Macro-microporous ZIF-8 MOF complexed with lysosomal pH-adjusting hexadecylsulfonylfluoride as tumor vaccine delivery systems for improving anti-tumor cellular immunity.

Tumor vaccine therapy, which can induce tumor antigen-specific cellular immune responses to directly kill tumor cells, is considered to be one of the most promising tumor immunotherapies. How to elicit effective tumor antigen-specific cellular immunity is the key for the development of tumor vaccines. However, current tumor vaccines with conventional antigen delivery systems mainly induce humoral immunity but not effective cellular immunity. In this study, based on pH-sensitive, ordered macro-microporous zeolitic imidazolate framework-8 (SOM-ZIF-8) and hexadecylsulfonylfluoride (HDSF), an intelligent tumor vaccine delivery system SOM-ZIF-8/HDSF was developed to elicit potent cellular immunity. Results demonstrated that the SOM-ZIF-8 particles could efficiently encapsulate antigen into the macropores, promote antigen uptake by antigen-presenting cells, facilitate lysosomal escape, and enhance antigen cross-presentation and cellular immunity. In addition, the introduction of HDSF could up-regulate the lysosomal pH to protect antigens from acid degradation, which further promoted antigen cross-presentation and cellular immunity. The immunization tests showed that the tumor vaccines based on the delivery system improved antigen-specific cellular immune response. Moreover, the tumor vaccines significantly inhibited tumor growth in B16 melanoma-bearing C57BL/6 mice. These results indicate that SOM-ZIF-8/HDSF as an intelligent vaccine delivery system could be used for the development of novel tumor vaccines.

MnO2 nanoparticles as a minimalist multimode vaccine adjuvant/delivery system to regulate antigen presenting cells for tumor immunotherapy.

In the field of tumor immunotherapy, tumor vaccines have unique advantages including fewer side effects, tumor-specificity and immune memory, and hence attract more and more attention. In the development of tumor vaccines, a critical challenge lies in the exploitation of appropriate vaccine adjuvants/delivery systems that need to meet multiple requirements to achieve potent cellular immunity while simultaneously requiring single composition to simplify the clinical translation process. Among numerous materials, only manganese dioxide (MnO2) nanoparticles with rare physicochemical properties seem to meet the demanding criteria of simplicity and multifunctionality. However, the potential of MnO2 nanoparticles as vaccine adjuvants/delivery systems has not been well exploited, despite their widespread applications in the biomedical field. In this study, the mechanism and efficacy of single MnO2 nanoparticles as a minimalist multi-mode tumor vaccine adjuvant/delivery system were fully investigated by using a model antigen ovalbumin (OVA) to construct tumor vaccines OVA/MnO2. The obtained results show that MnO2 nanoparticles act as an ideal delivery system by multiple modes to deliver the antigen to the cytoplasm of dendritic cells to induce cellular immune response. Moreover, MnO2 nanoparticles also act as a superior adjuvant depot to sustainably release Mn2+ to enhance the immune response through a STING pathway in dendritic cells. Both the delivery function and the adjuvant effect of MnO2 nanoparticles contribute to improved cellular immunity and anti-tumor efficacy of tumor vaccines OVA/MnO2. From the results, MnO2 nanoparticles are found to be a promising minimalist multi-mode vaccine adjuvant/delivery system for the development of practical tumor vaccines.

Acceleration of skin regeneration in full-thickness burns by incorporation of bFGF-loaded alginate microspheres into a CMCS-PVA hydrogel.

Two important issues in skin tissue engineering are the vascularization and regeneration of the dermis. Basic fibroblast growth factor (bFGF) is known to promote angiogenesis and accelerate wound healing. Direct delivery of bFGF to the wound area, however, would lead to a loss of bioactivity. To this end, bFGF-loaded alginate microspheres (Ms) were fabricated and incorporated into carboxymethyl chitosan (CMCS)-poly(vinyl alcohol) (PVA) to form a composite hydrogel. Scanning electron microscopy (SEM) results indicated that the incorporation of Ms does not significantly affect the inner structure of CMCS-PVA. In an in vitro study, the release of bFGF from Ms-CMCS-PVA in a sustained manner retained higher bioactivity over a 2-week period. Full-thickness burn wounds were created in the dorsal area of rats for in vivo evaluation of skin regeneration treated with CMCS-PVA hydrogel, with and without bFGF. Compared with the control, CMCS-PVA and bFGF-CMCS-PVA groups, the bFGF/Ms-CMCS-PVA group revealed significantly faster wound recovery rates, with re-epithelialization and regeneration of the dermis. Moreover, the bFGF/Ms-CMCS-PVA group had the highest density of newly formed and mature blood vessels during the 2 mweek treatment period. The ability of the bFGF/Ms-CMCS-PVA hydrogel to accelerate wound healing in a full-thickness burn model suggests its potential for use in dermal tissue regeneration. Copyright © 2015 John Wiley & Sons, Ltd.

Heparin-conjugated alginate multilayered microspheres for controlled release of bFGF.

In order to effectively immobilize and control release of basic fibroblast growth factor (bFGF) from alginate microspheres, heparin-conjugated alginate (H-Alg) was first synthesized by covalent binding. Then multilayered H-Alg microspheres (multilayered microspheres) were fabricated via an electrostatic droplet generation technique followed by a layer-by-layer (LbL) self-assembly technique. Several techniques such as Fourier transform infrared spectroscopy (FTIR), (1)H-NMR, zeta potential analysis and scanning electron microscopy (SEM) were used to characterize the properties of H-Alg (FTIR and (1)H-NMR) and multilayered microspheres (FTIR, zeta potential analysis and SEM). bFGF binding efficiency, release profiles of bFGF from multilayered microspheres and the biological activity of released bFGF were well investigated. It was found that the bFGF binding efficiency of H-Alg microspheres was increased up to five times higher than that of the alginate microspheres. Additionally, the release profiles of bFGF from multilayered microspheres were sustained for two weeks with relieved initial burst release, and the release rate to bFGF could be regulated by controlling the number of deposited layers. Importantly, the released bFGF still retained its biological activity as assessed by the in vitro proliferation of NIH-3T3 mouse fibroblasts. In conclusion, this study presented an easy yet effective method for the controlled, sustained release of heparin-binding growth factors, using polyelectrolyte multilayer-coated heparin-conjugated alginate microspheres.

Effects of the gene carrier polyethyleneimines on structure and function of blood components.

As a synthetic polycation, polyethylenimine (PEI) is currently one of the most effective non-viral gene carriers. For in vivo applications, PEI will enter systemic circulation and interact with various blood components and then affect their individual bio-functions. Up to now, overall and systematic investigation on the interaction of PEI with multiple blood components at cellular, membrane, and molecular levels is lacking, even though it is critically important for the in vivo safety of PEI. To learn a structure-activity relationship, we investigated the effects of PEI with different molecular weight (MW) and shape (branched or linear) on key blood components and function, specifically, on RBC aggregation and morphological change, platelet activation, conformation change of albumin (as a representative of plasma proteins), and blood coagulation process. Additionally, more proteins from plasma were screened and identified to have associations with PEI by a proteomic analysis. It was found that, the PEIs have severe impact on RBC membrane structure, albumin conformation, and blood coagulation process, but do not significantly activate platelets at low concentrations. Furthermore, 41 plasma proteins were identified to have some interaction with PEI. This indicates that, besides albumin, PEI does interact with a variety of blood plasma proteins, and could have unexplored effects on their structures and bio-functions. The results provide good insight into the molecular design and blood safety of PEI and other polycations for in vivo applications.

Preparation and characterization of PEM-coated alginate microgels for controlled release of protein.

In this study, calcium-alginate microgels coated with a polyelectrolyte multilayer (PEM) were fabricated as a controlled-release system. This system was constructed via an electrostatic droplet generation technique followed by a layer-by-layer (LbL) self-assembly technique. The electrostatic droplet generation technique was reported as an easy method of preparing microgels, due to their mild preparation conditions and ability to preserve the biological activity of the encapsulated drugs. With the LbL self-assembly technique, the PEM could be fabricated on the microgels attributed to the electrostatic attraction between positive-charged chitosan (Chi) and negative-charged dextran sulfate (Dex). The properties of the prepared microgels were investigated using dynamic laser scattering (DLS), scanning electron microscopy (SEM), x-ray photoelectron spectroscopy (XPS), Fourier transform infrared (FTIR) spectrum and zeta potential analyzer. In vitro release study indicated that the initial burst release of the bovine serum albumin (BSA) from PEM-coated microgels was less compared to the uncoated microgels (19% versus 31% in 24 h). In addition, the sustained release of BSA from the PEM-coated microgels was recorded up to 1 month without any damage to BSA integrity. Thus, our results demonstrated that the PEM-coated microgels not only prolonged the release time, but also relieved the initial burst problem to some degree and preserved the biological activity of the encapsulated drugs. Moreover, the release rate of BSA could be regulated by controlling the number of deposited layers. In conclusion, this study presented an easy yet effective method for the controlled, sustained release of biological macromolecules.

Intelligent hydrogels for drug delivery system.

Intelligent hydrogel, also known as smart hydrogels, are materials with great potential for development in drug delivery system. Intelligent hydrogel also has the ability to perceive as a signal structure change and stimulation. The review introduces the temperature-, pH-, electric signal-, biochemical molecule-, light- and pressure- sensitive hydrogels. Finally, we described the application of intelligent hydrogel in drug delivery system and the recent patents involved for hydrogel in drug delivery.