Menghuan Li

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.

Enhancement of local bone remodeling in osteoporotic rabbits by biomimic multilayered structures on Ti6Al4V implants.

To enhance long-term survival of titanium implants in patients with osteoporosis, chitosan/gelatin multilayers containing bone morphogenetic protein 2(BMP2) and an antiosteoporotic agent of calcitonin (CT) are deposited on the Ti6Al4V (TC4) implants through layer-by-layer (LBL) electrostatic assembly technique. Here, the obtained titanium alloy implant (TC4/LBL/CT/BMP2) can regulate the release of loaded calcitonin and BMP2 agents in a sustaining manner to accelerate the bone formation and simultaneously inhibit bone resorption. In vitro results show that the bone-related cells on TC4/LBL/CT/BMP2 present the lowest production level of tartrate resistant acid phosphatase (TRAP) but the highest (p < 0.05) level of alkaline phosphatase (ALP) activity, osteocalcin production, mineralization capacity and osteoblast-related gene expression among all groups after treatment for 7 or 21 days, respectively. Besides, in vivo studies of micro-CT analysis, routine histological and immunohistochemical analysis also collectively demonstrate that the TC4/LBL/CT/BMP2 implant can dramatically promote the formation and remodeling of new bone in osteoporotic rabbits after implantation for 30 days and 90 days, respectively. In vivo push-out testing further confirms that the TC4/LBL/CT/BMP2 implant has the highest (p < 0.01) interfacial shear strength and favorable bone-implant osseointegration. Overall, this study establishes a simple and profound methodology to fabricate a biofunctional TC4 implant for the treatment of local osteoporotic fractures in vivo.

Engineering of a Nanosized Biocatalyst for Combined Tumor Starvation and Low-Temperature Photothermal Therapy

Tumor hypoxia is one of the major challenges for the treatment of tumors, as it may negatively affect the efficacy of various anticancer modalities. In this study, a tumor-targeted redox-responsive composite biocatalyst is designed and fabricated, which may combine tumor starvation therapy and low-temperature photothermal therapy for the treatment of oxygen-deprived tumors. The nanosystem was prepared by loading porous hollow Prussian Blue nanoparticles (PHPBNs) with glucose oxidase (GOx) and then coating their surface with hyaluronic acid (HA) via redox-cleavable linkage, therefore allowing the nanocarrier to bind specifically with CD44-overexpressing tumor cells while also exerting control over the cargo release profile. The nanocarriers are designed to enhance the efficacy of the hypoxia-suppressed GOx-mediated starvation therapy by catalyzing the decomposition of intratumoral hydroperoxide into oxygen with PHPBNs, and the enhanced glucose depletion by the two complementary biocatalysts may consequently suppress the expression of heat shock proteins (HSPs) after photothermal treatment to reduce their resistance to the PHPBN-mediated low-temperature photothermal therapies.

Time-sequenced drug delivery approaches towards effective chemotherapeutic treatment of glioma

Glioma is the most common malignant brain tumor which has an overall terrible prognosis. Nevertheless, despite the tremendous research input that has been applied to treat gliomas, the efficacy of existing therapeutic modalities on real-life patients is still far from satisfactory, mostly due to several difficult obstacles unique to the CNS and gliomas themselves. Notably, the treatment efficiency of many anti-glioma chemotherapies based on small-molecule anticancer drugs is severely impaired by the blood–brain-barrier, blood–brain–tumor-barrier and resistance mechanisms related to intracranial gliomas, which prevent the therapeutic agents from gaining access to the desired site of action while aggravating associated side effects. Rationally based on the synergistic combination of multiple glioma-specific dosing approaches in chronological order, the time-sequenced targeting strategy is an emerging therapeutic paradigm to address these critical issues, which is capable of efficiently destroying the malignant glioma cells while sparing healthy brain cells and tissues. In this review, we will start with a brief introduction of the major difficulties associated with malignant gliomas and corresponding drug delivery strategies under clinical or laboratory studies, and then comprehensively summarize the recent advances in time-sequenced targeted anti-glioma nanoplatforms, in which their potential benefits and unsolved issues will both be covered.

Sustained raloxifene release from hyaluronan-alendronate-functionalized titanium nanotube arrays capable of enhancing osseointegration in osteoporotic rabbits

To enhance the localized bone remodeling at titanium-based implants under osteoporotic conditions, TiO2 nanotube arrays (TNT) were used as nanoreserviors for raloxifene (Ral) and then covered with the hybrid multilayered coating of chitosan and alendronate grafted hyaluronic acid (HA-Aln) via a spin-assisted layer-by-layer technique. The fabrication of this system (TNT/Ral/LBL-Aln) was characterized by field emission scanning electron microscopy (SEM), atomic force microscope (AFM) and X-ray photoelectron spectroscopy (XPS), respectively. The release test showed that the composited multilayers onto Ral-loaded TiO2 nanotube substrate (TNT/Ral) could prevent the burst release of Ral from TiO2 nanotube arrays and maintain stable Ral concentration at the implant site even after 192h. The TNT/Ral/LBL-Aln system demonstrated higher alkaline phosphatase (ALP) activity, mineralization capability in osteoblasts as well as lower tartrate-resistant acid phosphatase (TRAP) activity in osteoclasts compared to both bare TiO2 nanotube and TNT/Ral substrate, respectively. Moreover, the in vivo tests of micro-CT, histological staining and push-out testing showed that TNT/Ral/LBL-Aln implant could efficiently enhance the formation of new bone around the implant and promote bone binding in osteoporotic rabbits. The study indicated the potential application of TNT/Ral/LBL-Aln system for bone remodeling under osteoporotic condition.

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.

Construction of three-dimensional net-like polyelectrolyte multilayered nanostructures onto titanium substrates for combined antibacterial and antioxidant applications

Bacterial biofilm formation and oxidative stress induced by the production of reactive oxygen species (ROS) are major causes of implant failure. An emerging approach to overcome these issues is to combine chitosan-polycaprolactone (PCL) nanofibers and polyelectrolyte multilayers composed of tannic acid (TA) and gentamicin sulfate (GS) for the localized co-delivery of antioxidants and antibiotics from the titanium surface. The integration of nanofibers (NFs) and layer-by-layer (LBL) technology could provide a larger surface area and thus increase the number of cationic sites of Ti substrates. The coating of NF substrates with TA/GS resulted in higher (p < 0.05 or p < 0.01) cellular activities than those of Ti substrates, including enhanced proliferation and gene expression. Furthermore, in vitro investigation demonstrated that TA/GS-incorporated Ti-polydopamine (PDA)/NF implants exhibited excellent stability, and antibacterial and antioxidant properties. The results showed that Ti-PDA/NF/LBL substrates have a biodegradable character in vivo. All the results indicated that the combination of NFs and the bacteria-triggered antibiotic-releasing coating could be used for the tailored co-delivery of antibacterial and antioxidant agents from various metallic implantable devices to effectively improve early bone healing even under ROS stress and decrease the risk of biofilm-associated infections in patients.