Dopamine D3 receptor mediates natural and methamphetamine rewards via regulating the expression of miR-29c in the nucleus accumbens of mice.

The dopamine D3 receptor (D3R), principally confined to the nucleus accumbens (NAc), is involved in regulating natural and drug rewards; however, the molecular mechanisms underlying the associated process remain unclear. Earlier research has reported the concurrent influence of D3R and miR-29c expressed in the NAc on methamphetamine (METH)-induced reward behaviors and microglial activation, hinting at regulatory roles in reward processing. Herein, we performed viral manipulation-mediating D3R/miR-29c overexpression and inhibition in the whole NAc in male D3R knockout and wild-type mice to investigate this potential relationship. Behavioral responses to the rewarding stimuli were assessed using sucrose preference score, METH-induced locomotor sensitization, and METH-induced conditioned place preference tests. Overall, we observed a notable decrease in the behavioral response to sucrose and METH in D3R-deficient mice, accompanied by the downregulation of miR-29c expression in the NAc. Diminished responses to those rewarding stimuli in D3R-deficient mice primarily stemmed from the reduction of GSK3ß activity and subsequent down-regulation of miR-29c in the NAc. Microglial activation in the NAc mediates the effect of D3R-miR-29c deficiency on the reward effects of sucrose and METH. Pharmacological suppression of microglial activity rescued the reduced response in mice lacking D3R-miR-29c in the NAc. Overall, this study revealed the mechanism by which D3R regulates both natural and drug rewards via miR-29c in the murine NAc, highlighting the role of the NAc D3R-miR-29c pathway as a critical regulator of rewards, and providing new insights into the role of NAc D3R-miR-29c in encoding rewarding experiences.

Novel controlled drug release system engineered with inclusion complexes based on carboxylic graphene.

A novel drug carrier is constructed by compositing hydrophilic hydroxypropyl-ß-cyclodextrins (HP-ß-CD) and carboxylated graphene nanomaterial (GO-COOH). Fourier transform infrared spectroscopy confirms that the two materials are successfully combined via chemical bonds. Further, a crosslinking agent of glutaraldehyde is applied to fabricate composite GO-COO-HP-ß-CD nanospheres, as demonstrated by an atomic force microscope. Dexamethasone (DEX) is selected as the model drug, and the drug loading efficiency and water solubility of the nanospheres greatly increased. Additionally, the achieved DEX/nanosphere inclusion complex exhibits better heat resistance compared with pure DEX, which is a desired property for drug processing. More importantly, different models are applied to different releasing durations to investigate in detail the release profile of DEX. The best fitting release kinetics model is given to reveal the release mechanism of the drug delivery system. The highest hemolysis rate of the DEX/nanosphere inclusion is 0.44%, far lower than the standard of 5% delivered by the American Society for Testing and Materials, ensuring its safety in practical applications. Meanwhile, recalcification tests indicate that DEX/nanosphere retains the normal blood coagulation function. In vitro cytotoxicity tests of the inclusion demonstrate that the nanospheres have no toxicity and are qualified for intravenous applications with good blood compatibility. Finally, the bioactivity of DEX after release from the carriers is investigated. Results corroborate that the drug anti-inflammation efficacy is not affected and that the biomedical function can be well retained. The engineered controlled drug release system represents a promising formulation platform for a broad range of therapeutic medicine in pharmaceutical technology.

Carboxylated graphene oxide functionalized with ß-cyclodextrin-Engineering of a novel nanohybrid drug carrier.

In this paper, we selected biocompatible carboxylated graphene oxide (GeneO-COOH) as a base material. The nanohybrid drug carriers composed of GeneO-COOH and cyclodextrin (ß-CD), have been successfully synthesized through esterification and self-assembly technique. The nanohybrid drug carriers of GeneO-COO-ß-CD were characterized by X-ray diffraction (XRD), fourier infrared spectroscopy (FTIR), thermogravimetric analysis (TG), scanning electron microscopy (SEM), transmission electron microscopy (TEM) and solubility experiments. Results indicated that the nanohybrid was obtained with GeneO-COOH forming the core and a large number of ß-CD molecules forming the shell with a special structure. In the nanohybrid, the westerification between GeneO-COOH and ß-CD led to the formation of covalent bonds, while adjacent ß-CD molecules engineer an outer shell composed of 100 ß-CD molecules (ca. 800nm of thickness) in the form of a layer-by-layer self-assembly due to hydrogen-bonding interaction. The obtained novel nanohybrid drug carriers of GeneO-COO-ß-CD possessed good dispersibility in water media and the solutions were found to remain stable for 12 months，providing a possibility for further applications in biology, medicine, agriculture and other fields.

Hydroxypropyl-ß-cyclodextrin-graphene oxide conjugates: Carriers for anti-cancer drugs.

A novel drug carrier based on hydroxypropyl-ß-cyclodextrin (HP-ß-CD) modified carboxylated graphene oxide (GO-COOH) was designed to incorporate anti-cancer drug paclitaxel (PTX). The formulated nanomedicines were characterized by Fourier transform infrared spectroscopy (FTIR) and atomic force microscopy (AFM). Results showed that PTX can be incorporated into GO-COO-HP-ß-CD nanospheres successfully, with an average diameter of about 100 nm. The solubility and stability of PTX-loaded GO-COO-HP-ß-CD nanospheres in aqueous media were greatly enhanced compared with the untreated PTX. The results of hemolysis test demonstrated that the drug-loaded nanospheres were qualified with good blood compatibility for intravenous use. In vitro anti-tumor activity was measured and results demonstrated that the incorporation of PTX into the newly developed GO-COO-HP-ß-CD carrier could confer significantly improved cytotoxicity to the nanosystem against tumor cells than single application of PTX. GO-COO-HP-ß-CD nanospheres may represent a promising formulation platform for a broad range of therapeutic agent, especially those with poor solubility.

GO-COO-HP-ß-CD nanosphere: a complex construction and its drug-loading properties.

A novel nanosphere based on carboxylated GO (GO-COOH) and hydroxypropyl-beta-CD (HP-ß-CD) was synthesized to construct a complex of GO-COO-HP-ß-CD. The complex formation process was studied using spectral characterization and transmission electron microscopy (TEM). X-ray diffraction and energy dispersive spectroscopy patterns show that HP-ß-CD molecules either cover or intercalate into GO-COOH interlayers in the complex. Fourier transform infrared spectroscopy results indicate that GO-COOH and HP-ß-CD are linked with covalent bonds formed via esterification. When employed as nanohybrid drug carriers for dexamethasone, the inclusion displays good dispersibility validated by dynamic light scattering (DLS). Cytotoxicity assays and hemolysis testing demonstrate that the nanospheres possess good biological compatibility. The loading capacity of dexamethasone is as high as 32.33%, with loading efficiency 64.66%.

Novel GO-COO-ß-CD/CA inclusion: its blood compatibility, antibacterial property and drug delivery.

GO-COO-ß-CD/CA inclusion (carboxylated graphene-ß-cyclodextrin/chlorhexidine acetate) was fabricated with a graphene-based drug carrier. The reaction time and ratio of carrier to drug were optimized by X-ray diffraction spectra to ensure the complete wrapping of CA. Hemolysis test and recalcification test demonstrated that the inclusion possessed good blood compatibility due to the inherent biocompatibility of ß-CD molecules in the carrier. The inclusion displayed excellent inhibition effect on both gram negative bacteria of Escherichia coli and gram positive bacteria of Staphylococcus Aureus, while showing no cytotoxicity. More importantly, the drug efficiency was greatly improved with CA dosage as less as one-third of the pure drug due to the synergistic effect of the drug and carrier. Dynamic simulation implies that the delivery profile of CA from the inclusion is in accordance with the first-order dynamic equation, i.e. ln(1-Mt/M) = -kt.

Long-term and controlled release of chlorhexidine-copper(II) from organically modified montmorillonite (OMMT) nanocomposites.

Drug/metal ion complexes exhibit improved antimicrobial activity and intercalating the above complexes into the interlayer of clay endows a long-term and controlled-release behavior. In this study, chlorhexidine was first complexed with copper (II) ion and then intercalated into the interlayer of MMT to form chlorhexidine-copper (II)/montmorillonite (CHX-Cu/MMT) nanocomposites. The nanocomposites were characterized with Fourier transform infrared (FT-IR), X-ray diffraction (XRD) and thermogravimetric analysis (TGA). A nearly lateral-monolayer arrangement of CHX-Cu was supposed for the intercalation. Release kinetics indicated that the release process satisfied a pseudo-second-order mode. The antibacterial results showed that the CHX-Cu/MMT composites had long-term and controlled-release behavior.