoporous silica nanoparticles (MSNs) for targeted drug delivery. The system was fabricated by employing heparin as an end-capping agent to seal the mesopores of MSNs via disulfide bonds as intermediate linkers for intracellular glutathione triggered drug release. Lactobionic acid molecules were then coupled to heparin end-capped MSNs that serve as targeting motifs for facilitating the uptake of doxorubicin (DOX) loaded MSNs by HepG2 cells and tumors, respectively. Detailed investigations demonstrated that the fabricated drug delivery systems could deliver DOX to cancer cells to induce cell apoptosis in vitro and tumor tissue for the inhibition of tumor growth in vivo with minimal side effects. The study affords a promising nanocarrier for redox-responsive cargo delivery with high curative efficiency for cancer therapy.

Enzyme responsive drug delivery system based on mesoporous silica nanoparticles for tumor therapy in vivo.

To reduce the toxic side effects of traditional chemotherapeutics in vivo, we designed and constructed a biocompatible, matrix metalloproteinases (MMPs) responsive drug delivery system based on mesoporous silica nanoparticles (MSNs). MMPs substrate peptide containing PLGLAR (sensitive to MMPs) was immobilized onto the surfaces of amino-functionalized MSNs via an amidation reaction, serving as MMPs sensitive intermediate linker. Bovine serum albumin was then covalently coupled to linker as end-cap for sealing the mesopores of MSNs. Lactobionic acid was further conjugated to the system as targeting motif. Doxorubicin hydrochloride was used as the model anticancer drug in this study. A series of characterizations revealed that the system was successfully constructed. The peptide-functionalized MSNs system demonstrated relatively high sensitivity to MMPs for triggering drug delivery, which was potentially important for tumor therapy since the tumors microenvironment overexpressed MMPs in nature. The in vivo experiments proved that the system could efficiently inhibit the tumor growth with minimal side effects. This study provides an approach for the development of the next generation of nanotherapeutics toward efficient cancer treatment.

Tumor therapy: targeted drug delivery systems

Recently, targeted drug delivery systems (TDDSs) have been extensively studied as a promising therapeutic for tumor therapy. In this review, we investigate the typical targeting mechanisms of TDDSs, covering both passively and actively targeting DDSs for tumor therapy. We highlight the popular active targeting strategies for different sites of action, including tumor cytomembrane or various organelles. Finally, we present some recent representative TDDSs that are under testing in preclinical/clinical trials and have shown excellent clinical potential as the alternate treatment strategy for tumor therapy. Although TDDSs are proving to be promising therapeutic nanoplatforms for tumor therapy, extended investigations should be considered in the landscape for highly efficient tumor therapy with good biosafety.

Dendrimerlike Mesoporous Silica Nanoparticles as pH-Responsive Nanocontainers for Targeted Drug Delivery and Bioimaging

In this work, we employed dendrimerlike mesoporous silica nanoparticles with hierarchical pores (HPSNs) to fabricate drug delivery system bioimaging and targeted tumor therapy in vivo. N,N-phenylenebis(salicylideneimine)dicarboxylic acid (Salphdc) was used both as the gatekeeper of HPSNs via pH-responsive coordination bonds between -COOH of Salphdc and In(3+) ions and as a fluorescence imaging agent. Folic acid was then conjugated to Salphdc as the targeting unit. The results revealed that the system could deliver model drug DOX to the tumor site with high efficiency and then cause cell apoptosis and tumor growth inhibition. Moreover, the conjugated Salphdc was proved to be a promising fluorescence probe for tracing distribution of the system in vivo. The study affords a potential nanoconainer for cancer therapy and biological imaging.

Alendronate-loaded hydroxyapatite-TiO2 nanotubes for improved bone formation in osteoporotic rabbits

Early mechanical fixation between an implant and native bone is critically important for successful orthopedic implantation, especially for hosts suffering osteoporosis with reduced bone mass. To endow a titanium-based implant with a desirable local anti-osteoporosis property for enhancing its early osseointegration, alendronate-loaded hydroxyapatite-TiO2 nanotube (TNT-HA-Aln) substrates were fabricated and systematically characterized in this study. The results of Aln/Ca2+ release and Ca2+ concentration in an osteoclast medium verified that the release of Aln was significantly accelerated along with the acidity rise caused by osteoclast differentiation. Other in vitro tests, such as CCK-8, alkaline phosphatase (ALP), mineralization, gene expression (Runx2, Osterix, ALP, Col I, OPN, OC, OPG and RANKL), protein production (OPG and RANKL) and tartrate-resistant acid phosphatase (TRAP), proved that TNT-HA-Aln substrates have great potential for improving osteoblast proliferation/differentiation and inhibiting osteoclast differentiation. Moreover, in vivo tests, such as the push-out test, micro-CT and H&E staining proved that TNT-HA-Aln implants could efficiently improve local osseointegration after implantation for 3 months. The study provides an alternative to exploiting drug-device combinations to enhance early osseointegration in osteoporosis.

A pH-responsive nanocontainer based on hydrazone-bearing hollow silica nanoparticles for targeted tumor therapy

A pH-responsive drug delivery system based on hollow mesoporous silica nanoparticles (HMSNs) was fabricated for targeted tumor therapy by using hydrazone bonds as pH-sensitive linkers and hyaluronic acid (HA) molecules as both blocking and targeting agents. HMSNs were synthesized with good dispersion and dimensions of around 88 nm. Detailed material characterisation suggested that the drug delivery system was successfully constructed. It displayed a fast pH stimulus response for controlled drug release in vitro. Besides, systematic biological investigations revealed that the drug delivery system had good biocompatibility, which could effectively target tumor cells and deliver therapeutic cargo to induce tumor cell apoptosis in vitro and suppression of tumor growth in vivo. This study reports a promising drug delivery system for potential clinical application against tumor therapy.

A transferrin-conjugated hollow nanoplatform for redox-controlled and targeted chemotherapy of tumor with reduced inflammatory reactions

Purpose: In this study, we report the design, development and evaluation of a hollow drug delivery nanoplatform for cancer therapy in vitro and in vivo. This composite nanosystem was prepared by modifying hollow mesoporous silica nanoparticles (HMSNs) with transferrin (Tf) targeting moieties via redox-liable linkage, and was capable of delivering therapeutic cargos (doxorubicin) specifically to the tumor site and subsequently releasing them in an on-demand manner. Moreover, the Tf corona could simultaneously reduce the inflammatory response after intravenous administration in vivo. Methods: Nanostructural morphology of the drug delivery system was observed by scanning electron microscope and transmission electron microscope. The preparation process was monitored primarily using Fourier-transform infrared spectroscopy, dynamic light scattering, nitrogen adsorption/desorption isotherm, and thermogravimetric analysis. The release profile in solution was monitored by fluorescence spectroscopy. In vitro drug delivery efficacy was evaluated on MDA-MB-231 breast cancer cell line using confocal laser scanning microscopy, MTT assay and flow cytometry. In vitro inflammatory response was evaluated on RAW264.7 macrophage cells. In vivo therapeutic experiments were carried out using in situ mouse breast cancer models. Results: The experimental results evidently demonstrate that the developed nanocarrier could effectively deliver anticancer drugs to the tumor site in a targeted manner and release them in response to the elevated glutathione level inside tumor cells, resulting in improved anticancer efficacy both in vitro and in vivo. Moreover, the Tf conjugation significantly ameliorated the inflammatory reaction triggered by the administration of the nanocarrier. Conclusions: This manuscript demonstrated that the Tf-conjugated HMSNs could enhance the delivery efficiency of anticancer drugs, while simultaneously alleviating the adverse side effects. The current study presents a promising integrated delivery system toward effective and safe cancer treatment.

Phenylboronic acid-modified hollow silica nanoparticles for dual-responsive delivery of doxorubicin for targeted tumor therapy

Abstract This work reports a multifunctional nanocarrier based on hollow mesoporous silica nanoparticles (HMSNs) for targeting tumor therapy. Doxorubicin (DOX) was loaded into HMSNs and blocked with cytochrome C conjugated lactobionic acid (CytC–LA) via redox-cleavable disulfide bonds and pH-disassociation boronate ester bonds as intermediate linkers. The CytC–LA was used both as sealing agent and targeting motif. A series of characterizations demonstrated the successful construction of the drug delivery system. The system demonstrated pH and redox dual-responsive drug release behavior in vitro. The DOX loading HMSNs system displayed a good biocompatibility, which could be specifically endocytosed by HepG2 cells and led to high cytotoxicity against tumor cells by inducing cell apoptosis. In vivo data (tumor volume, tumor weight, terminal deoxynucleotidyl transferase dUTP nick end labeling and hematoxylin and eosin staining) proved that the system could deliver DOX to tumor site with high efficiency and inhibit tumor growth with minimal toxic side effect.

Fabrication of hyaluronidase-responsive biocompatible multilayers on BMP2 loaded titanium nanotube for the bacterial infection prevention

Infection associated with orthopedic implants is the chief cause of implant failure. An important consideration to prevent the infection at implants is to inhibit the biofilm formation for the initial 6 h. Therefore, we fabricated hyaluronidase-sensitive multilayers of chitosan (Chi)/sodium hyaluronate-lauric acid (SL) onto the surface of bone morphogenetic protein 2 (BMP2) loaded titanium nanotube (TNT) via spin-assisted layer-by-layer technique. The results of both Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance (1H NMR) confirmed the successful synthesis of SL. The multilayer structure on BMP2 loaded TNT was characterized by field-emission scanning electron microscopy (FE-SEM), atomic force microscopy (AFM) and water contact angle, respectively. The release profiles confirmed that hyaluronidase could trigger the release of lauric acid (LA) from the SL multilayer and accelerate the release of BMP2 in the system. The hyaluronidase-sensitive-multilayer-coated BMP2-loaded TNT (TNT/BMP2/(Chi/SL/Chi/Gel)4) not only demonstrated good antibacterial capability, but also showed good biocompatibility in in vitro usage, which was supported by the efficient growth inhibition of both Staphylococcus aureus and Escherichia coli, as well as higher cell viability, alkaline phosphatase activity, mineralization capability, and higher gene expression of osteoblasts on TNT/BMP2/(Chi/SL/Chi/Gel)4. This study developed an alternative approach to fabricate effective antibacterial implants for orthopedic implantation.

Functionalizing titanium surface with PAMAM dendrimer and human BMP2 gene via layer‐by‐layer assembly for enhanced osteogenesis†

The study reports on the gene functionalization of titanium substrates with multilayered functional human BMP2 (hBMP2) gene plasmid and its effects on osteogenesis in vitro and in vivo. The multilayers comprising cationic poly(amidoamine) (PAMAM) dendrimer/EGFP-hBMP2 plasmid DNA complex (d-DNA) and anionic naked plasmid were deposited on titanium substrates via layer-by-layer (LbL) assembly technique, which was revealed by atomic force microscopy (AFM), water contact angle measurement, and release profiles. The expression of marker gene EGFP and functional gene hBMP2 were observed in osteoblasts. The assays of alkaline phosphatase activity, collagen secretion, ECM mineralization, and osteogenesis-related genes expression indicated that the multilayered structure improved the osteogenic differentiation in vitro. Moreover, the femur and subcutaneous transplantation of multilayered titanium implants were also investigated to reveal osteogenesis peri-implant by using histological examination and X-ray imaging. The in vivo histologic results showed that the BMP2 group (containing functional gene hBMP2) resulted in improved osteogenic proteins expression in subcutaneous and femur tissue, as well as high level of bone formation and % bone-implant contact (%BIC) peri-implant. The study offers an effective dendrimer and hBMP2 based strategy for surface functionalization of titanium implants in potential orthopedic applications.