Regeneration of Pancreatic Cells Using Optimized Nanoparticles and l-Glutamic Acid-Gelatin Scaffolds with Controlled Topography and Grafted Activin A/BMP4.

Regeneration of insulin-producing cells (IPCs) from induced pluripotent stem cells (iPSCs) under controlled conditions has a lot of promise to emulate the pancreatic mechanism in vivo as a foundation of cell-based diabetic therapy. l-Glutamic acid-gelatin scaffolds with orderly pore sizes of 160 and 200 µm were grafted with activin A and bone morphogenic proteins 4 (BMP4) to differentiate iPSCs into definitive endoderm (DE) cells, which were then guided with fibroblast growth factor 7 (FGF7)-grafted retinoic acid (RA)-loaded solid lipid nanoparticles (FR-SLNs) to harvest IPCs. Response surface methodology was adopted to optimize the l-glutamic acid-to-gelatin ratio of scaffolds and to optimize surfactant concentration and lipid proportion in FR-SLNs. Experimental results of immunofluorescence, flow cytometry, and western blots revealed that activin A (100 ng/mL)-BMP4 (50 ng/mL)-l-glutamic acid (5%)-gelatin (95%) scaffolds provoked the largest number of SOX17-positive DE cells from iPSCs. Treatment with FGF7 (50 ng/mL)-RA (600 ng/mL)-SLNs elicited the highest number of PDX1-positive ß-cells from differentiated DE cells. To imitate the natural pancreas, the scaffolds with controlled topography were appropriate for IPC production with sufficient insulin secretion. Hence, the current scheme using FR-SLNs and activin A-BMP4-l-glutamic acid-gelatin scaffolds in the two-stage differentiation of iPSCs can be promising for replacing impaired ß-cells in diabetic management.

Optimized lipopolymers with curcumin to enhance AZD5582 and GDC0152 activity and downregulate inhibitors of apoptosis proteins in glioblastoma multiforme.

Inhibition to glioblastoma multiforme (GBM) propagation is a critical challenge in clinical practice because binding of inhibitors of apoptosis proteins (IAPs) to caspase prevents cancer cells from death. In this study, folic acid (FA), lactoferrin (Lf) and rabies virus glycoprotein (RVG) were grafted on lipopolymers (LPs) composed of poly(ε-caprolactone) and Compritol 888 ATO to encapsulate AZD5582 (AZD), GDC0152 (GDC) and curcumin (CURC). The standard deviations of initial particle diameter and particle diameter after storage for 30 days were involved in LP composition optimization. The functionalized LPs were used to permeate the blood-brain barrier (BBB) and constrain IAP quantity in GBM cells. Experimental results revealed that an increase in Span 20 (emulsifier) concentration enlarged the size of LPs, and enhanced the entrapment and releasing efficiency of AZD, DGC and CURC. 1H nuclear magnetic resonance spectra showed that the hydrogen bonds between the LPs and drugs supported the sustained release of AZD, DGC and CURC from the LPs. The LPs modified with the three targeting biomolecules facilitated the penetration of AZD, GDC and CURC across the BBB, and could recognize U87MG cells and human brain cancer stem cells. Immunofluorescence staining, flow cytometry and western blot demonstrated that CURC-incorporated LPs enhanced AZD and GDC activity in suppressing cellular IAP 1 (cIAP1) and X-linked IAP (XIAP) levels, and raising caspase-3 level in GBM. Surface FA, Lf and RVG also promoted the ability of the drug-loaded LPs to avoid carcinoma growth. The current FA-, Lf- and RVG-crosslinked LPs carrying AZD, DGC and CURC can be promising in hindering IAP expressions for GBM management.

Vapour-Phase Selective Hydrogenation of γ-Valerolactone to 2-Methyltetrahydrofuran Biofuel over Silica-Supported Copper Catalysts.

2-Methyltetrahydrofuran (MTHF) is a desirable biomass-based platform chemical with excellent potential as an ideal biofuel, green solvent, and raw material for synthesizing downstream chemicals. In this work, a series of copper nanoparticles encapsulated on SiO2 were prepared by the wet impregnation method and evaluated as efficient non-noble metal catalysts for the vapour-phase hydrogenation of γ-valerolactone (GVL) to MTHF in a fixed-bed reactor under mild reaction conditions. The obtained catalyst properties were determined by XRD, FE-SEM, TEM, UV-DRS, TPR, NH3-TPD, N2O decomposition and pore size distribution measurements. Meanwhile, the parameters/variables tuning their catalytic performance (activity, conversion, selectivity and stability) were examined. Various Cu loadings featured on the SiO2 support are essential for tuning the catalytic activity. Among the catalysts tested, a 5 wt% Cu/SiO2 catalyst showed a 97.2% MTHF selectivity with 71.9% GVL conversion, and showed a stability for 33 h time-on-stream, achieved at 260 °C and atmospheric pressure conditions. It was found that a huge dispersion of Cu metal in support, hydrogen activation ability, abundant acidic sites and surface area are all beneficial for improved MTHF selectivity.

Enhanced activity of AZD5582 and SM-164 in rabies virus glycoprotein-lactoferrin-liposomes to downregulate inhibitors of apoptosis proteins in glioblastoma.

Upregulated proliferation of neoplastic cells from suppressing apoptotic signals associated with the inhibitors of apoptosis proteins (IAP) makes difficult the achievement of therapeutic efficiency against glioblastoma multiforme. Studies in the last few years have witnessed a paradigm focusing on targeting IAP using its antagonists, such as Smac mimetics, to restrain tumor malignancy. A Smac mimetic compound needs to penetrate the blood-brain barrier (BBB), and must be internalized into cerebral tumor for improved chemotherapy. Rabies virus glycoprotein (RVG) and lactoferrin (Lf)-grafted liposomes were developed in this study to carry two IAP antagonists, AZD5582 and SM-164, across the BBB and to induce apoptosis in U87 MG and human brain cancer stem cells (HBCSCs). Liposomes modified with RVG slightly reduced BBB tightness and enhanced capability of AZD5582 and SM-164 for traversing the barrier because of their brain-targeting ability. Immunofluorescence and western-blot results revealed that AZD5582- and SM-164-encapsulated liposomes facilitated mutual curative intensity, effectively triggered apoptosis of U87 MG and HBCSCs, reduced the expression of cellular IAP 1 (cIAP1) and X-linked IAP (XIAP), and enhanced the expression of caspase-3. Hence, RGV-Lf-liposomes carrying AZD5582 and SM-164 can be promising formulations to activate apoptosis of U87 MG and HBCSCs, and this functionalized drug delivery system targeting cIAP and XIAP is a potential strategy to cure glioblastoma in clinical cancer management.

Astragaloside IV- and nesfatin-1-encapsulated phosphatidylserine liposomes conjugated with wheat germ agglutinin and leptin to activate anti-apoptotic pathway and block phosphorylated tau protein expression for Parkinson's disease treatment.

Heap-up of α-synuclein (α-Syn) and its association with tau protein are esteemed to trigger the onset of Parkinson's disease (PD). The purpose of this study was to develop multi-functional liposomes incorporated with 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), cholesterol, 1,2-dimyristoyl-sn-glycero-3-phosphocholine and phosphatidylserine (PS) to load astragaloside IV (AS-IV) and nestifin-1 (NF-1), followed by grafting with wheat germ agglutinin (WGA) and leptin (Lep) (WGA-Lep-AS-IV-NF-1-PS-liposomes) to protect dopaminergic neurons from apoptosis. Experimental results showed that increasing the mole percentage of DSPC and PS enhanced the particle size, particle stability and entrapment efficiency of AS-IV and NF-1, and reduced the drug releasing rate. Strong affinity of NF-1 to PS was evidenced by nuclear magnetic resonance spectroscopy. WGA-Lep-AS-IV-NF-1-PS-liposomes diminished transendothelial electrical resistance and improved the capacity of propidium iodide, AS-IV and NF-1 to penetrate the blood-brain barrier (BBB). Immunocytochemical staining exhibited the ability of functionalized liposomes to target Lep receptor and α-Syn in MPP+-insulted SH-SY5Y cells. Western blots revealed a substantial reduction of α-Syn and phosphorylated tau protein in the anti-oxidative pathway through interaction with PS. During the course of treatment with WGA-Lep-AS-IV-NF-1-PS-liposomes, the combined activity of AS-IV and NF-1 and recognition capability simultaneously decreased the expression of Bax, and increased the expressions of Bcl-2, tyrosine hydroxylase and dopamine transporter. The liposomes carrying AS-IV and NF-1 can rescue degenerated neurons and are a promising formulation to achieve better PD management.

Glutathione- and apolipoprotein E-grafted liposomes to regulate mitogen-activated protein kinases and rescue neurons in Alzheimer's disease.

Neurodegenerative disorders, such as Alzheimer's disease (AD), present biomedical challenges due to inability of pharmaceuticals to permeate the blood-brain barrier (BBB) and lack of therapeutic specificity in definite sites against multiple pathologies. Phosphatidylcholine (PC)-liposomes carrying curcumin (CURC), quercetin (QU), epigallocatechin gallate (EGCG) and rosmarinic acid (RA) with crosslinked glutathione (GSH) and apolipoprotein E (ApoE) were fabricated to recognize brain microvascular endothelial cells and amyloid beta (Aß), and reduce tau protein hyperphosphorylation for AD management. Addition of stearic acid to liposomal bilayers ameliorated particle stability, promoted drug entrapment efficiency, and prolonged drug release duration. The triple targeting liposomes boosted the capability of CURC, QU, EGCG and RA for crossing the BBB with the assistance of grafted GSH and ApoE and docking Aß around SK-N-MC cells using ApoE and PC. Moreover, GSH-ApoE-PC-liposomes benefited the 4 medicines in simultaneously transporting to Aß1-42-insulted neurons, in functioning against hyperphosphorylated mitogen-activated protein kinases, including p-c-Jun N-terminal protein kinase, p-extracellular signal-regulated protein kinase 1/2 and p-p38, in downregulating tau protein at S202, caspase-3 and interleukin-6, and in upregulating p-cyclic adenosine monophosphate response element-binding protein. GSH-ApoE-PC-liposomes can be promising colloidal carriers in delivering CURC, QU, EGCG and RA to degenerated neural tissue in a controlled manner, targeting pathological factors for neuroprotection, and raising preclinical effectualness for AD treatment.

Glutathione Liposomes Carrying Ceftriaxone, FK506, and Nilotinib to Control Overexpressed Dopamine Markers and Apoptotic Factors in Neurons.

Advances in liposomal formulation carrying multiple neuroprotective drugs, such as ceftriaxone (CEF), FK506, and nilotinib, can point toward an approach to obviating the difficulties in Parkinson's disease (PD) treatment. We prepared functionalized liposomes decorated with glutathione (GSH) to penetrate the blood-brain barrier (BBB) and cardiolipin (CL) to link up apoptotic neurons. Further, the effect of CEF-FK506-nilotinib-GSH-CL-liposomes on a PD model established by SH-SY5Y cells with 1-methyl-4-phenylpyridinium-induced neurotoxicity was investigated. An increment of the mole percentage of dihexadecyl phosphate and CL increased the particle size and the absolute value of ζ potential, improved the entrapment efficiency of CEF, FK506, and nilotinib, and reduced the drug-releasing rate. The toxicity studies revealed that CEF, FK506, and nilotinib-encapsulated liposomes could enhance the survival of SH-SY5Y cells. Western blot and immunofluorescence revealed that incorporation of CL in a lipid bilayer ameliorated the docking of CEF-FK506-nilotinib-GSH-CL-liposomes at α-synuclein (α-syn), indicating a better targeting capability of the liposomes to degenerated neurons. Treatment with CEF-FK506-nilotinib-GSH-CL-liposomes reduced the expression of Bax and α-syn and promoted the expression of Bcl-2, tyrosine hydroxylase, and the dopamine transporter. GSH- and CL-conjugated liposomes showed combined activity of targeting the BBB and α-syn and augmented the efficiency of the three drugs in rescuing dopaminergic neurons for neurodegenerative therapy.

Use of leptin-conjugated phosphatidic acid liposomes with resveratrol and epigallocatechin gallate to protect dopaminergic neurons against apoptosis for Parkinson's disease therapy.

Complex liposomes were assembled with 1,2-distearoyl-sn-glycero-3-phosphocholine, dihexadecyl phosphate (DHDP), cholesterol and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphate (PA) to act as drug carriers for resveratrol (RES) and epigallocatechin gallate (EGCG). The liposomes were modified with leptin (Lep) on the surface to cross the blood-brain barrier (BBB) and to rescue degenerated dopaminergic neurons. The activity of RES and EGCG against neurotoxicity was investigated using an in vitro neurodegenerative model established by SH-SY5Y cells with an insult of 1-methyl-4-phenylpyridinium (MPP+). The results indicated that increasing the mole percentage of DHDP and PA increased the particle size and absolute zeta potential value, and improved the entrapment efficiency of RES and EGCG; however, this increase reduced the release rate of RES and EGCG and the grafting efficiency of Lep. The ability of Lep/RES-EGCG-PA-liposomes to cross the BBB was found to be higher than that of non-modified liposomes. Further, the addition of PA and Lep into liposomes enhanced cell viability and target efficiency. The immunofluorescence results demonstrated that the conjugation of Lep with liposomes enabled the docking of HBMECs and SH-SY5Y cells via Lep receptor, and enhanced their ability to permeate the BBB and cellular uptake. Immunofluorescence and western blot analysis also revealed that RES and EGCG encapsulated into liposomes could be a neural defensive strategy by reducing the apoptosis promotor protein Bcl-2 associated X protein and α-synuclein, and enhancement in the apoptosis inhibitor protein B cell lymphoma 2, tyrosine hydroxylase, and the dopamine transporter. Hence, Lep-PA-liposomes can be an excellent choice of potential delivery system for PD treatment.

Enhanced integrin affinity and neural differentiation of induced pluripotent stem cells using Ln5-P4-grafted amphiphilic solid lipid nanoparticles.

Amphiphilic solid lipid nanoparticles (ASLNs) with surface PPFLMLLKGSTR peptide (Ln5-P4) (Ln5-P4/ASLNs) were prepared to load nerve growth factor (NGF) and retinoic acid (RA) and to guide the differentiation of induced pluripotent stem cells (iPSCs) toward neurons. Beeswax (BW) and lecithin played predominant roles in microemulsion and in the average diameter, zeta potential, encapsulation efficiency of NGF and RA and release kinetics of NGF- and RA-loaded Ln5-P4/ASLNs (Ln5-P4/NGF-RA-ASLNs). An increasing BW weight percentage from 0% to 75% decreased the particle size and zeta potential along with improved encapsulation efficiency of RA and NGF with enhanced positive expression of ß-tubulin III to 93.72% in cultured cells. Strong affinity of Ln5-P4/NGF-RA-ASLNs to α3ß1 integrin expressed on iPSCs facilitated internalization of Ln5-P4/NGF-RA-ASLNs. The capability of Ln5-P4/NGF-RA-ASLNs to induce neuronal differentiation was much higher than that of free NGF-ASLNs and RA-ASLNs, as visualized using immunochemical staining. Flow cytometry analysis indicated that Ln5-P4 on NGF-RA-ASLNs promoted the uptake of NGF and RA by iPSCs and accelerated neuronal production. Ln5-P4/NGF-RA-ASLNs are a promising colloidal delivery system to generate mature neurons from iPSCs and can be potential for treating neurodegenerative disease and nerve injury in regeneration medicine.

Dual functional liposomes carrying antioxidants against tau hyperphosphorylation and apoptosis of neurons.

Quercetin (QU) and rosmarinic acid (RA) were loaded in phosphatidic acid-liposomes (QU/RA-PA-liposomes) with surface apolipoprotein E (ApoE) using a process of thin-film hydration, followed by covalent crosslinking to activate biological pathways for penetrating the blood-brain barrier (BBB) and redeeming the neuronal apoptosis from attack of ß-amyloid 1-42 (Aß1-42) and neurofibrillary tangles. The conjugation of liposomes with PA improved the activity of QU and RA against neurotoxicity of Aß1-42. The fluorescent images of brain capillaries revealed that surface modification with ApoE improved the permeation ability of QU/RA-PA-ApoE-liposomes across the BBB. In addition, the highest therapeutic efficacy was obtained in the case of QU/RA-PA-ApoE-liposomes, compared to other QU/RA formulations studied using in vivo Aß1-42-insulted rats mimicking Alzheimer's disease (AD). The cellular and molecular evidence from AD rats included the decrease in Aß1-42 plaque formation and interleukin-6 secretion, increase in the neuronal count in Nissl staining, and reduction in the expression of phosphorylated extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase, p38 kinase and tau protein at serine 202 as well as caspase-3. The use of PA-ApoE-liposomes as a dual targeting formulation enhances the QU and RA ability to infiltrate the BBB, docks Aß1-42 plaques and can be a potent approach to rescue degenerated neurons from AD.

Targeting human brain cancer stem cells by curcumin-loaded nanoparticles grafted with anti-aldehyde dehydrogenase and sialic acid: Colocalization of ALDH and CD44.

The use of chemotherapy against brain tumors faces various limitations to achieving its therapeutic effect, due to both the inability of anticancer agents to cross the blood-brain barrier (BBB) and the formation of brain cancer stem cells (BCSCs). Without adequate exposure, these chemotherapeutic drugs cannot have an antiproliferative effect on the tumors. Here, we developed curcumin (CCM)-loaded chitosan-poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) modified with sialic acid (SA) to permeate the BBB and with anti-aldehyde dehydrogenase (anti-ALDH) to target BCSCs. An increased chitosan concentration plays a pivotal role in maintaining a steady release of CCM from NPs. The viability of BBB cells and transendothelial electrical resistance were maintained after treatment with NPs for 4 h. Immunochemical staining of human brain microvascular endothelial cells confirmed that modification of SA on the surface of NPs greatly helped in permeation of the BBB through the use of N-acetylglucosamine. In addition, immunofluorescence images evidenced the assistance of anti-ALDH in inhibiting U87MG cells and BCSCs through targeting ALDH. ALDH was colocalized with CD44 in U87MG cells and BCSCs. The cell viability assay of U87MG cells and BCSCs supported the high level of inhibition after treatment with anti-ALDH-modified NPs. The drug delivery system in this study was designed in such a way to deliver CCM into the brain and subsequently inhibit the proliferation of glioblastoma cells and BCSCs.

Challenges in the treatment of Alzheimer's disease: recent progress and treatment strategies of pharmaceuticals targeting notable pathological factors.

Introduction: Alzheimer's disease (AD), a commonly encountered neurodegenerative disorder, causes cognitive decline and has a devastating effect on the quality of life. AD occurs mainly through abnormal amyloid ß peptide (Aß) and tau protein (tau) activity around/in neurons. Aß-based therapeutic techniques have been struggled to treat AD over the past few decades. In addition, the complexity in treating AD is due to diverse factors regulating its pathology. Areas covered: This review emphasizes recent advances regarding various pathological approaches and provides an overview of the most recent medications for AD. The authors focus on the regulatory factors, which mediate AD pathology, and discuss a variety of newly developed drugs and compounds used to inhibit ß-secretase and γ-secretase activity, remove oligomeric Aß and aggregated Aß that is given responsibility in the amyloid cascade hypothesis, prevent tau hyperphosphorylation, restrain phosphorylated tau (p-tau) aggregation, remove aggregated p-tau that is proposed in tauopathy, and other related pathways. Expert opinion: The approaches to the treatment of AD towards Aß and tau have failed in most clinical attempts due to insufficient disease models arising from complex AD biology. It is the time to look for other approaches and pathological factors to cure AD.

Optimized liposomes with transactivator of transcription peptide and anti-apoptotic drugs to target hippocampal neurons and prevent tau-hyperphosphorylated neurodegeneration.

Liposomes (lip) carrying pharmaceuticals have shown promise in their ability to advance the therapy for neurodegenerative diseases. However, the low nerve-targeting capacity and poor penetration rate of lip through the blood-brain barrier (BBB) are major hurdles to achieving successful treatment. Herein, we developed lip incorporating cardiolipin (CL) and phosphatidic acid (PA) to promote their capability against hyperphosphorylation of tau protein, and a transactivator of transcription (TAT) peptide to permeate the BBB for delivering nerve growth factor (NGF), rosmarinic acid (RA), curcumin (CURC) and quercetin (QU). We derived an optimization method to assess a better composition of phospholipids in the lip loaded with the four medicines. Experimental results revealed that this optimized lip increased the viability of SK-N-MC cells insulted with ß-amyloid peptide (Aß) fibrils and prevented Wistar rat brain from producing hyperphosphorylated tau. CL and PA and the grafted TAT peptide on the carrier surface improved the rescue efficiency by inhibiting Aß deposition and reducing the expressions of phosphorylated extracellular signal-regulated protein kinase 1/2 (p-ERK1/2), c-Jun N-terminal protein kinase, p38, tau at serine 202 and caspase-3. The lip also enhanced the expressions of p-ERK5 and p-cyclic adenosine monophosphate response element-binding protein. The amalgamated activity of NGF, RA, CURC and QU, and the effect of charged CL/PA on Aß deposits supported the therapeutic efficacy of lip. The optimized TAT-NGF-RA-CURC-QU-CL/PA-lip can be a capable drug delivery system to cross the BBB and protect Alzheimer's disease brains from tau hyperphosphorylation. STATEMENTS OF SIGNIFICANCE: The therapeutic efficiency of liposomes (lip) against neurodegenerative disorder depends on their nerve-targeting capacity and ability to permeate the blood-brain barrier (BBB). Lip was developed incorporating cardiolipin (CL) and phosphatidic acid (PA) to promote their target specificity against hyperphosphorylation of tau protein, and a transactivator of transcription (TAT) peptide to permeate the BBB. We have successfully derived an optimization method using a new mathematical expression for the first time to assess a better composition of phospholipids in lip loaded with nerve growth factor (NGF), rosmarinic acid (RA), curcumin (CURC) and quercetin (QU). The optimized TAT-NGF-RA-CURC-QU-CL/PA-lip efficaciously down-regulated the expressions of phosphorylated extracellular signal-regulated protein kinase 1/2 (p-ERK1/2), c-Jun N-terminal protein kinase, p38, tau at serine 202 and caspase-3, and up-regulated the expressions of p-ERK5 and p-cyclic adenosine monophosphate response element-binding protein in Alzheimer's disease Wistar rat model.

Targeted delivery of etoposide, carmustine and doxorubicin to human glioblastoma cells using methoxy poly(ethylene glycol)­poly(ε­caprolactone) nanoparticles conjugated with wheat germ agglutinin and folic acid.

Wheat germ agglutinin (WGA) and folic acid (FA)-grafted methoxy poly(ethylene glycol) (MPEG)­poly(ε­caprolactone) (PCL) nanoparticles (WFNPs) were applied to transport anticancer drugs across the blood-brain barrier and treat glioblastoma multiforme (GBM). PCL was copolymerized with MPEG, and MPEG-PCL NPs were stabilized with pluronic F127 using a microemulsion-solvent evaporation technique and crosslinked with WGA and FA. The targeting ability of WFNPs loaded with etoposide (ETO), carmustine (BCNU) and doxorubicin (DOX) was investigated via the binding affinity of drug-loaded NP formulations to N­acetylglucosamine expressed in human brain microvascular endothelial cells and to folate receptor in malignant U87MG cells. We found that a shorter PCL chain in drug-loaded MPEG-PCL NPs yielded a smaller average size of the particles. An increase in PCL chain length (stronger hydrophobicity) enhanced drug entrapment efficiencies in MPEG-PCL NPs, and reduced drug-releasing rates from NP formulations. In addition, anti-proliferative activity against U87MG cells for the 3 drugs followed the order of WFNPs > FA-grafted NPs > WGA-grafted NPs > MPEG-PCL NPs. Immunofluorescence staining revealed that the ligands of drug-loaded WFNPs connected to N­acetylglucosamine and folate receptor with the help of surface WGA and FA. WFNPs carrying ETO, BCNU and DOX acted as dual-targeting nanocarriers, and their use can be a promising approach to inhibiting GBM growth in the brain.

Protection against Neurodegeneration in the Hippocampus Using Sialic Acid- and 5-HT-Moduline-Conjugated Lipopolymer Nanoparticles.

Significant involvement of oxidative stress in the brain can develop Alzheimer's disease (AD); however, a great number of clinical trials explains the limited success of antioxidant therapy in dealing with this neurodegenerative disease. Here, we established a lipopolymer system of poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) incorporated with phosphatidic acid (PA) and modified with sialic acid (SA) and 5-hydroxytryptamine-moduline (5HTM) to improve quercetin (QU) activity against oxidative stress induced by amyloid-ß (Aß) deposits. Morphological studies revealed a uniform exterior of QU-SA-5HTM-PA-PLGA NPs with a spherical structure and enhanced aggregation with inclusion of PA in the formulation. A better brain-targeted delivery of the lipopolymeric NPs was verified from the high blood-brain barrier (BBB) permeability of QU through strong interactions of surface SA and 5HTM with O-linked N-acetylglucosamine and 5-HT1B receptors, respectively. Immunofluorescence staining images also supported QU-SA-5HTM-PA-PLGA NPs to traverse the microvessels of AD rat brain. Western blot analysis showed that QU-loaded PA-PLGA NPs suppressed caspase-3 expression. The ability of the nanocarriers to recognize Aß fibrils was demonstrated from the reduced senile plaque formation and the attenuated acetylcholinesterase and malondialdehyde activity in the hippocampus. Hence, the medication of QU-SA-5HTM-PA-PLGA NPs can facilitate the BBB penetration and prevent Aß accumulation, lipid peroxidation, and neuronal apoptosis for the AD management.

Layer-by-layer assembled gold nanoparticles/lower-generation (Gn≤3) polyamidoamine dendrimers-grafted reduced graphene oxide nanohybrids with 3D fractal architecture for fast, ultra-trace, and label-free electrochemical gene nanobiosensors.

Three layer-by-layer (LBL) assembled gold nanoparticles (AuNPs)/lower-generation (Gn≤3) polyamidoamine dendrimer (PD) with reduced graphene oxide (rGO) as the core/mercaptopropinoic acid (MPA)/Au were successfully fabricated and employed as electrochemical gene nanobiosensing platforms with three-dimensional (3D) fractal nanoarchitecture for fast, ultra-trace determination of label-free DNA hybridization. Three Gn≤3PD were initially grafted to graphite oxide (GO) via the covalent functionalization between amino terminals of PD and carboxyl terminals of GO where a concomitant reduction of GO, which were covalently linked onto MPA that was self-assembled onto Au substrate, and finally AuNPs were encapsulated onto GG1PD by strong physicochemical interaction between AuNPs and -OH of rGO in GG1PD, Their morphologies, structures, electrochemical properties, and gene nanobiosensing performances were characterized and evaluated. AuNPs/GG2PD-based probe displayed the best excellent structural stability, lowest mobility on solid surface with the increasing charge resistance, widest linear range (1.1 × 10-6 - 1 × 10-18), and the lowest limit of detection (1.87 × 10-19 M) in comparison with both AuNPs/GG1PD-based and AuNPs/GG3PD-based probes. This work will provide a new candidate for the development of metal nanoparticles functionalized PD with inorganic nonmetallic nanomaterials as cores with 3D fractal nanoarchitecture and promising electrochemical gene nanobiosensing platforms based on dendrimer-nanoinorganic hybrids with 3D nanoarchitectures and LBL assembly for fast and ultra-trace detection of label-free DNA hybridization with potential application in bioanalysis and medical diagnosis of genetic diseases.

Layer-by-Layer-Assembled AuNPs-Decorated First-Generation Poly(amidoamine) Dendrimer with Reduced Graphene Oxide Core as Highly Sensitive Biosensing Platform with Controllable 3D Nanoarchitecture for Rapid Voltammetric Analysis of Ultratrace DNA Hybridization.

The structure and electrochemical properties of layer-by-layer-assembled gold nanoparticles (AuNPs)-decorated first-generation (G1) poly(amidoamine) dendrimer (PD) with reduced graphene oxide (rGO) core as a highly sensitive and label-free biosensing platform with a controllable three-dimensional (3D) nanoarchitecture for the rapid voltammetric analysis of DNA hybridization at ultratrace levels were characterized. Mercaptopropinoic acid (MPA) was self-assembled onto Au substrate, then GG1PD formed by the covalent functionalization between the amino terminals of G1PD and carboxyl terminals of rGO was covalently linked onto MPA, and finally AuNPs were decorated onto GG1PD by strong physicochemical interaction between AuNPs and -OH of rGO in GG1PD, which was characterized through different techniques and confirmed by computational calculation. This 3D controllable thin-film electrode was optimized and evaluated using [Fe(CN)6]3-/4- as the redox probe and employed to covalently immobilize thiol-functionalized single-stranded DNA as biorecognition element to form the DNA nanobiosensor, which achieved fast, ultrasensitive, and high-selective differential pulse voltammetric analysis of DNA hybridization in a linear range from 1 × 10-6 to 1 × 10-13 g m-1 with a low detection limit of 9.07 × 10-14 g m-1. This work will open a new pathway for the controllable 3D nanoarchitecture of the layer-by-layer-assembled metal nanoparticles-functionalized lower-generation PD with two-dimensional layered nanomaterials as cores that can be employed as ultrasensitive and label-free nanobiodevices for the fast diagnosis of specific genome diseases in the field of biomedicine.

Synthesis of silver nanoparticles using bacterial exopolysaccharide and its application for degradation of azo-dyes.

In this study, the synthesis and characterization of exopolysaccharide-stabilized sliver nanoparticles (AgNPs) was carried out for the degradation of industrial textile dyes. Characterization of AgNPs was done using surface plasmon spectra using UV-Vis spectroscopy, X-ray diffraction (XRD) and Raman spectroscopy. The morphological nature of AgNPs was determined through transmission electron microscopy (TEM), scanning electron microscopy (SEM) and atomic force microscopy (AFM), which indicated that the AgNPs were spherical in shape, with an average size of 35 nm. The thermal behaviour of AgNPs revealed that it is stable up to 437.1 °C and the required energy is 808.2J/g in TGA-DTA analysis. Ability of EPS stabilized AgNPs for degradation of azo dyes such as Methyl orange (MO) and Congo red (CR) showed that EPS stabilized AgNPs were found to be efficient in facilitating the degradation process of industrial textile dyes. The electron transfer takes place from reducing agent to dye molecule via nanoparticles, resulting in the destruction of the dye chromophore structure. This makes EPS-AgNPs a suitable, cheap and environment friendly candidate for biodegradation of harmful textile dyes.

Chitosan/γ-poly(glutamic acid) scaffolds with surface-modified albumin, elastin and poly-l-lysine for cartilage tissue engineering.

Cartilage has limited ability to self-repair due to the absence of blood vessels and nerves. The application of biomaterial scaffolds using biomimetic extracellular matrix (ECM)-related polymers has become an effective approach to production of engineered cartilage. Chitosan/γ-poly(glutamic acid) (γ-PGA) scaffolds with different mass ratios were prepared using genipin as a cross-linker and a freeze-drying method, and their surfaces were modified with elastin, human serum albumin (HSA) and poly-l-lysine (PLL). The scaffolds were formed through a complex between NH3+ of chitosan and COO- of γ-PGA, confirmed by Fourier transform infrared spectroscopy, and exhibited an interconnected porous morphology in field emission scanning electron microscopy analysis. The prepared chitosan/γ-PGA scaffolds, at a 3:1 ratio, obtained the required porosity (90%), pore size (≥100µm), mechanical strength (compressive strength>4MPa, Young's modulus>4MPa) and biodegradation (30-60%) for articular cartilage tissue engineering applications. Surface modification of the scaffolds showed positive indications with improved activity toward cell proliferation (deoxyribonucleic acid), cell adhesion and ECM (glycoaminoglycans and type II collagen) secretion of bovine knee chondrocytes compared with unmodified scaffolds. In caspase-3 detection, elastin had a higher inhibitory effect on chondrocyte apoptosis in vitro, followed by HSA, and then PLL. We concluded that utilizing chitosan/γ-PGA scaffolds with surface active biomolecules, including elastin, HSA and PLL, can effectively promote the growth of chondrocytes, secrete ECM and improve the regenerative ability of cartilaginous tissues.

Targeted delivery of rosmarinic acid across the blood-brain barrier for neuronal rescue using polyacrylamide-chitosan-poly(lactide-co-glycolide) nanoparticles with surface cross-reacting material 197 and apolipoprotein E.

Rosmarinic acid-loaded polyacrylamide-chitosan-poly(lactide-co-glycolide) nanoparticles (RA-PAAM-CH-PLGA NPs) were grafted with cross-reacting material 197 (CRM197) and apolipoprotein E (ApoE) for targeting of the blood-brain barrier (BBB) and rescuing degenerated neurons. The polymeric nanocarriers were prepared by microemulsion, solvent diffusion, grafting, and surface modification, and CRM197-ApoE-RA-PAAM-CH-PLGA NPs were used to treat human brain-microvascular endothelial cells, RWA264.7 cells, and Aß-insulted SK-N-MC cells. Experimental results revealed that an increase in the weight percentage of PAAM decreased the particle size, zeta potential, and grafting efficiency of CRM197 and ApoE. In addition, surface DSPE-PEG(2000) could protect CRM197-ApoE-RA-PAAM-CH-PLGA NPs against uptake by RWA264.7 cells. An increase in the concentration of CRM197 and ApoE decreased the transendothelial electrical resistance and increased the ability of propidium iodide and RA to cross the BBB. The order in the viability of apoptotic SK-N-MC cells was CRM197-ApoE-RA-PAAM-CH-PLGA NPs > CRM197-RA-PAAM-CH-PLGA NPs > RA. Thus, CRM197-ApoE-RA-PAAM-CH-PLGA NPs can be a promising formulation to deliver RA to Aß-insulted neurons in the pharmacotherapy of Alzheimer's disease.