Nanodrug Carrier System Research Articles

Platelet and Erythrocyte Membranes Coassembled Biomimetic Nanoparticles for Heart Failure Treatment.

Cardiac fibrosis is a prevalent pathological process observed in the progression of numerous cardiovascular diseases and is associated with an increased risk of sudden cardiac death. Although the BRD4 inhibitor JQ1 has powerful antifibrosis properties, its clinical application is extremely limited due to its side effects. There remains an unmet need for effective, safe, and low-cost treatments. Here, we present a multifunctional biomimetic nanoparticle drug delivery system (PM&EM nanoparticles) assembled by platelet membranes and erythrocyte membranes for targeted JQ1 delivery in treating cardiac fibrosis. The platelet membrane endows PM&EM nanoparticles with the ability to target cardiac myofibroblasts and collagen, while the participation of the erythrocyte membrane enhances the long-term circulation ability of the formulated nanoparticles. In addition, PM&EM nanoparticles can deliver sufficient JQ1 with controllable release, achieving excellent antifibrosis effects. Based on these advantages, it is demonstrated in both pressures overloaded induced mouse cardiac fibrosis model and MI-induced mouse cardiac fibrosis that injection of the fusion membrane biomimetic nanodrug carrier system effectively reduced fibroblast activation, collagen secretion, and improved cardiac fibrosis. Moreover, it significantly mitigated the toxic and side effects of long-term JQ1 treatment on the liver, kidney, and intestinal tract. Mechanically, bioinformatics prediction and experimental validation revealed that PM&EM/JQ1 NPs reduced liver and kidney damage via alleviated oxidative stress and mitigated cardiac fibrosis via the activation of oxidative phosphorylation activation. These results highlight the potential value of integrating native platelet and erythrocyte membranes as a multifunctional biomimetic drug delivery system for treating cardiac fibrosis and preventing drug side effects.

The therapeutic efficacy of different configuration nano-polydopamine drug carrier systems with photothermal synergy against head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignant tumor worldwide. Considering its special anatomical site and the progressive resistance to chemotherapy drugs, the development of more effective, minimally invasive and precise treatment methods is urgently needed. Nanomaterials, given their special properties, can be used as drug carrier systems to improve the therapeutic effect and reduce the adverse effects. The drug carrier systems with photothermal effect can promote the killing of cancer cells and help overcome drug resistance through heat stress. We selected dopamine, a simple raw material, and designed and synthesized three different configurations of nano-polydopamine (nPDA) nanomaterials, including nPDA balls, nPDA plates and porous nPDA balls. In addition to the self-polymerization and self-assembly, nPDA has high photothermal conversion efficiency and can be easily modified. Moreover, we loaded cisplatin into three different configurations of nPDA, creating nPDA-cis (the nano-drug carrier system with cisplatin), and comparatively studied the properties and antitumor effects of all the nPDA and nPDA-cis materials in vitro and nPDA-cis in vivo. We found that the photothermal effect of the nPDA-cis balls drug carrier system had synergistic effect with cisplatin, resulting in excellent antitumor effect and good clinical application prospects. The comparison of the three different configurations of drug carrier systems suggested the importance of optimizing the spatial configuration design and examining the physical and chemical properties in the future development of nano-drug carrier systems. In this study, we also noted the duality and complexity of the influences of heat stress on tumors in vitro and in vivo. The specific mechanisms and the synergy with chemotherapy and immunotherapy will be an important research direction in the future.

Rod-like graphitic carbon nitride nanosheets with copper ions for effective DNA cleavage and anticancer studies

Graphitic Carbon Nitride (g-CN) nanomaterials are emerging effective biomaterials and play a vital role in the biodiversity research area due to their biocompatibility, and less toxic nature. The nanosized g-CN rod-like nanosheets were synthesized and characterized with XRD, FTIR, UV–Vis and Fluorescence spectroscopy, FESEM, EDAX and HRTEM analysis. The g-CN appears almost immediately. DNA cleavage and anticancer activity investigations were conducted using Cu2+ ions. The size and Lewis acidic and Lewis basic functions of Cu2+/g-CN played a vital role in effective DNA cleavage and anticancer activity were demonstrated. The g-CN, Cu2+ ions, Cu2+/g-CN nanostructure and its various concentrations at different times were studied for the DNA cleavage and anticancer activity. The DNA interaction with Cu2+ ions/g-CN rod-like nanosheets was also established with UV–Vis and Fluorescence analysis. The Cu2+/g-CN nanostructure showed highly efficient activity than the other concentrations and controls were used in this study. The specificity and effectiveness of the present DNA slicing agent and anticancer nano-drug carrier system may value the investigation of cancer pharmaceutics.

Aptamer-mediated hollow MnO2 for targeting the delivery of sorafenib

Sorafenib (SRF) presents undesirable effects in clinical treatment, due to the lack of targeting, poor water solubility, and obvious side effects. In this study, we constructed a novel nanodrug carrier system for accurate and efficient delivery of SRF, improving its therapeutic effects and achieving tumor-specific imaging. The hollow mesoporous MnO2 (H-MnO2) nanoparticles equipped with target substance aptamers (APT) on the surface were used to load SRF for the first time. The resulting H-MnO2-SRF-APT could specifically bound to glypican-3 (GPC3) receptors on the surface of hepatocellular carcinoma (HCC), rapidly undergoing subsequent degradation under decreased pH conditions in the tumor microenvironment (TME) and releasing the loaded SRF. In this process, Mn2+ ions were used for T1-weighted magnetic resonance imaging simultaneously. The in vitro cell experiments indicated that H-MnO2-SRF-APT showed much more effects on the inhibition in the proliferation of Huh7 and HepG2 HCC cells than that of the non-targeted H-MnO2-SRF and free SRF. Besides, the in vivo results further confirmed that H-MnO2-SRF-APT could effectively inhibit the growth of xenograft tumors Huh7 in the naked mouse with good biosafety. In conclusion, H-MnO2-SRF-APT could significantly enhance the therapeutic effect of SRF and is expected to be a new way of diagnosis and treatment of HCC.

Preparation of gastrodin-modified dendrimer-entrapped gold nanoparticles as a drug delivery system for cerebral ischemia-reperfusion injury.

This study sought to evaluate the feasibility of multifunctional gastrodin (GAS)-containing nano-drug carrier system against cerebral ischemia-reperfusion injury (CIRI). The drug-loaded nanocomposite (Au-G5.NHAc-PS/GAS) with certain encapsulation efficiency (EE) was prepared by physical adsorption method using different proportions of GAS and drug-carrying system (Au-G5.NHAc-PS). High-performance liquid chromatography was used to determine the drug loading and EE. Cultured rat astrocytes and hypothalamic neurons were assigned into four groups: PBS, Au-G5.NHAc-PS, Au-G5.NHAc-PS/GAS, and GAS. CCK-8 assay, flow cytometry, and quantitative real-time PCR were performed to examine the cell viability, apoptosis, and the expression of tumor necrosis factor-α (TNF-α), IL-1β, and IL-6 in the astrocytes and hypothalamic neurons, respectively. Cellular uptake of GAS and Au-G5.NHAc-PS/GAS was analyzed by using Hoechst 33342 staining. The animal model with focal cerebral ischemia was generated by middle cerebral artery occlusion (MCAO) in healthy male Sprague Dawley (SD) rats, and pathological changes of brain tissue and major organs in the rats were identified by hematoxylin and eosin (HE) staining. Apoptosis in rat astrocytes and hypothalamic neurons was detected by TUNEL staining and flow cytometry. Au-G5.NHAc-PS had a spherical shape with a uniform size of 157.3nm. Among the nanoparticles, Au-G5.NHAc-PS/GAS with an EE of 70.3% displayed the best release delay effect. Moreover, we observed that in vitro cytotoxicity and cellular uptake of Au-G5.NHAc-PS/GAS were higher than those of GAS, whereas the expression of TNF-α, IL-1β, and IL-6 was significantly downregulated in Au-G5.NHAc-PS/GAS group as compared to G5.NHAc-PS group. Notably, HE staining revealed that although Au-G5.NHAc-PS/GAS had no toxic and side effects on the main organs of rats, it alleviated the damage of brain tissue in the MCAO rats. Besides, Au-G5.NHAc/GAS markedly reduced MCAO-induced apoptosis. Au-G5.NHAc-PS showed favorable surface morphology, sustained drug release ability, no measurable toxicity, and good biocompatibility, indicating that GAS exerts anti-inflammatory and antiapoptotic effects on CIRI.

Effects of Biofilm Nano-Composite Drugs OMVs-MSN-5-FU on Cervical Lymph Node Metastases From Oral Squamous Cell Carcinoma.

This work was developed to the effects of biofilm composite nano-drug delivery system (OMVs-MSN-5-FU) on lymph node metastasis from oral squamous cell carcinoma. Mesoporous silica nanoparticles loaded with 5-FU (MSN-5-FU) were prepared first. Subsequently, the outer membrane vesicles (OMV) of Escherichia coli were collected to wrap MSN-5-FU, and then OMVs-MSN-5-FU was prepared. It was then immersed in artificial gastric juice and artificial intestinal juice to explore the drug release rate. Next, the effects of different concentrations of the nano-drug delivery systems on the proliferation activity of oral squamous carcinoma cell line KOSC-2 cl3-43 were analyzed. Tumor-bearing nude mice models were prepared by injecting human tongue squamous cell carcinoma cells Tca8113 into BALB/c-nu nude mice. They were injected with the OMVs-MSN-5-FU nano drug carrier system, and peri-carcinoma tissue and cervical lymph node tissue were harvested to observe morphological changes by Hematoxylin – eosin (HE) staining. The scanning electron microscope (SEM) results showed that all MSN, MSN-5-FU, OMV, and OMV-MSN-5-FU were spherical and uniformly distributed, with particle sizes of about 60nm, 80nm, 90nm, and 140nm, respectively. Among them, OMV had a directional core-shell structure. The cumulative drug release rates of artificial gastric juice in 48 hours were 61.2 ± 2.3% and 26.5 ± 3.1%, respectively. The 48 hours cumulative drug release rates of artificial intestinal juice were 70.5 ± 6.3% and 32.1 ± 3.8%, respectively. The cumulative release of MSN-5-FU was always higher than OMV-MSN-5-FU. The cumulative release of MSN-5-FU was always higher than OMV-MSN-5-FU. After injection of OMVS-MSN-5-FU, the number of cancer cells was significantly reduced and cervical lymph node metastasis was significantly controlled. HE staining results showed that OMVS-MSN-5-FU injection reduced the number of stained cells. Dense lymphocytes were clearly observed in the cortex of neck lymphocytes. The OMVs-MSN-5-FU drug delivery system can slow down the drug release rate, significantly inhibit the proliferation activity of oral squamous cancer cells, and control the metastasis of cancer cells to cervical lymph nodes.

Manifestation of Urinary Tract Injury during Cervical Cancer Surgery Based on CT Urography Secretion Phase Images.

Methods We grouped the patients who had undergone cervical cancer surgery in a hospital in this article and compared the nanodrug carrier system under CT imaging with traditional laparoscopy. The postoperative physical parameters of surgical patients are collected from cervical cancer patients of different degrees, and the parameters and prognostic health of patients after different operations are compared. Results The results of the study show that the postoperative patient's body parameters of the nanodrug delivery system under the CT imaging technology used in this article are better than those of the traditional surgery group, and the average intraoperative blood loss is about 20% less than that of the traditional surgery. Postoperative complications occur. The situation is even lower, more than 30% lower than traditional surgery. Conclusion This shows that the operation of the nanodrug delivery system based on CT imaging technology has broken through some of the limitations of the development of laparoscopic technology and has played an important role in the surgical treatment of cervical cancer.

Nanodrug Transmembrane Transport Research Based on Fluorescence Correlation Spectroscopy.

Although conventional fluorescence intensity imaging can be used to qualitatively study the drug toxicity of nanodrug carrier systems at the single-cell level, it has limitations for studying nanodrug transport across membranes. Fluorescence correlation spectroscopy (FCS) can provide quantitative information on nanodrug concentration and diffusion in a small area of the cell membrane; thus, it is an ideal tool for studying drug transport across the membrane. In this paper, the FCS method was used to measure the diffusion coefficients and concentrations of carbon dots (CDs), doxorubicin (DOX) and CDs-DOX composites in living cells (COS7 and U2OS) for the first time. The drug concentration and diffusion coefficient in living cells determined by FCS measurements indicated that the CDs-DOX composite distinctively improved the transmembrane efficiency and rate of drug molecules, in accordance with the conclusions drawn from the fluorescence imaging results. Furthermore, the effects of pH values and ATP concentrations on drug transport across the membrane were also studied. Compared with free DOX under acidic conditions, the CDs-DOX complex has higher cellular uptake and better transmembrane efficacy in U2OS cells. Additionally, high concentrations of ATP will cause negative changes in cell membrane permeability, which will hinder the transmembrane transport of CDs and DOX and delay the rapid diffusion of CDs-DOX. The results of this study show that the FCS method can be utilized as a powerful tool for studying the expansion and transport of nanodrugs in living cells, and might provide a new drug exploitation strategy for cancer treatment in vivo.

Construction and antitumor properties of a targeted nano-drug carrier system responsive to the tumor microenvironment

Doxorubicin (DOX) is one of the most commonly used and effective chemotherapy drugs among anthracyclines. An inherent limitation of DOX is its nonspecificity, which can cause serious side effects, thereby preventing the therapeutic use of high drug doses. In this study, we designed and created a simple nano-drug delivery system (PEG-MAF = P) with low biological toxicity that was responsive to the tumor environment. PEG-MAF = P was designed to self-assemble into nanospheres via control of a phenylalanine dipeptide (FF). The N-terminus of the peptide was linked to aldehyde groups at both ends of oxidized Pluronic F127 (F127-CHO) via Schiff bonds. The acidic environment surrounding the tumors was suitable for triggering the Schiff bonds, causing the nanospheres to disintegrate. The C-terminus of FF was connected to a ligand peptide, ATN-161, which was able to recognize cells expressing high levels of integrin α5β1 antigens both in vivo and in vitro. To prevent the impediment in drug release, PEG was linked via a matrix metalloproteinase-9 response peptide. Therefore, in an acidic tumor microenvironment containing MMP-9, PEG-MAF = P disintegrated and rapidly released the drug. PEG-MAF = P exhibited low cytotoxicity, high drug-loading rate, and excellent antitumor properties both in vivo and in vitro. Compared with free DOX, PEG-MAF = P-DOX reduced injury to normal tissues.

Experimental study on nuclear-targeted plasmid-based short hairpin RNA (ShRNA) to hypoxia inducible factor-1α (PshHIF-1α) PshHIF-1α nano-drug carrier system for breast cancer treatment in rats

This study was aimed at exploring the regulatory mechanism of auclear-targeted pshHIF-1α nano-drug carrier system (NPNCS) in the treatment of breast cancer in rats. MDA-MB-231 cell was cultured and DJ-1 and PTEN mRNA level was detected by qRT-PCR along with analysis of cell viability by CCK-8 and apoptosis by means of flow cytometry. The rats were assigned into control group, nuclear-targeted pshHIF-1α nanopharmaceutical system treatment group, and nuclear-targeted pshHIF-1α nano-pharmaceutical system+PTEN inhibitor SF1670 group, followed by analysis of cell proliferation by EdU staining, cell apoptosis by flow cytometry, and the levels of DJ-1, PTEN, and p-AKT. Compared with MDA-MB-231 cells treated with NPNCS, cells without intervention showed decreased PTEN and increased DJ-1 level. NPNCS induced cell apoptosis. Administration of nuclear-targeted pshHIF-1α nano-drug delivery system down-regulated DJ-1 and up-regulated PTEN. Combined treatment with SF1670 promoted p-AKT level and decreased the inhibitory effect of NPNCS on p-AKT level. In conclusion, the nuclear-targeted pshHIF-1α nano-drug delivery system down-regulated DJ-1 and exerted a tumor suppressor and pro-apoptotic effect, which wasrelated to p-AKT phosphorylation and up-regulation of PTEN.

Preparation of Graphene Nano-Drug Carrier System and Its Killing Effect on Tumor Cells

Preparation of Graphene Nano-Drug Carrier System and Its Killing Effect on Tumor Cells

Fluorescent bovine serum albumin-silver nanoclusters loaded with paclitaxel can traverse the blood-brain barrier to inhibit the migration of glioma

Abstract Objective: Glioma is the most common and aggressive primary brain tumor. Here, we aimed to establish a nano-drug carrier system to traverse the blood-brain barrier for the treatment and inhibition of glioma migration. Methods: The synthesis of bovine serum albumin protected-silver nanoclusters (BSA-AgNCs) was performed using chemical reduction. The drug paclitaxel (PTX) can be loaded into BSA-AgNCs through electrostatic and hydrophobic interactions to formulate spherical BSA-AgNC-PTX nanoparticles (BSA-AgNC-PTX NPs). A glioma mouse model was established by injecting U251-GFP-Luc cells into the mouse striatum, and all surgical procedures were approved by the Animal Ethics Committee of Nanchang University (SYXK2019-0003) on December 29, 2019. Results: The BSA-AgNC-PTX NPs were able to efficiently pass through the blood-brain barrier, both in vitro and in vivo, to deliver the drug to the tumor site. The in vivo assessment of BSA-AgNC-PTX NPs in glioblastoma multiforme-bearing mice revealed the significant inhibition of tumor growth and migration, prolonging the survival of the mice. Conclusion: These results indicated that BSA-AgNCs might represent an ideal nanocarrier for the treatment of glioma and has the potential to be used in the treatment of a variety of central nervous system diseases.

Synthesis and antiparkinsonian activity of nanocomposite of chitosan-tripolyphosphate-Mucuna pruriens L extract (CS-TPP-MP)

Mucuna pruriens L. (MP) has antiparkinsonian activity because it contains levodopa that acts as a dopamine precursor and plays a role to stimulate dopaminergic receptors in Parkinson's sufferers. The therapeutic efficacy of MP extract can be improved by using a nano drug carrier system, such as chitosan-tripolyphosphate (CS-TPP). This study aims to synthesize, characterize, and evaluate antiparkinsonian activity of chitosan-tripolyphosphate-MP extract (CS-TPP-MP) nanocomposite in mice. MP seed powder was extracted by maceration method using water-ethanol (1:1) by adding citric acid until it reached pH 3. The CS-TPP-MP nanocomposite was synthesized by using ionic gelation method with variations in reactant composition and reaction time. The CS-TPP-MP nanocomposite was characterized by Scanning Electron Microscopy-Energy Dispersive X-ray (SEM-EDX), X-Ray Diffraction (XRD) and Fourier-Transform Infrared (FTIR) Spectroscopy. Catalepsy test was performed to find the antiparkinsonian activity level of CS-TPP-MP nanocomposite at doses of 5, 10, 15, 20, and 25 mg/kg body weight. Based on the results of CS-TPP-MP synthesis, it was found that the reactant composition (CS-TPP:MP) of 1:3 with reaction time of 20 minutes produced the highest yield (14.21%.) SEM-EDX characterization showed that the morphology of CS-TPP-MP nanocomposite was predominantly spherical and the size was approximately 120-170 nm with a composition of C = 55.43%, O = 30.46%, N = 13.46%, P = 0.44%. XRD diffractogram showed that CS-TPP-MP nanocomposite has amorphous structure. FTIR analysis showed the appearance of absorption at wavelength of 1643.35 cm−1 which proved the interaction between the primary amine group of chitosan and the carbonyl group of EMP. Catalepsy test demonstrated that CS-TPP-MP nanocomposite at the doses of 5, 10, 15, 20, and 25 mg/kg body weight could reduce catalepsy symptoms in mice significantly, and the best dosage was 20 mg/kg body weight.

Chemical and biological evaluation of cross-linked halloysite-curcumin derivatives

Well designed and safe nano drug carrier systems are an important tool in biomedical applications. The combination of two or more drugs has been used in medicine both to enhance the therapeutic effect and to decrease the side effects of drugs. Biocompatible halloysite nanotubes, that possess two different surfaces, are a suitable nanomaterial for a simultaneous carrier and release of two drugs that can exert a synergistic effect against cancer cells. In this study, three curcumin derivatives and doxorubicin were loaded by supramolecular and covalent linkage at the lumen and external surface of the halloysite nanotubes. The obtained multifunctional systems were characterized by several techniques and the kinetic release of the drugs from the lumen was also investigated. Finally, the cytotoxic effects of the multifunctional carriers were evaluated on different cancer cell lines, namely breast cancer cell lines (SUM-149 and MDA-MB-231) and acute myeloid leukemia cell lines (HL60 and HL60R). The obtained results show promising cytotoxicity activity of the hybrids which is correlated to the nanoparticles size and to the release profile of the drug supramolecularly loaded on Hal surfaces.

PH-responsive ultrasonic self-assembly spinosad-loaded nanomicelles and their antifungal activity to Fusarium oxysporum

In this paper, we synthesized amphiphilic chitosan using one-pot method with the goal to develop delivery system for the natural pesticide spinosad. Chitosan-Isoleucine-Polyethylene glycol methyl ether (CIP) copolymers based nanomicelles (CIPNMs) were prepared by self-assembly with the assistance of ultrasonic treatment and then the spinosad was loaded on the micelles. Sphere-shaped spinosad-loaded CIPNMs (SSD@CIPNMs) with the particle sizes of approximately 454.9 nm were obtained with the CIP co-polymers. The shell of CIPNMs could effectively prevent the photodegradation of spinosad and played a role of protective barrier. In addition, the prepared SSD@CIPNMs not only delayed the release of spinosad but also had a property of pH-responsive. The release rate of SSD@CIPNMs at pH = 6.4 was greater than that of at pH = 7.0. And, the contact angle of SSD@CIPNMs on banana leaves surface was 60.47°, which meant SSD@CIPNMs had a good affinity with banana leaves. Furthermore, SSD@CIPNMs showed higher antifungal activity against Fusarium oxysporum compared with the unencapsulated spinosad at the same drug dose. This work was contribution to the development of nano-drug carrier systems of natural polymer materials, with a great potential for targeted treatment of banana wilt.

PEGylation of Ginsenoside Rg3-Entrapped Bovine Serum Albumin Nanoparticles: Preparation, Characterization, and In Vitro Biological Studies

Ginsenoside Rg3 (Rg3) is one of three triterpene saponins from red ginseng. It has important structural functions and pharmacological properties. However, due to its poor solubility, low bioavailability, and short half-life in blood circulation, its clinical application was unsuccessful for the treatment of a variety of cancers. In order to overcome this limitation, this study prepared mPEGylation-Rg3 bovine serum albumin nanoparticles (mPEG-Rg3-BSA NPs). The characteristics of the NPs, such as drug entrapment efficiency, drug loading efficiency, surface morphology, thermal stability, and cytotoxicity in vitro, were investigated. The results showed that the appropriate particle size of the obtained NPs was 149.5 nm, the water solubility and stability were better than free Rg3, and the drug entrapment efficiency and drug loading efficiency were 76.56% and 17.65%, respectively. Moreover, the cytotoxicity assays of the mPEG-Rg3-BSA NPs and free Rg3 revealed that the mPEG-Rg3-BSA NPs have greater anticancer effects in HepG2 cells and A549 cells. However, the cytotoxic effect of free Rg3 was higher than the mPEG-Rg3-BSA NPs in L929 cells. The results indicated that using the mPEGylation method and selecting BSA as a carrier to form the nanodrug carrier system were effective for improving the properties of Rg3.

Multi-functionalized chitosan nanoparticles for enhanced chemotherapy in lung cancer

Chemotherapy-based treatment for cancer has made great progress in the past decades. However, there is still a big challenge for the treatment of lung cancer. Herein, a multifunctional nanocarrier was developed through electrostatic interaction between the fluorescent gold nanocluster-conjugated chitosan and the nucleolin targeting AS1411 aptamer. Then methotrexate was loaded into the multifunctional nanocarrier through hydrophobic interaction to obtain the nanodrug carrier systems. The prepared nanodrug carrier systems have an average nanoparticle size of 200 nm with 13.8% drug loading efficiency. The drug release is pH-dependent. The in vitro results demonstrated that the nanodrug carrier systems were selectively taken up by cancer cells in a time-dependent manner and exhibited significantly enhanced anticancer activity in a model of lung cancer A549 cells. The in vivo results showed that intravenous administration of nanodrug carrier systems into BALB/c mice led to accumulation of methotrexate at the tumor site and significantly inhibited the tumor growth but without overt toxicity. The present study suggests that the prepared multifunctional nanocarrier can be used as an effective drug delivery system for anticancer drugs and exhibits great potential in clinical applications.

Fabrication of a triptolide-loaded and poly-γ-glutamic acid-based amphiphilic nanoparticle for the treatment of rheumatoid arthritis.

Triptolide (TP) exhibits immunosuppressive, cartilage-protective and anti-inflammatory effects in rheumatoid arthritis. However, the toxicity of TP limits its widespread use. To decrease the toxic effects, we developed a novel nano-drug carrier system containing TP using poly-γ-glutamic acid-grafted di-tert-butyl L-aspartate hydrochloride (PAT). PAT had an average diameter of 79±18 nm, a narrow polydispersity index (0.18), a strong zeta potential (−32 mV) and a high drug encapsulation efficiency (EE1=48.6%) and loading capacity (EE2=19.2%), and exhibited controlled release (t1/2=29 h). The MTT assay and flow cytometry results indicated that PAT could decrease toxicity and apoptosis induced by free TP on RAW264.7 cells. PAT decreased lipopolysaccharides/interferon γ-induced cytokines expression of macrophage (P<0.05). In vivo, PAT accumulated at inflammatory joints, improved the survival rate and had fewer side effects on tumor necrosis factor α transgenic mice, compared to TP. The blood biochemical indexes revealed that PAT did not cause much damage to the kidney (urea nitrogen and creatinine) and liver (alanine aminotransferase and aspartate aminotransferase). In addition, PAT reduced inflammatory synovial tissue area (P<0.05), cartilage loss (P<0.05), tartrate-resistant acid phosphatase-positive osteoclast area (P<0.05) and bone erosion (P<0.05) in both knee and ankle joints, and showed similar beneficial effect as free TP. In summary, our newly formed nanoparticle, PAT, can reduce the toxicity and guarantee the efficacy of TP, which represents an effective drug candidate for RA with low adverse side effect.

Calmodulin inhibitor ameliorates cognitive dysfunction via inhibiting nitrosative stress and NLRP3 signaling in mice with bilateral carotid artery stenosis.

Vascular dementia (VaD) is a heterogeneous brain disorder for which there are no effective approved pharmacological treatments available. We aimed to evaluate the effect of calmodulin inhibitor, DY-9836, and its loaded nanodrug carrier system on cognitive impairment and gain a better understanding of the protective mechanisms in mice with bilateral carotid artery stenosis (BCAS). DY-9836 (0.5 or 1mg/kg) or DY-9836 (0.25mg/kg)-encapsulated polysialic acid-octadecylamine (PSA-ODA) micelles (PSA-ODA/DY) were given to BCAS mice for 4weeks. Administration of DY-9836 or PSA-ODA/DY reduced escape latency in space exploration and working memory test compared with vehicle group. Vehicle-treated mice showed reduced phospho-CaMKII (Thr286/287) levels in the hippocampus, whereas partially restored by DY-9836 (1mg/kg) or PSA-ODA/DY (0.25mg/kg) treatment. In accordance with the pharmacological profile of DY-9836 observed during behavioral studies, experimental molecular and biochemical markers induced by BCAS, such as protein tyrosine nitration, Nod-like receptor protein 3 (NLRP3), caspase-1, and interleukin-1β, were reduced by DY-9836 and PSA-ODA/DY treatment. These data disclose novel findings about the therapeutic potential of DY-9836, and its encapsulated nanodrug delivery system significantly enhanced the cognitive function via inhibitory effect on nitrosative stress and NLRP3 signaling in VaD mice.

Target Recognition Molecules and Molecular Modeling Studies.

Targeted delivery systems aim to deliver drugs to their intended site of action and as such they are expected to show more desired effects and less unwanted effects. The system itself is composed of a vesicle-encapsulated drug with "target recognition molecules" on the envelop. Ideally, these target recognition molecules, being either small non-peptidic molecules or peptides, are basically high-affinity ligands for a receptor or other protein that is expressed specifically and at high concentrations on the target cells. This review will focus on several widely used examples of target recognition molecules and on how molecular modelling studies have been used in the development of nano drug carrier systems in general.