Pancreatic cancer (PC) is a malignant tumor of the digestive tract with poor patient prognosis. The PC incidence is still increasing with a 5-year survival rate of only 10%. At present, surgical resection is the most effective method to treat PC, however, 80% of the patients missed the best time for surgery after they have been diagnosed as PC. Chemotherapy is one of the main treating methods but PC is insensitive to chemotherapy, prone to drug resistance, and is accompanied by many side effects which are related to a lack of specific target. Exosomes are nanoscale vesicles secreted by almost all cell types and can carry various bioactive substances which mediate cell communication and material transport. They are characterized by a low immunogenicity, low cytotoxicity, high penetration potential and homing capacity, and possess the potential of being used as advanced drug carriers. Therefore, it is a hot research topic to use drug-loaded exosomes for tumor therapy. They may alleviate chemotherapy resistance, reduce side effects, and enhance the curative effect. In recent years, exosome drug carriers have achieved considerable results in PC chemotherapy studies.
Humans ; Exosomes/metabolism* ; Drug Carriers/metabolism* ; Pancreatic Neoplasms/diagnosis* ; Antineoplastic Agents/therapeutic use*

Objective:To prepare PLGA nanoparticles loaded with Der f 1/IGF-1（Der f 1/IGF-1 NPs） and investigate their role in promoting the formation of Treg cells. Methods:NPs coated with Der f 1/IGF-1 were prepared by double emulsion method and their physicochemical properties and cumulative release rate in vitro were analyzed. After pretreatment, BMDC was divided into Saline group, Blank NPs group, Der f 1/IGF-1 group and Der f 1/IGF-1 NPs group. Determination of the expression of IL-10 and TGF-β in BMDC by ELISA. The number of Treg cells was detected by flow cytometry. Results:The results showed that Der f 1/IGF-1 NPs were spherical structures, with good dispersion, particle size less than 200 nm, negative charge and stable slow-release effect of Zeta potential. After BMDC pretreatment, the expression levels of TGF-β and IL-10 in BMDC cells in the Der f 1/IGF-1 NPs group were significantly increased compared with the Blank NPs group, and the difference was statistically significant（P<0.001）. After co-culture with CD4+ T cells, the proportion of Treg cells produced in the Der f 1/IGF-1 NPs group was significantly increased, and the difference was statistically significant（P<0.001）. Conclusion:Der f 1/IGF-1 NPs can induce Treg cell generation in vitro. This study provides a new and more effective method for the reconstruction of immune tolerance dysfunction.
Humans ; T-Lymphocytes, Regulatory/metabolism* ; Interleukin-10/metabolism* ; Insulin-Like Growth Factor I ; Transforming Growth Factor beta ; Nanoparticles/chemistry* ; Particle Size ; Drug Carriers/chemistry*

In the present study, a gastric retention floating system for Brucea javanica oil, composed of alginate and carrageenan, was prepared using ionotropic gelation. Parameters for floatability, drug load, encapsulation efficiency, bead morphology, in vitro release, and in vivo gastric retention were evaluated. The optimized formulation via Box-Behnken design consisted of 1.7% alginate (W/V), 1.02% carrageenan (W/V), 1.4% CaCO (W/V), and a gelling bath of pH 0.8. The alginate-carrageenan-Brucea javanica oil beads had a porous structure and exhibited up to 24 h of in vitro floatability with a load capacity of 45%-55% and an encapsulation efficiency of 70%-80%. A 6-h sustained release was observed in vitro. The beads had a prolonged gastric retention (> 60% at 6 h) in fasted rats, compared to non-floating beads (15% at 6 h), as measured by gamma scintigraphy with single-photon emission tomography/computed tomography (SPET/CT). In conclusion, the alginate-carrageenan-Brucea javanica oil system showed enhanced oil encapsulation efficiency, excellent floating and gastric retention abilities, and a favorable release behavior.
Alginates ; chemistry ; Animals ; Biological Availability ; Brucea ; chemistry ; Carrageenan ; chemistry ; Delayed-Action Preparations ; administration & dosage ; chemistry ; pharmacokinetics ; Drug Carriers ; chemistry ; Drug Delivery Systems ; methods ; Drug Evaluation, Preclinical ; Gastric Mucosa ; metabolism ; Glucuronic Acid ; chemistry ; Hexuronic Acids ; chemistry ; Microspheres ; Plant Oils ; administration & dosage ; chemistry ; pharmacokinetics ; Rats ; Rats, Sprague-Dawley

OBJECTIVE: To construct a novel non-viral vector loaded with growth and differentiation factor-5 (GDF-5) plasmid using chitosan, hyaluronic acid, and chondroitin sulfate for osteoarthritis (OA) gene therapy. METHODS: Nano-microspheres (NMPs) were prepared by mixing chitosan, hyaluronic acid, and chondroitin sulfate. GDF-5 plasmid was encapsulated in the NMPs through electrostatic adsorption. The basic characteristics of the NMPs were observed, and then they were co-cultured with chondrocytes to observe their effects on extracellular matrix (ECM) protein expression. Finally, NMPs loaded with GDF-5 were injected into the articular cavities of rabbits to observe their therapeutic effects on OA in vivo. RESULTS: NMPs exhibited good physicochemical properties and low cytotoxicity. Their average diameter was (0.61±0.20) μm, and encapsulation efficiency was (38.19±0.36)%. According to Cell Counting Kit-8 (CCK-8) assay, relative cell viability was 75%-99% when the total weight of NMPs was less than 560 μg. Transfection efficiency was (62.0±2.1)% in a liposome group, and (60.0±1.8)% in the NMP group. There was no significant difference between the two groups (P>0.05). Immunohistochemical staining results suggested that NMPs can successfully transfect chondrocytes and stimulate ECM protein expression in vitro. Compared with the control groups, the NMP group significantly promoted the expression of chondrocyte ECM in vivo (P<0.05), as shown by analysis of the biochemical composition of chondrocyte ECM. When NMPs were injected into OA model rabbits, the expression of ECM proteins in chondrocytes was significantly promoted and the progression of OA was slowed down. CONCLUSIONS Based on these data, we think that these NMPs with excellent physicochemical and biological properties could be promising non-viral vectors for OA gene therapy.
Animals ; Cell Differentiation ; Cell Survival/drug effects* ; Chitosan/chemistry* ; Chondrocytes/cytology* ; Chondroitin Sulfates/chemistry* ; Drug Carriers ; Extracellular Matrix/metabolism* ; Genetic Therapy/methods* ; Growth Differentiation Factor 5/genetics* ; Hyaluronic Acid/chemistry* ; Microspheres ; Nanomedicine ; Osteoarthritis/therapy* ; Plasmids/metabolism* ; Rabbits

The present study was designed to prepare and compare bio-adhesive pellets of panax notoginseng saponins (PNS) with hydroxy propyl methyl cellulose (HPMC), chitosan, and chitosan : carbomer, explore the influence of different bio-adhesive materials on pharmacokinetics behaviors of PNSbio-adhesive pellets, and evaluate the correlation between in vivo absorption and in vitro release (IVIVC). In order to predict the in vivo concentration-time profile by the in vitro release data of bio-adhesive pellets, the release experiment was performed using the rotating basket method in pH 6.8 phosphate buffer. The PNS concentrations in rat plasma were analyzed by HPLC-MS-MS method and the relative bioavailability and other pharmacokinetic parameters were estimated using Kinetica4.4 pharmacokinetic software. Numerical deconvolution method was used to evaluate IVIVC. Our results indicated that, compared with ordinary pellets, PNS bio-adhesive pellets showed increased oral bioavailability by 1.45 to 3.20 times, increased C, and extended MRT. What's more, the release behavior of drug in HPMC pellets was shown to follow a Fickian diffusion mechanism, a synergetic function of diffusion and skeleton corrosion. The in vitro release and the in vivo biological activity had a good correlation, demonstrating that the PNS bio-adhesive pellets had a better sustained release. Numerical deconvolution technique showed the advantage in evaluation of IVIVC for self-designed bio-adhesive pellets with HPMC. In conclusion, the in vitro release data of bio-adhesive pellets with HPMC can predict its concentration-time profile in vivo.
Acrylic Resins ; Adhesives ; Animals ; Chitosan ; Drug Carriers ; Drug Liberation ; In Vitro Techniques ; Intestinal Absorption ; Male ; Methylcellulose ; Panax notoginseng ; chemistry ; Plant Extracts ; administration & dosage ; metabolism ; pharmacokinetics ; Rats, Sprague-Dawley ; Saponins ; administration & dosage ; metabolism ; pharmacokinetics

The purpose of this study is to explore the feasibility of wheat germ agglutinin (WGA) modified liposome as a vehicle for ophthalmic administration. Liposome loaded with 5-carboxyfluorescein (FAM) was prepared by lipid film hydration method. WGA was thiolated and then conjugated to the surface of the liposome via polyethylene glycol linker to constitute the WGA-modified and FAM-loaded liposome (WGA-LS/FAM). The amount of thiol groups on each WGA molecule was determined, and the bioactivity of WGA was estimated after it was modified to the surface of liposome. The physical and chemical features of the WGA-modified liposome were characterized and the ocular bioadhesive performance was evaluated in rats. The result showed that each thiolated WGA molecule was conjugated with 1.32 thiol groups. WGA-LS/FAM had a mean size of (97.40 +/- 1.39) nm, with a polydispersity index of 0.23 +/- 0.01. The entrapment efficacy of FAM was about (2.95 +/- 0.21)%, and only 4% of FAM leaked out of the liposome in 24 h. Erythrocyte agglutination test indicated that after modification WGA preserved the binding activity to glycoprotein. The in vivo ocular elimination of WGA-LS/FAM fitted first-order kinetics, and the elimination rate was significantly slower than that of the unmodified liposome, demonstrating WGA-modified liposome is bioadhesive and suitable for ophthalmic administration.
Absorption, Physicochemical ; Adhesiveness ; Administration, Ophthalmic ; Animals ; Drug Carriers ; Eye ; metabolism ; Fluoresceins ; chemistry ; Liposomes ; administration & dosage ; chemistry ; pharmacokinetics ; Male ; Particle Size ; Polyethylene Glycols ; chemistry ; Rats ; Rats, Sprague-Dawley ; Wheat Germ Agglutinins ; administration & dosage ; chemistry ; pharmacokinetics

The core-crosslinked polymeric micelles were used as a new drug delivery system, which can decrease the premature drug release in blood circulation, improve the stability of the micelles, and effectively transport the drug into the therapy sites. Then the drug bioavailability increased further, while the side effect reduced. Most drugs were physically entrapped or chemically covalent with the polymer in the internals of micelles. Based on the various constitutions and properties of polymeric micelles as well as the special characteristics of body microenvironment, the environment-responsive or active targeting core-crosslinked micelles were designed and prepared. As a result, the drug controlled release behavior was obtained. In the present paper, the research progress of all kinds of core-crosslinked micelles which were published in recent years is introduced. Moreover, the characteristic and application prospect of these micelles in drug delivery system are analyzed and summarized.
Animals ; Antineoplastic Agents ; administration & dosage ; chemistry ; therapeutic use ; Cross-Linking Reagents ; chemistry ; metabolism ; Drug Carriers ; chemistry ; metabolism ; Humans ; Micelles ; Molecular Structure ; Neoplasms ; drug therapy ; Particle Size ; Pharmaceutical Preparations ; administration & dosage ; Polyethylene Glycols ; chemistry ; metabolism ; Polymers ; chemistry ; metabolism

A novel recombinant Bacille Calmette-Guerin (rBCG) vaccine co-expressed Eimeria tenella rhomboid and cytokine chicken IL-2 (chIL-2) was constructed, and its efficacy against E. tenella challenge was observed. The rhomboid gene of E. tenella and chIL-2 gene were subcloned into integrative expression vector pMV361, producing vaccines rBCG pMV361-rho and pMV361-rho-IL2. Animal experiment via intranasal and subcutaneous route in chickens was carried out to evaluate the immune efficacy of the vaccines. The results indicated that these rBCG vaccines could obviously alleviate cacal lesions and oocyst output. Intranasal immunization with pMV361-rho and pMV361-rho-IL2 elicited better protective immunity against E. tenella than subcutaneous immunization. Splenocytes from chickens immunized with either rBCG pMV361-rho and pMV361-rho-IL2 had increased CD4+ and CD8+ cell production. Our data indicate recombinant BCG is able to impart partial protection against E. tenella challenge and co-expression of cytokine with antigen was an effective strategy to improve vaccine immunity.
Adjuvants, Immunologic/genetics/*metabolism ; Administration, Intranasal ; Animals ; Antigens, Protozoan/genetics/*immunology ; BCG Vaccine/administration & dosage/*genetics ; CD4-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/immunology ; Chickens ; Coccidiosis/*prevention & control ; Disease Models, Animal ; Drug Carriers/administration & dosage ; Eimeria tenella/genetics/*immunology ; Genetic Vectors ; Injections, Subcutaneous ; Interleukin-2/genetics/*metabolism ; Protozoan Vaccines/administration & dosage/genetics/*immunology ; Spleen/immunology ; Vaccines, Synthetic/administration & dosage/genetics/immunology

The applications of targeting gene delivery systems in tumor therapy have attracted extensive attention of researchers in recent years, as they can selectively deliver the therapeutic gene to tumor sites, improve the success rate of gene therapy and reduce the side effects. Therefore, design and development of novel gene delivery vehicles have been a hot area of current research. Recent studies have shown that mesenchymal stem cells (MSCs) have the ability to migrate towards and engraft into the tumor sites. Therefore, these properties make them a great hope for efficient targeted-delivery vehicles in cancer gene therapy. In this review, we examine the promising of utilization of MSCs as a targeted-delivery vehicle for cancer gene therapy, and summarize various challenges and concerns regarding this therapy.
Animals ; Cell Movement ; genetics ; Drug Carriers ; Gene Targeting ; methods ; Gene Transfer Techniques ; Genetic Therapy ; methods ; Genetic Vectors ; Humans ; Mesenchymal Stromal Cells ; cytology ; metabolism ; physiology ; Neoplasms ; genetics ; therapy ; Recombinant Proteins ; genetics ; metabolism ; Transfection

To investigate the effects of particle size, mPEG molecular weight, coating density and zeta potential of monomethoxyl poly(ethylene glycol)-poly(lactic-co-glycolic acid) (mPEG-PLGA) nanoparticles on their transportation across the rat nasal mucosa, mPEG-PLGA-NPs with different mPEG molecular weights (M(r) 1 000, 2 000) and coating density (0, 5%, 10%, 15%) and chitosan coated PLGA-NP, which loaded coumarin-6 as fluorescent marker, were prepared with the nanoprecipitation method and emulsion-solvent evaporation method, and determine their particle size, zeta potential, the efficiency of fluorescent labeling, in vitro leakage rate and the stability with the lysozyme were determined. The effects of physical and chemical properties on the transmucosal transport of the fluorescent nanoparticles were investigated by confocal laser scanning microscopy (CLSM). The result showed that the size of nanoparticles prepared with nanoprecipitation method varied between 120 and 200 nm; the size of nanoparticles prepared with emulsion-solvent evaporation method varied between 420 and 450 nm. Nanoparticles dispersed uniformly; the zeta potential of PLGA-NPs was negative; mPEG-PLGA-NPs was close to neutral; chitosan coated PLGA-NPs was positive; and the efficiency of fluorescent labeling were higher than 80%. In vitro leak was less than 5% within 4 h and nanoparticles were basically stable with lysozyme. The CLSM results show that the transportation efficiency of mPEG-PLGA-NPs with a high PEG coating density and high mPEG molecular weight was significantly higher than that of uncoated PLGA nanoparticles and also that of chitosan coated PLGA-NPs (P < 0.05). The hydrophilcity, zeta potential and particle size of nanoparticles play important roles on the efficiency of mPEG-PLGA nanoparticles to transport across the rat nasal mucosa.
Animals ; Biological Transport ; Chitosan ; chemistry ; Drug Carriers ; chemistry ; Female ; Male ; Microscopy, Confocal ; Molecular Weight ; Nanoparticles ; Nasal Mucosa ; metabolism ; Particle Size ; Polyesters ; chemistry ; pharmacokinetics ; Polyethylene Glycols ; chemistry ; pharmacokinetics ; Rats ; Rats, Sprague-Dawley