Release Model of Water-soluble Chitosan Nanoparticles for Protein Delivery

[Objective] The experiment aimed to explore release rule of water-soluble chitosan (WSC) in vitro. [Method]The bovine serum albumin(BSA) was taken as a model protein drug and some existing release models such as Kinetics model, Gompertz model, Weibull model, Higuchi model and Logistic model were used to fit the BSA release profile from WSC carriers. [Result] Except Higuchi model and Logistic model, other models could fit BSA release profile better. [Conclusion] Gompertz two-order kinetics model could fit the release of WSC nano-particles better and model parameters had practical physical meaning.

Chitosan nanoparticles crosslinked by glycidoxypropyltrimethoxysilane for pH triggered release of protein

pH-responsive-chitosan nanoparticles for the control release of protein drug were prepared by combining two-step crosslinking method, in which chitosan was subsequently crosslinked by sodium tripolyphosphate （TPP） and glycidoxypropyltrimethoxysilane （GPTMS）. Compared with TPP crosslinked chitosan particles, the two-step crosslinked nanoparticles were not only pH-responsive but also more stable in wide pH range. Fluorescein isothiocyanate （FITC） labeled anti-human-IgG antibody was used as a model protein drug for evaluating the control release profile of the nano-carrier. The amount of released antibody increased from 5.6% to 50% when the pH of solution shifted from 7.4 to 6.0. The results suggest the possible application of the nanoparticles as pH- responsive drug delivery materials.

Study on energy release characteristics of reactive material casings under explosive loading

Reactive Materials(RMs),a new material with structural and energy release characteristics under shockinduced chemical reactions,are promising in extensive applications in national defense and military fields.They can increase the lethality of warheads due to their dual functionality.This paper focuses on the energy release characteristics of RM casings prepared by alloy melting and casting process under explosive loading.Explosion experiments of RM and conventional 2A12 aluminum alloy casings were conducted in free field to capture the explosive fireballs,temperature distribution,peak overpressure of the air shock wave and the fracture morphology of fragments of reactive material(RM)warhead casings by using high-speed camera,infrared thermal imager temperature and peak overpressure testing and scanning electron microscope.Results showed that an increase of both the fireball temperature and air shock wave were observed in all RM casings compared to conventional 2A12 aluminum ally casings.The RM casings can improve the peak overpressure of the air shock wave under explosion loading,though the results are different with different charge ratios.According to the energy release characteristics of the RM,increasing the thickness of RM casings will increase the peak overpressure of the near-field air shock wave,while reducing the thickness will increase the peak overpressure of the far-field air shock wave.

Amino functionalized chiral mesoporous silica nanoparticles for improved loading and release of poorly water-soluble drug

In the present paper, chiral mesoporous silica nano-cocoon(A-CMSN) functionalized with amino group was synthesized, and its loading and release of indomethacin(IMC), a poorly soluble drug, was studied. Due to the use of chiral anionic surfactants as a template, ACMSN possessed 2D hexagonal nano-cocoon morphology with curled channels on its surface, which was quite different from another 2D hexagonal mesoporous silica nanoparticles(MCM-41) with straightway channels. After being loaded into the two silica carriers by hydrogen bond, crystalline IMC converted to amorphous form, leading to the improved drug dissolution. And IMC loading capacity of A-CMSN was higher than MCM-41 because curled loading process originating from curvature chiral channels can hold more drug molecules. Compared with IMC, IMC loaded A-CMSN presented obviously fast release throughout the in vitro release experiment, while IMC loaded MCM-41 released faster than IMC at the initial 5 h then showed controlled slow release afterwards, which was closely related to the mesoporous silica nanoparticles and different channel mesostructures of these two carriers. A-CMSN possessed nano-cocoon morphology with curled 2D hexagonal channel and its channel length was shorter than MCM-41, therefore IMC molecules can easily get rid of the constraint of A-CMSN then to be surrounded by dissolution medium.

Succinylated soybean protein as novel excipient for matrix sustained release microspheres

Many native proteins possess limited functionality, and modification such as succinylation is often performed to expand the range of functional properties available for pharmaceutical dosage form. Succinylation could be useful for modulating protein-based system swelling and drug delivery properties especially for sustained controlled release dosage form like microsphere. A well designed controlled drug delivery system can overcome the problems of conventional drug therapy and gives better therapeutic efficacy of a drug.

Characterization of physiochemical and biological properties of spherical protein crystals for sustained release

This study presents an exploration on extending the action of therapeutic proteins by crystallization strategy without new molecular entities generation.Recombinant human interferon a-2b(rhIFN),a model protein drug in this case,was crystallized using a hanging drop vapor diffusion method.A novel chelating technique with metal ions was employed to promote crystals formation.The physico-chemical characterization of the protein crystals,including morphology,particle size,X-ray diffraction,circular dichroism and biological potency evaluations were performed.In addition,the in vitro release behavior of rhIFN from crystal lattice suggested an exciting possibility of protein crystals as a longacting formulation.The work described here demonstrates the possibility of spherical crystals of biomacromolecules for controllable delivery application of therapeutic proteins.

Interpenetrated Chitosan-Poly(Acrylic Acid-Co-Acrylamide) Hydrogels. Synthesis, Characterization and Sustained Protein Release Studies

Interpenetrated polymer networks of chitosan (CHI), polyacrylic acid (PAA) and polyacrylamide (PAM) were prepared by free radical polymerization. These hydrogels were either washed with double distilled water (CHI/PAA/PAM) A or hydrolyzed with 1M sodium hydroxide (NaOH), (CHI/PAA/PAM) S. Both types of hydrogels were characterized by infrared spectroscopy, microstructural techniques and compressive mechanical testing. Finally, hydrogels were loaded with bovine serum albumin (BSA) and release followed at different pHs. Infrared spectra analysis showed correspondence between hydrogels and monomer feed compositions. Hydrolyzed hydrogels, had increased water content and pH swelling dependence. Compression modulus of swelled hydrolyzed hydrogels decreased with increasing equilibrium water content. Higher BSA loadings were achieved on hydrolyzed hydrogels due to their high water content and porosity. Protein release from hydrogels was low (≤ 20% after 10 hours) at pH 1.2, but sustained release was observed at pH 6.8 and 7.4. The integrity of the protein released at 6.8 and 7.4 by hydrolyzed hydrogels was unaffected. The hydrogles showed no cytotoxic effects on human skin dermal fibroblasts as determined by MTT assay except for two compositions of (CHI/PAA/PAM) A samples, which after seven days presented a viability lower than 80% respect to the control.

Altered expression of stromal interaction molecule(STIM)-calcium release-activated calcium channel protein(ORAI) and inositol1,4,5-trisphosphate receptors(IP_3Rs)in cancer:will they become a new battlefield for oncotherapy?

The stromal interaction molecule(STIM)-calcium release-activated calcium channel protein(ORAI) and inositol1,4,5-trisphosphate receptors(IP_3Rs) play pivotal roles in the modulation of Ca^(2+)-regulated pathways from gene transcription to cell apoptosis by driving calcium-dependent signaling processes.Increasing evidence has implicated the dysregulation of STIM-ORAI and IP_3Rs in tumorigenesis and tumor progression.By controlling the activities,structure,and/or expression levels of these Ca^(2+)-transporting proteins,malignant cancer cells can hijack them to drive essential biological functions for tumor development.However,the molecular mechanisms underlying the participation of STIM-ORAI and IP_3Rs in the biological behavior of cancer remain elusive.In this review,we summarize recent advances regarding STIM-ORAI and IP_3Rs and discuss how they promote cell proliferation,apoptosis evasion,and cell migration through temporal and spatial rearrangements in certain types of malignant cells.An understanding of the essential roles of STIM-ORAI and IP_3Rs may provide new pharmacologic targets that achieve a better therapeutic effect by inhibiting their actions in key intracellular signaling pathways.

Accommodating the bacterial decoding release factor as an alien protein among the RNAs at the active site of the ribosome

The decoding release factor （RF） triggers termination of protein synthesis by functionally mimicking a tRNA to span the decoding centre and the peptidyl transferase centre （PTC） of the ribosome. Structurally, it must fit into a site crafted for a tRNA and surrounded by five other RNAs, namely the adjacent peptidyl tRNA carrying the completed polypeptide, the mRNA and the three rRNAs. This is achieved by extending a structural domain from the body of the protein that results in a critical conformational change allowing it to contact the PTC. A structural model of the bacterial termination complex with the accommodated RF shows that it makes close contact with the first, second and third bases of the stop codon in the mRNA with two separate loops of structure＂ the anticodon loop and the loop at the tip of helix orS. The anticodon loop also makes contact with the base following the stop codon that is known to strongly influence termination efficiency. It confirms the close contact of domain 3 of the protein with the key RNA structures of the PTC. The mRNA signal for termination includes sequences upstream as well as downstream of the stop codon, and this may reflect structural restrictions for specific combinations of tRNA and RF to be bound onto the ribosome together. An unbiased SELEX approach has been investigated as a tool to identify potential rRNA-binding contacts of the bacterial RF in its different binding conformations within the active centre of the ribosome.

Understanding the Glycoproteins Release from Alginate-Barium Capsules in Physiologic Enviroments

The authors carried out a steady and unsteady mass transfer studies to simulate both the release of proteins in physiologic environments and proteins transport through a tissue or organ from polymeric capsules by using a substance, the rhodamine B isothiocyanate dextran (RBID) that mimics the behaviour of glycoproteins such as vascular endothelial growth factor (VEFG). These studies highlighted the importance of electrostatic interactions between alginate and proteins in the release processes. Thereby, this fact has opened new perspectives in order to use these kind of capsules in protein recognition processes. The electrostatic interactions between alginate and RBID allow pH-dependent controlled release systems that simulate the behaviour of glycoproteins.

Malarial pigment does not induce MMP-2 and TIMP-2 protein release by human monocytes

Dear editor, In the recent years growing evidence on the involvement of human matrix metalloproteinases(MMPs) and tissue inhibitors of metalloproteinases(TIMPs) in cerebral malaria (CM) has been reported[1]and a role for malarial pigment haemozoin(HZ) has been proposed[2,3].In a recent work my group showed that in human microvascular endothelial

Production Technology and Application of Slow-Release Non-protein Nitrogen Extruded Feed Additive

Slow-release non-protein nitrogen feed has a large market demand. It has a long research history, but its production technology needs further improvement in order to realize the industrial production of slow-release non-protein nitrogen extruded feed. By designing the best formula and using chelating and emulsifying process, the slow-release non-protein nitrogen extruded feed additives were produced. This product increases milk yield and improves milk quality, thus increasing economic efficiency.

Surface lurking and interfacial ion release strategy for fabricating a superhydrophobic coating with scaling inhibition

The design and manufacture of anti-scaling surface is a prospective way to prevent scaling in oil field.In this work,a novel superhydrophobic Cu^(2+)-loaded and DTPMPA-modified anodized copper oxide(S-Cu^(2+)/D-ACO)coating was fabricated by modification of 1H,1H,2H,2H-perfluorodecyltriethoxysilane.The valid storing of scale inhibitors at the coating surface and the interfacial release of Cu^(2+)ions contribute to enhancing the anti-scaling of the S-Cu^(2+)/D-ACO coating.The water contact angle of the S-Cu^(2+)/D-ACO coating is 163.03°and exhibits superhydrophobicity,which makes it difficult for CaCO_(3)to deposit at the surface of the coating.DTPMPA will steadily lurk into the inner space,and Cu^(2+)will be loaded at the interface in the form of the DTPMPA:Cu^(2+)chelate.During the deposition of CaCO_(3),the dynamic release of DTPMPA can be realized by transferring DTPMPA:Cu^(2+)to DTPMPA:Ca^(2+).Interestingly,the released Cu^(2+)hinders the active growth of CaCO_(3).After 48 h of scaling,the mass of CaCO_(3)scale at the S-Cu^(2+)/D-ACO coating surface is only 44.1%that of the anodized copper oxide coating.The excellent anti-scaling performance of the S-Cu^(2+)/D-ACO coating is determined by the synergistic effect of the DTPMPA lurking and dynamic release,as well as the Cu^(2+)inhibition at the interface of superhydrophobic coating and against CaCO_(3)deposition.This research provides a new exploration for designing and fabricating anti-scaling superhydrophobic surface for oil field development.

A novel nanogel delivery of poly-α,β-polyasparthydrazide by reverse microemulsion and its redox-responsive release of 5-Fluorouridine

To achieve GSH-responsive 5-Fluorouridine(5-FU) delivery, a novel family of nanogel drug carriers has been successfully prepared. The new class of PAHy-based nanogels was prepared by the crossing-link reaction of poly-α, β-polyasparthydrazide(PAHy) chains and 3,3′-dithiodipropionic acid(DTDPA) consisting of a redox-responsive chain network. This particle highlights recent efforts in introducing a disulfide bond to drug delivery nanogel by DTDPA,and the increased release properties of complex nanogels produced excellent glutathione(GSH)-sensitivity and significant anti-tumor therapeutic efficacy. The PAHy-based nanogels were characterized by Fourier transform infrared spectroscopy(FT-IR), dynamic light scattering(DLS)(nano-particle size ~200 nm), UV–vis spectrometry, X-ray diffraction(XRD) and differential scanning calorimetric(DSC). PAHy-based nanogels are promising controlledrelease carriers for the tumor-targeting delivery of the anticancer agent 5-Fluorouridine.

Effect of rhBMP-2 sustained-release nanocapsules on the ectopic osteogenesis process in Sprague-Dawley rats

Objective:To explore the effect of sustained-release recombinant human bone morphogenetic protein-2(rhBMP-2) on ectopic osteogenesis in the muscle pouches of rats through preparing rhBMP-2 sustained-release capsules by wrapping morphogenesis protein bones-2(BMP-2)using chitosan nanoparticles,and compositing collagen materials.Methods:Twenty four SpragueDawley rats were randomly divided into four groups with six rats in each group,that is Group A(control group),Group B(only treated with collagen),Group C(rhBMP-2+collagen treated group) and Group D(rhBMP-2/cs+collagen treated group).The composite materials for each group were implanted in the bilateral peroneal muscle pouches in rats.The peroneal muscles were only separated without implanting any materials in control group.Rats were sacrificed 2 weeks and 4 weeks post treatment and samples were cut off for general observation,Micro CT scans and histological observation.Results:General observation showed no new bone formation in Groups A and B mice,while new bones were formed in Groups C and D mice.Two weeks after treatment Micro CT scans showed that The bone volume fraction(BVF),trabecular thickness(Tb. Th),bone mineral density(BMD) in Group C mice were all higher than that in Group D(P<0.05). At the fourth week,the BVK,Tb.Th and BMD were significantly higher than that at the second week(P<0.01).Conclusions:The slow-release effect of rhBMP-2/cs sustained-release capsules can significantly promote ectopic osteogenesis.Its bone formation effect is better than that of rhBMP-2 burst-release group.

Combination immunotherapy with Survivin and luteinizing hormone-releasing hormone fusion protein in murine breast cancer model

AIM To investigate the therapeutic potential of two recombinant proteins, Survivin and luteinizing hormone-releasing hormone (LHRH) fusion protein [LHRH(6 leu)-LTB] for immunotherapy of breast cancer.METHODS Murine 4 T-1 breast cancer model was used to evaluate the efficacy of recombinant proteins in vivo. Twenty four Balb/c mice were divided into 4 groups of 6 mice each. Recombinant Survivin and LHRH fusion protein, alone or in combination, were administered along with immunomodulator Mycobacterium indicus pranii (MIP) in Balb/c mice. Unimmunized or control group mice were administered with phosphate buffer saline. Each group was then challenged with syngeneic 4 T-1 cells to induce the growth of breast tumor. Tumor growth was monitored to evaluate the efficacy of immune-response in preventing the growth of cancer cells.RESULTS Preventive immunization with 20 μg recombinant Survivin and MIP was effective in suppressing growth of 4 T-1 mouse model of breast cancer (P = 0.04) but 50 μg dose was ineffective in suppressing tumor growth. However, combination of Survivin and LHRH fusion protein was more effective in suppressing tumor growth (P = 0.02) as well as metastasis in vivo in comparison to LHRH fusion protein as vaccine antigen alone.CONCLUSION Recombinant Survivin and MIP suppress tumor growth significantly. Combining LHRH fusion protein with Survivin and MIP enhances tumor suppressive effects marginally which provides evidence for recombinant Survivin and LHRH fusion protein as candidates for translating the combination cancer immunotherapy approaches.

Polymeric Hydrogel Nanocapsules: A Thermo and pH Dual-responsive Carrier for Sustained Drug Release

Hydrogel capsules show attractive prospects in drug delivery recently because of high drug loading and sustained release behavior. In this study we reported a simple and convenient route to fabricate poly(acrylic acid)-poly(N-isopropylacrylamide)(PAA-PNIPAm) hydrogel capsules by using hydroxypropylcellulose-poly(acrylic acid)(HPC-PAA) complexes as the templates. The capsules showed a high drug loading(～280% to the weight of capsules) for Doxorubicin hydrochloride. The release of drug from the capsules was responsive to the temperature and p H of the surroundings, showing a low-rate but sustained release behavior favorable for low-toxic and long-term therapy. Together with the convenient preparation, high drug loading, dual responsivity as well as the sustained release feature, it is implied that this polymeric hydrogel capsule might be a promising candidate for new drug carriers.

ON CRACK-TIP STRAIA ENERGY RELEASE RATE IN NON-PRINCIPAL DIRECTIONS OF ELASTICITY FOR SIMPLE LAYER PLATE OF COMPOSITE MATERIALS

In this paper,the fracture problem in non-principal directions of elasticity for a simple layer plate of linear-elastic orthotropic composite materials is studied.The formulae of transformation between characteristic roots,coefficients of elastic compliances in non-principal directions of elasticity and corresponding parameters in principal directions of elasticity are derived.Then,the computing formulae of strain energy release rate under skew-symmetric loading in terms of engineering parameters for principal directions of elasticity are obtained by substituting crack-tip stresses and displacements into the basic formula of the strain energy release rate.

Kisspeptin regulates gonadotropin-releasing hormone secretion in gonadotropin-releasing hormone/enhanced green fluorescent protein transgenic rats

Kisspeptin is essential for activation of the hypothalamo-pituitary-gonadal axis. In this study, we established gonadotropin-releasing hormone/enhanced green fluorescent protein transgenic rats. Rats were injected with 1, 10, or 100 pM kisspeptin-10, a peptide derived from full-length kisspeptin, into the arcuate nucleus and medial preoptic area, and with the kJsspeptJn antagonist peptJde 234 into the lateral cerebral ventricle. The results of immunohistochemical staining revealed that pulsatile luteinizing hormone secretion was suppressed after injection of antagonist peptide 234 into the lateral cerebral ventricle, and a significant increase in luteinizing hormone level was observed after kisspeptin-10 injection into the arcuate nucleus and medial preoptic area. The results of an enzyme-linked immunosorbent assay showed that luteinizing hormone levels during the first hour of kisspeptin-10 infusion into the arcuate nucleus were significantly greater in the 100 pM kisspeptin-10 group than in the 10 pM kisspeptin-10 group. These findings indicate that kisspeptin directly promotes gonadotropin-releasing hormone secretion and luteinizing hormone release in gonadotropin-releasing hormone/enhanced green fluorescent protein transgenic rats. The arcuate nucleus is a key component of the kisspeptin-G protein-coupled receptor 54 signaling pathway underlying regulating luteinizing hormone pulse secretion.

Recent advances in crystalline and amorphous particulate protein formulations for controlled delivery

The number of particulate delivery systems for biologics is negligible compared to liquid dosage forms, signifying the complications associated with development of solid protein delivery systems. Particulate protein delivery systems can improve stability, reduce viscosity of suspensions at high protein concentration and allow for controlled drug release. This review discusses current advances in controlled delivery of particulate protein formulations. While the focus lies on protein crystals and delivery systems employing protein crystals,amorphous protein particles will also be addressed. Crystallization and precipitations methods and modifications allowing controlled delivery with and without encapsulation are summarized and discussed.