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Purpose The aim of this research work was to explore the possibility of providing multifunctional oral insulin delivery system by conjugating several types of dipeptides on chitosan and trimethyl chitosan to be used as drug carriers. Method Conjugates of Glycyl-glycine and alanyl-alanine of chitosan and trimethyl chitosan (on primary alcohol group of polymer located on carbon 6) were synthesized and nanoparticles containing insulin were prepared for oral delivery. Preparation conditions of nanoparticles were optimized and their performance to enhance the permeability of insulin as well as cytotoxicity of nanoparticles in Caco-2 cell line was evaluated. To evaluate the efficacy of orally administered nanoparticles, nanoparticles with the most permeability enhancing ability were studied in male Wistar rats as animal model by measuring insulin and glucose Serum levels. Result Structural study of all the conjugates by infrared spectroscopy and nuclear magnetic resonance confirmed the successful formation of the conjugates with the desirable substitution degree. By optimizing preparation conditions, nanoparticles with expected size (157.3–197.7 nm), Zeta potential (24.35–34.37 mV), polydispersity index (0.365–0.512), entrapment efficiency (70.60–86.52%) and loading capacity (30.92–56.81%), proper morphology and desirable release pattern were obtained. Glycyl-glycine and alanyl-alanine conjugate nanoparticles of trimethyl chitosan showed 2.5–3.3 folds more effective insulin permeability in Caco-2 cell line than their chitosan counterparts. In animal model, oral administration of glycyl-glycine and alanyl-alanine conjugate nanoparticles of trimethyl chitosan demonstrated reasonable increase in Serum insulin level with relative bioavailability of 17.19% and 15.46% for glycyl-glycine and alanyl-alanine conjugate nanoparticles, respectively, and reduction in Serum glucose level compared with trimethyl chitosan nanoparticles ( p  < 0.05). Conclusion It seems that glycyl-glycine and alanyl-alanine conjugate nanoparticles of trimethyl chitosan have met the aim of this research work and have been able to orally deliver insulin with more than one mechanism in animal model. Hence, they are promising candidates for further research studies. [ABSTRACT FROM AUTHOR]

Abstract: The aim of present study was to investigate the potential of mucoadhesive polymer chitosan (CS) and N-trimethyl chitosan (TMC) based nanoparticulate systems for oral bioavailability enhancement of low molecular weight heparin (LMWH). The TMC was synthesized by methylation of chitosan followed by characterization using infrared spectroscopy and 1H-NMR spectroscopy. The IR and NMR spectra of TMC confirmed the presence of trimethyl groups and estimated the degree of quaternization for TMC about 46%. TMC nanoparticles were then prepared by ionic gelation method. The developed CS-NPs and TMC-NPs were characterized for various parameters including morphology, particle size, zeta potential, entrapment efficiency, in vitro release behavior and storage stability at different temperature and simulated gastrointestinal tract conditions. The fluorescent microscopy study confirmed the higher particle uptake of TMC-NPs by gastrointestinal epithelium in comparison to the CS-NPs. The concentration of LMWH in the systemic circulation followed by oral administration of formulations was estimated using FXa chromogenic assay. A significant increase (p <0.05) in the oral bioavailability of LMWH was observed with TMC-NPs than both CS-NPs as well as plain LMWH solution. These findings suggested that TMC nanoparicles hold promise for oral delivery of LMWH and clinical applicability for the treatment of vascular disorders like deep vein thrombosis and pulmonary embolism, etc. [Copyright &y& Elsevier]

Abstract: Polyelectrolyte complexes (PEC) formed between chitosan derivatives and enoxaparin were prepared by a self-assembly process and were characterized in terms of particle size and surface charge. The morphology was observed by atomic force microscopy (AFM). The colloidal stability and bioadhesion of the PEC were characterized by dynamic light scattering (DLS). The absorption of enoxaparin in rats was evaluated by activated partial thromboplastin time (APTT) assay. It was shown that the prepared PEC had a spherical shape with positive charge and a mean diameter in the range of 200–600nm. An increase in temperature led to a decrease in particle size (ca. 10%) with an increased kcps value (ca. 10–20%) for the PEC studied, depending on the polymer structure. Thiolation and methylation of chitosan could significantly improve the corresponding PEC''s bioadhesion and hence the oral absorption of enoxaparin. A good relationship between bioadhesion and in vivo absorption was established. However, PEC of PEGylated chitosan did not display a significantly enhanced permeation of enoxaparin compared with unmodified chitosan. In conclusion, the oral bioavailability of enoxaparin can be enhanced by improving the bioadhesive properties of PEC via the chemical modification of chitosan employed. [Copyright &y& Elsevier]

Abstract: The effects of the molecular weight (MW) and concentration of trimethyl chitosan (TMC) on the characteristics of Coenzyme Q10-loaded liposomes coated with trimethyl chitosan were investigated while the efficacy of the antioxidant Coenzyme Q10 in delaying selenite-induced cataract was assessed. The existence of a thick polymer layer on the surface of the liposomes nanoparticle system was affirmed by transmission electron microscopy (TEM) analysis and the changes in particle size distribution and zeta potential. The entrapment efficiency was almost the same as when the polymer was added to liposomes. The Draize test and histological analysis demonstrated the excellent ocular tolerance of TMC for topical administration. Gamma scintigraphic data clearly showed that the drug elimination of polymer-coated liposomes is significantly slower than the radiolabelled solution used as a control. An almost 4.8-fold increase in the precorneal residence time was achieved in the presence of TMC with a higher Mw compared with the control group. Furthermore, the anti-cataract effect was evaluated by morphological examination and analysis of biochemical changes. Coenzyme Q10 exhibited a markedly anti-cataract effect with the percentage of lens opacity being about 53% at the final examination. The mean activities of superoxide dismutase and reduced glutathione were significantly higher in the Coenzyme Q10-treated group than in the cataract model group, while malondialdehyde was significantly lower. In conclusion, the physical properties and precorneal retention time of liposomes could be modified with TMC and ophthalmic instillation of Coenzyme Q10 is able to retard selenite-induced cataract formation. [Copyright &y& Elsevier]

Abstract: The aim was to evaluate the influence of the degree of quaternization of N-trimethyl chitosans (TMCs) on the mucoadhesive and penetration enhancement properties towards buccal mucosa. Fluorescein isothiocyanate dextran (MW 4400Da) (FD4) was used as model molecule. TMCs, obtained from chitosans of different MW (1460 and 580kDa, respectively), were hydrated in distilled water and in pH 6.4 phosphate buffer (simulating the buccal fluid). The polymer solutions were subjected to mucoadhesion measurements towards bovine submaxillary mucin dispersion and porcine buccal mucosa and to FD4 permeation tests through porcine cheek epithelium. The trimethylation of chitosan allows maintenance or improvement of the mucoadhesive properties of the starting chitosans dependently on quaternization degree. In particular, the mucoadhesive properties increase on increasing degree of quaternization. The trimethylation does not produce any change in chitosan penetration enhancement properties when the medium is distilled water while if pH 6.4 buffer is used, the trimethylation produces an improvement in chitosan penetration enhancing effect. TMC derived from the lower MW chitosan and characterized by the highest degree of quaternization shows the best mucoadhesive and penetration enhancement properties and is the most promising TMC to improve the bioavailability of hydrophilic and large MW molecules (like peptides and proteins) when administered via buccal route. [Copyright &y& Elsevier]

• TMC-CMD NPs are low toxicity and biocompatible nanoparticles. • STAT3/NIK siRNA and BV6 loaded in CMD-TMC NPs induce apoptosis in murine cell line. • STAT3/NIK siRNA and BV6 loaded in CMD-TMC NPs reduce cell migration and metastasis. • STAT3/NIK siRNA and BV6 loaded in CMD-TMC NPs reduce angiogenesis. High expression of inhibitor of apoptosis (IAP) molecules in cancer cells promotes cancer cell chemoresistance. Use of BV6, a well-known IAP inhibitor, along with inhibition of signal transducer and activator of transcription 3 (STAT3), which is an important factor in the survival of tumor cells, and NIK as a mediator of BV6 unpredicted side effects, can induce effective apoptosis in tumor cells. The present study has investigated the combination therapy of cancer cells using Carboxymethyl Dextran-conjugated trimethyl chitosan (TMC-CMD) nanoparticles (NPs) loaded with NIK/STAT3-specific siRNA and BV6 to synergistically induce apoptosis in the breast, colorectal and melanoma cancer cell lines. Our results showed that in addition to enhanced pro-apoptotic effects, this combination therapy reduced proliferation, cell migration, colony formation, and angiogenesis, along with expression of factors including IL-10 and HIF in tumor cells. The results indicate the potential of this combination therapy for further investigation in animal models of cancer. [ABSTRACT FROM AUTHOR]