Smart redox-sensitive micelles based on chitosan for dasatinib delivery in suppressing inflammatory diseases.

Dasatinib (DAS) exhibits anti-inflammatory effects by retrieving the balance between inflammatory and anti-inflammatory cytokines secreted by macrophages. The aim of this study was the development of redox-responsive micelles with the potential of passive targeting and on-demand drug release for DAS delivery to macrophages. For this purpose, two molecular weights of chitosan (CHIT) were conjugated to DAS at different molar ratios using 3,3'-dithiodipropionic anhydride (DTDPA) as disulfide bond containing linker to synthesize a series of CHIT-S-S-DAS amphiphilic conjugates. Micelles obtained by the sonication method had particle sizes of 129.3-172.2 nm, zeta potentials of +17.5 to +20.9 mV, drug contents of 0.90-7.20 %, CMC values of 35.3-96.6 µg/ml, and exhibited redox-responsive in vitro drug release. Optimized micelles were non-toxic and dramatically more efficient than non-redox responsive micelles in reducing TNF-α and IL-6 and increasing IL-10 secretion from LPS-stimulated RAW264.7 cells. Furthermore, the redox-responsive micelles were able to reduce the mice paw edema, reduce the plasma levels of pro-inflammatory cytokines and increase plasma level of IL-10, considerably more than free DAS and non-redox responsive micelles in carrageenan-induced mice paw edema model of inflammation.

Enhanced Solubility and Permeability of Naringenin Across Non-Everted Sacs of Rat Small Intestine by Lipid Nanocapsules.

BACKGROUND: Naringenin (NRG) has many health benefits, including; anti-atherogenic, antiinflammatory, antitumor, and anticancer activity, as well as improvement of lipid metabolism. However, its use is limited due to its low solubility and bioavailability. OBJECTIVES: The aim of the present patent study was the preparation and optimization of NRG loaded Novel Lipid Nanocapsules (LNCs) for the improvement of NRG solubility and gut permeability. METHODS: Studied variables included; Solutol® HS15 and NRG concentration and the ratio of cold diluent water to primary emulsion. The storage stability of the LNCs was evaluated for 32 days and thermal analyses were conducted by Differential Scanning Calorimetry (DSC). The antioxidant properties of the NRG in LNCs were studied by measuring the 2,2-Diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging activity. The enhancement of permeation of NRG by the LNCs from the intestine was evaluated by the non-everted gut sac method. RESULTS: The optimized NRG-LNCs had a hydrodynamic diameter of 29.41±1.25 nm, a low polydispersity index, and high entrapment efficiency of 99.25±2.31%. The LNCs could retain NRG radical scavenging activity, showed good storage stability, and significantly improved NRG solubility (69 fold) and permeation through non-everted rat intestinal sac (4.33 fold). CONCLUSION: LNCs of NGR enhance solubility and intestinal permeability of this flavonoid and may be useful in the improvement of its bioavailability.

Pulmonary Delivery of Triptorelin Loaded in Pluronic Based Nanomicelles in Rat Model.

INTRODUCTION: Triptorelin, the synthetic analog of gonadotrophin-releasing hormone, is used for the treatment of sex hormone dependent diseases via parenteral administration. The aim of the present study was to investigate the possibility of triptorelin pulmonary delivery and preparation of a pulmonary nanocarrier delivery system for it. METHODS: Triptorelin was loaded in Pluronic-F127 grafted poly (methyl vinyl ether-alt-maleic acid) nanomicelles by direct dissolution method. Effects of the processing variables including: drug/polymer ratio, temperature, stirring rate and time on the physicochemical properties of nanomicelles including zeta potential, particle size, drug entrapment efficiency and release profiles of triptorelin loaded nanomicelles were evaluated. For animal studies 24 Wistar rats were separated into four groups of six. Group 1 received blank nanomicelles, groups 2, 3 and 4 were treated with a single dose of 250 µg.kg-1 of triptorelin solution subcutaneously (sc), pulmonary spraying of triptorelin solution (250 µg.kg-1) and pulmonary spraying of triptorelin nanomicelles (250 µg.kg-1), respectively by microsprayer. RESULTS: The optimized micelles had particle size of 87.35 nm, zeta potential of -12.8 mV, entrapment efficiency of 84.36% and release efficiency of 65%. The area under the blood testosterone levels increment differed significantly (p<0.05) between pulmonary triptorelin nanomicelles and drug solution. The pharmacological activity of the simple solution was 59.38%, while it was 80.18% for the nanomicelles relative to sc route of administration with prolonged residence time. CONCLUSION: The results of this study show that not only triptorelin is absorbable from the lungs but also nanomicelles can significantly enhance its pulmonary absorption compared to its simple solution.

Lipoprotein Like Nanoparticles Used in Drug and Gene Delivery.

BACKGROUND: Native lipoproteins as nanoparticulate drug delivery systems have gained considerable attention in recent years. This is due to their biocompatibility, being endogenous, no triggering the immunological responses, relatively long half-life in the circulation, simple diffusion from vascular to extravascular compartments due to their nanometric particle size, potentially targeting capability to cellular receptors, simple preparative processes in the reconstituted forms, easy functionalization and high capacity for drug loading. Clinical application of many therapeutic agents like anticancer drugs and genes is hampered due to their susceptibility to degradation and difficult delivery into cells. Several nanoparticle platforms for siRNA delivery have been developed to overcome the major limitations facing the therapeutic uses of bioactive therapeutic agents. METHODS: This review covers a broad spectrum of lipoproteins as non-viral drug and gene delivery systems. These nanoparticles are developed for enhanced cellular uptake and specially targeted gene silencing in vitro and in vivo and their characteristics and opportunities for clinical applications of therapeutic agents are discussed in this article. Various types of lipoprotein nanovectors including: natural and modified lipoproteins used to deliver drugs, bioactive and genetic materials are introduced and the development of theranostics and combinational treatments are also discussed. RESULTS: The unique physicochemical properties of lipoproteins as natural nanostructures in biological systems and their structural diversity, including chylomicrons, VLDL, LDL and HDL, has caused their utility as potent pharmaceutical carriers. CONCLUSION: According to the literatures, different lipoproteins especially the artificial lipoproteins, reconstituted and modified ones have potential to be used in targeted delivery of therapeutic agents to the tumors and effective delivery of the corresponding genetic and other bioactive components involving in diseases.