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In recent years, Ru(ii) complexes have gained high importance in medicinal chemistry due to their significant anti-cancer activities, which are directly related to their DNA binding ability.

Background Scaffolds containing two kinds of regular pore size that support differentiation and proliferation of induced pluripotent stem cells (iPSC) are important approaches to artificial pancreas. Methods This study aimed to differentiate iPSC in dual-sized gelatin (Gel)-alginate (Alg)-hyaluronic acid (HA) scaffolds containing inverted colloidal crystal (ICC) topography with 70-µm and 160-µm pore sizes for insulin production. The pore surface of dual-sized Gel-Alg-HA ICC scaffolds was grafted with growth differentiation factor 8 (GDF-8) and Wnt3a, and treated with retinoic acid (RA) and noggin to improve the differentiation of iPSC toward endodermic cells, and then islet cells. Findings An increasing weight percentage of Gel increased the adhesion efficiency of iPSC. Moreover, Alg and HA helped to promote the proliferation and survival rate of iPSC, which resulted in a higher availability of iPSC for differentiation into insulin-production cells. Immunofluorescence staining, flow cytometry and western blot evidenced that dual-sized Gel-Alg-HA ICC scaffolds grafted with GDF-8 and Wnt3a enhanced the differentiation of iPSC into endodermic cells. When subsequent treatment with RA and noggin, endodermic cells differentiation into insulin-production cells in the scaffolds were improved. Precisely controlling the physical and biomedical properties of dual-sized Gel-Alg-HA ICC scaffolds can guide iPSC to differentiate first into endodermic cells, and then into pancreatic β-cells for diabetic treatment.

Recent advances in attempting maturation of pancreatic β cells derived from induced pluripotent stem cells (iPSCs) have initiated a gateway to developing innovated materials and protocols for artificial pancreas implantation in diabetic management. In this study, we proposed a tissue-engineering scheme using iPSCs-laden aldehyde hyaluronic acid (AHA)-polyacrylamide (PAAM) inverted colloidal crystal constructs (ICCCs) associated with controlled release of induction molecules to generate insulin-producing cells (IPCs). Based on physicochemical properties, AHA-PAAM inverted colloidal crystal scaffolds (ICCSs) at a 1:1 weight ratio of AHA to PAAM were used, modified with growth and differentiation factor 8, and grafted with CHIR99021-loaded solid lipid nanoparticles (CHIR99021-SLNs-GDF8-AHA-PAAM ICCSs) to differentiate iPSCs into definitive endoderm (DE) cells. Induction with fibroblast growth factor 7-grafted retinoic acid-loaded SLNs (FGF7-RA-SLNs) further differentiated DE cells into insulin-producing cells (IPCs) in the constructs. An introduction of sustained delivery facilitated bioavailability of CHIR99021 and RA during DE and islet formation, and yielded a high quantity of secreted insulin from IPCs after stimulation of glucose. Loaded CHIR99021 and grafted FGF7 acted as supporters to promote the main function of grafted GDF8 and loaded RA in DE and islet growth. From the highest expression of pancreatic and duodenal homeobox 1, we have reached the appropriate concentration of GDF8, CHIR99021, RA and FGF7 for regenerating IPCs. These data showed that the 2-stage guided differentiation of iPSCs into IPCs in CHIR99021-SLNs-GDF8-AHA-PAAM ICCSs can be promising in ameliorating insulin secretion by β-cell regeneration.

The unique structural characteristics and superior biocompatibility make the protein nanofibers promising immobilization platforms/substrates for catalysts/enzymes. Metal nanoparticles have been employed as the catalysts in industries due to their excellent catalytic activity and stability, whereas their high surface energy leads to nanoparticle aggregation, thereby hampering their catalytic performance. Here, amyloid fibril (AF) derived from whey protein isolate (WPI) was chosen as the support of silver nanoparticles (AgNP) and utilized for the catalytic reduction of methylene blue (MB). The one-dimensional amyloid-based hybrid materials (AgNP/WPI-AF) were first synthesized via chemical or photochemical route. The characterization of AgNP/WPI-AF by UV-vis spectrophotometry and electron microscopy revealed that the sizes of AgNP on WPI-AF's surface ranged from 2 to 30 nm. Next, the catalytic performances of AgNP/WPI-AF prepared by various routes for MB degradation were investigated. Additionally, the kinetic data were analyzed using two different models and the apparent rate constants and thermodynamic parameters were further determined accordingly. Moreover, the reusability of AgNP/WPI-AF was assessed by monitoring the percentage removal of MB over consecutive filtering cycles. Our results indicated that Langmuir-Hinshelwood-type mechanism better described the catalytic MB reduction using AgNP/WPI-AF. This work provides a nice example of application of nanoparticle-amyloid fibril composite materials for catalysis.

Central nervous system (CNS)-related disease treatments using pharmaceuticals lack therapeutic efficacy due to unknown pathologies and the inability of remedies to pass through the blood-brain barrier (BBB). The BBB acting as a CNS protector plays a predominant role as a barricade to drugs, monoclonal antibodies and small interfering ribonucleic acids to achieve effective treatment for Alzheimer's disease (AD), Parkinson's diseases (PD) and glioblastoma mutiforme (GBM). The biomaterial-incorporated drug delivery carrier (DDC) eases the passage of active pharmaceutical ingredients across the BBB and delivers them to diseased tissue with improved bioavailability. The surface of DDC can be modified with ligands, such as dual functional DDC with one to traverse the BBB via interacting with receptors on endothelial membrane without causing much damage to BBB integrity, and with another to target specific disease sites after reaching the brain for sustained release of active ingredients carried by the DDC. Polymer nanoparticles, liposomes and solid lipid nanoparticles, including nanostructured lipid carriers, have been widely studied as DDC with good biocompatibility to transport pharmaceuticals to the brain and prolong medicinal activity. The present review deals with recently developed biomaterial-based DDC and their surface modification that enhance docking capability of active ingredients to permeate the BBB and to treat AD, PD and GBM.

A wide variety of drugs, drug delivery systems (DDS) that carry them, technologies, and treatment methodologies have been developed to treat cancer, and none of them have achieved full efficacy owing to several known and unknown factors. Glioblastoma multiforme (GBM), as grade IV brain tumors, have become an eminent threat in recent clinical practice. Inhibitors of apoptosis proteins (IAP) have been identified as an effective target to activate the apoptosis of cancer cells and overcome chemotherapy resistance. Now scientists/engineers are dealing with the hurdles to treating gliomas and how to overcome them with the development of target-specific DDS with active ligands. Further, this review discusses the importance of second mitochondria derived activator of caspase mimetics, interacting with siRNA, as IAP inhibitors that induce apoptosis of cancer cells, including gliomas. The combination of IAP antagonists with anticancer drugs has decreased the resistance to chemotherapeutic remedies. Moreover, biomaterial-based DDS have improved the activity of IAP antagonists by ameliorating their docking capacity and bioavailability in GBM. The development of DDS with active ligands carrying IAP antagonists and chemotherapeutic drugs becomes an essential issue for IAP in GBM targeting to enhance apoptosis, and that this can be an effective approach to GBM treatment.

Management of glioblastoma multiforme (GBM), a cerebral glioma with highest-grade malignancy, is a crucial challenge to current anticancer treatment because the lack of GBM-targeting capability of antitumor drug, such as carmustine (BCNU) with a short half-life, along with low blood-brain barrier (BBB) permeability to achieve the clinical efficacy. Hence, polyethyleneimine-poly(lactic-co-glycolic acid) nanoparticles comprising stable core-shell structure with tamoxifen were crosslinked with sialic acid (SA-TAM-PEI-PLGA NPs) as nanocarriers to improve bioavailability of BCNU for pharmacotherapy. The brain-targeted experiments revealed that an increasing SA level improved BBB permeability for BCNU, and was associated with a reduction in transendothelial electrical resistance and an increase in propidium iodide penetration of endothelial monolayer. Immunocytochemical staining images evidenced that surface SA was critical in triggering transcytosis through N-acetylglucosamine on human cerebral microvessel endothelia, and surface crosslinking restrained macrophage phagocytosis. A high TAM level on the carrier surface reduced the survival rate of human U87, and western blots showed that conjugated TAM induced apoptosis of the cancer cells. The use of SA-TAM-PEI-PLGA NPs carrying BCNU as a pharmaceutical preparation is an effective strategy to overcome the BBB restriction and activate apoptosis of tumor cells to prevent the proliferation of GBM.

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 β-amyloid 1-42 (Aβ1-42) and neurofibrillary tangles. The conjugation of liposomes with PA improved the activity of QU and RA against neurotoxicity of Aβ1-42. 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 Aβ1-42-insulted rats mimicking Alzheimer’s disease (AD). The cellular and molecular evidence from AD rats included the decrease in Aβ1-42 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 Aβ1-42 plaques and can be a potent approach to rescue degenerated neurons from AD.

Internal aqueous phase was incorporated in solid lipid nanoparticles (SLNs) containing 5 lipid components to form dual-phase SLNs (DPSLNs), which were then conjugated with transferrin (Tf) to transport nerve growth factor (NGF), rosmarinic acid (ROA), curcumin (CURC) and quercetin (QU) for enhanced activity against neuronal apoptosis. Particle size, physical stability, loading rate of drugs and releasing rate of drugs were measured to determine the most appropriate lipid composition of DPSLNs. The results showed that DPSLNs not only acted as a drug carrier, but also served to decrease drug-induced cytotoxicity to blood-brain barrier (BBB) cells through sustained release. QU-CURC-ROA-NGF-DPSLNs with modified Tf on the surface facilitated the capacity of drugs to infiltrate the BBB. Interaction between lecithin and Tf assisted in BBB-targeting ability of DPSLNs. Moreover, addition of cardiolipin in DPSLNs improved the therapeutic efficacy via recognizing β-amyloid around neurons. Combining QU, CURC, ROA and NGF in DPSLNs promoted their roles in the reduction of neurotoxicity by mutual collaboration. Immunofluorescence and western-blot analysis revealed suppressed expressions of caspase-3, extracellular signal-regulated kinases 1/2 (ERK1/2), c-Jun N terminal kinase and p38, and enhanced expressions of cAMP-response element-binding protein (CREB) and ERK5 after treatment with QU-CURC-ROA-NGF-DPSLNs. Hence, the drug-loaded DPSLNs with grafted Tf can be promising in rescuing degenerated neurons for Alzheimer's disease therapy.

A three-dimensional scaffold enables the formation of realistic tissue architecture and promotes physiological responses to activate the differentiation of induced pluripotent cells (iPSCs) into pancreatic islets. Poly(vinyl alcohol) (PVA), alginate (Alg) and gelatin (Gel) were conjugated with methacrylic anhydride (MA) and were photo-crosslinked to prepare PVAMA-AlgMA-GelMA hydrogel scaffolds using a water-in-oil self-assembly method. The swelling ratio, porosity and cell entrapment in the hydrogel were investigated with various molar percentages of polymer matrix. PVAMA and AlgMA assisted in improving the water content of the hydrogel, which created high porosity for the migration of iPSCs, and GelMA enhanced the cell entrapment efficiency. The self-assembled scaffolds with composition of PVAMA:AlgMA:GelMA = 1:1:2 were grafted with activin A and bone morphogenic protein 4 (BMP4) to induce iPSCs to definitive endoderm (DE) lineage, followed by treatment with retinoic acid-loaded solid lipid nanoparticles for controlled release and guided differentiation of DE cells into insulin-producing cells. Flow cytometry analysis and immunochemical staining evidenced that the scaffolds with crosslinked BMP4 boosted the role of surface activin A at activin A:BMP4 = 3:1 in endodermal differentiation of iPSCs to produce the highest level of insulin after pancreatic induction and glucose stimulation. The iPSC-laden PVAMA-AlgMA-GelMA hydrogel constructs composed of repeated units and modified with activin A and BMP4 can be promising in generating pancreas-mimetic structure and supporting the functions of pancreatic islets.

The capillary electrophoresis (CE) technique has been widely used to improve our understanding of biochemistry, and has become one of the best choices to address critical issues in neurobiology. In this study, doubled-emulsified solid lipid nanoparticles (DESLNs) grafted with PPFLMLLKGSTR (PM12) were fabricated to carry retinoic acid (RnA) and nerve growth factor (NGF), and to differentiate induced pluripotent stem cells (iPSCs) into nerve cells. The membrane charge of differentiated neuron-like cells was investigated using a high-performance CE. We found that surface PM12 enhanced the uptake of RnA- and NGF-loaded DESLNs (RnA-NGF-DESLNs) via strong interaction with cellular integrin α3β1 and α5β1, as evidenced by immunofluorescence assay. Further, highly expressed βIII-tubulin, a typical neuronal marker, suggested the improved neurite outgrowth of differentiating iPSCs. The enhanced electrophoretic mobility also demonstrated the reproduction of neurons from iPSCs treated with various kinds of DESLNs. After longer induction, the major CE elution peak appeared in shorter time, evidencing an increase in electrostatic potential (more negative) and effective neuronal regeneration. Induction with PM12-RnA-NGF-DESLNs to differentiate iPSCs resulted in the largest electrophoretic mobility (more negative), zeta potential and membrane charge. Thus, this study showed the ability of CE to analyze the charge variation during guided differentiation of iPSCs with drug carriers, and the CE method can be promising in evaluating the formation of matured neurons from iPSCs.

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.

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.

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 (Aβ), 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 Aβ around SK-N-MC cells using ApoE and PC. Moreover, GSH-ApoE-PC-liposomes benefited the 4 medicines in simultaneously transporting to Aβ1-42-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.

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 β peptide (Aβ) and tau protein (tau) activity around/in neurons. Aβ-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 β-secretase and γ-secretase activity, remove oligomeric Aβ and aggregated Aβ 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 Aβ 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.

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 β-amyloid peptide (Aβ) 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 Aβ 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 Aβ 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.

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-β (Aβ) 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 Aβ 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 Aβ accumulation, lipid peroxidation, and neuronal apoptosis for the AD management.

Polymers with very low surface conductivity can easily accumulate an electric charge through surface friction. If the charged entities are grounded with conductive materials, they may discharge electricity associated with sparks that will interrupt the production process, and more seriously, cause industrial disasters. In order to avoid damage from electrical sparks, an antistatic agent (ASA) is employed with the polymer during production. In this study, conductive iron oxide (Fe3O4) nanoparticles (NPs) with hydrophobic modification by oleic acid (OA) were prepared using a co-precipitation method. Fourier transformed infrared spectra and thermogravimetric analysis confirmed that OA-Fe3O4 was formed through chemisorption interactions between OA and Fe3O4. Fe3O4 NPs were entrapped in solid lipid NPs (SLNs) and poly(lactide-co-glycolide) NPs through hydrophobic interactions to obtain new composite antistatic NPs (CANs). Surfactants and their concentration played a decisive role in the zeta potential and particles size of CANs. Sodium dodecyl sulfate (SDS) created some regular-shaped CANs, and didodecyldimethylammonium bromide (DMAB) and glycerol monostearate (GMS) created irregular-shaped CANs. 10% methanol and 1% Tween 80 yielded an appropriate contact angle with polymer films. The surface electrical resistance value of CANs was found to be in the order of SDS > DMAB > GMS. GMS-based CANs reached a lower electrical resistance value of around 108 Ω/Sq, and can be used as an ASA in engineering practice. Keywords: Composite antistatic nanoparticle, Polymer film, Surface electrical resistance, Sodium dodecyl sulfate, Didodecyldimethylammonium bromide, Glycerol monostearate

Background The difficulty of drugs to cross the blood-brain barrier (BBB) to reach specific sites and target multiple factors responsible for neurovegetative diseases necessitates the development of an effective drug delivery system. Methods Rabies virus glycoprotein (RVG)- and transferrin (Tf)-grafted liposomes were constructed to deliver epigallocatechin gallate (EGCG) and FK506 to BBB against neurodegeneration for Parkinson's disease (PD) treatment. Significant findings Surface RVG and Tf revealed substantial improvement in BBB permeability of EGCG and FK506, and incorporation of phosphatidy-l-serine (PS) in RVG-Tf-EGCG-FK506-liposomes ameliorated α-synuclein docking. EGCG and FK506-encapsulated liposomes decreased cytotoxicity to 1-methyl-4-phenylpyridinium-impacted neurons. Immunofluorescence and western blot studies demonstrated better activity of RVG-Tf-EGCG-FK506-PS-liposomes in suppressing Bax, α-synuclein, caspase-3, p-tau protein, p-p38, p-ERK1/2 and p-cJNK expressions, and in increasing Bcl-2, tyrosine hydroxylase, dopamine transporter, p-CREB and p-ERK5 expressions. Multi-targeted RVG-Tf-PS-liposomes advantaged BBB permeation and contributed to neuroprotective effect to promote the efficiency of EGCG and FK506 in PD management.

Pluronic® F127-modified water-dispersible poly(acrylic acid)-bound iron oxide (PF127-PAAIO) nanoparticles have been prepared as diagnostic agents. A blood–brain-barrier penetrating peptide, angiopep-2 (ANG), was further conjugated onto the surface of the PF127-PAAIO (ANG-PF127-PAAIO) for brain targeting. The ANG-PF127-PAAIO shows negligible cell cytotoxicity, better cellular uptake, and higher T2-weighted image enhancement than the PF127-PAAIO in U87 cells. Using an ex vivo blood–brain barrier (BBB) model, we showed that the ANG-PF127-PAAIO shows better permeability to bypass the BBB. This is because the ANG-PF127-PAAIO has a dual-targeting ability, recognition of the low-density lipoprotein receptor-related protein and clathrin-mediated receptor on the U87 surface. Thus, the ANG-PF127-PAAIO is a potential nanotheranostic agent for brain dysfunction.

Parkinson's disease (PD) is a neurodegenerative disorder second only to Alzheimer's disease in seriousness and tends to worsen with aging. Several drugs and genes have been developed and identified to treat PD. However, their activity against PD as solo agents has been hindered by their inability to permeate the blood–brain barrier (BBB), and also that they have a short half-life. Drug delivery systems (DDS) play a vital role in drug transport to specific tissue sites in the central nervous system by overcoming the hurdle presented by the BBB. A variety of DDS, including nanosized polymers, liposomes, solid lipid nanoparticles and exosomes, have been introduced to improve the capability of drug/gene. The DDS surface has been modified with active components, such as lactoferrin, transferrin, wheat germ agglutinin, Angiopep, Trojan horse and antibody OX26, to facilitate BBB permeation. Of the DDS, exosomes, a natural vehicle, is exposed to a limited extent and may be an efficacious carrier system in the near future. Though there is still a lack of clinical trials investigating DDS for PD management, DDS have assisted in improving therapeutic efficiency in animal models. This review is focused on an overview of DDS established to enhance the efficacy of drug/gene in PD treatment.

Effective treatment methods for neurodegenerative disorders in the central nervous system are still facing a great many hurdles due to inability of drugs to permeate the blood–brain barrier (BBB). In this study, a drug carrier system of apolipoprotein E (ApoE)-modified liposomes conjugated with phosphatidic acid (PA) was fabricated to improve BBB penetration and release quercetin (QU) and rosmarinic acid (RA) to inhibit β-amyloid (1–42) (Aβ1-42)-induced Alzheimer's disease (AD). An in vitro BBB model validated the enhanced ability of the dual-functioning ApoE-QU-RA-PA-liposomes to infiltrate the BBB and preserve high viability of endothelia, compared with Tween 80-QU-RA-PA-liposomes. Immunochemical staining images exhibited evidence that ApoE-QU-RA-PA-liposomes were able to penetrate the BBB through the aid of strong attractions between ApoE and low-density lipoprotein receptors in brain microvascular endothelial cells, and also inhibited the apoptosis of Aβ1-42-insulted SK-N-MC cells. In anin vivo AD model, ApoE-QU-RA-PA-liposomes decreased acetylcholinesterase activity and lipid peroxidation level, and lowered Aβ plaque formation. The surface functionalization of liposomes using PA and ApoE can be a promising approach to crossing the BBB and delivering QU and RA to the brain in management of Aβ1-42-induced neurotoxicity.

An in vitro human blood–brain barrier (BBB) model was developed using human brain microvascular endothelial cells (HBMECs) co-cultured with human brain vascular pericytes (HBVPs) and human astrocytes (HAs) at various ratios (HBVPs:HAs = 1:1, 1:2, 1:6), associated with pericyte-conditioned medium (PCM) and astrocyte-conditioned medium (ACM). After 7 days of co-culturing of HBMECs with HBVPs and HAs at a ratio of 1:2, and a 1:1 ratio of PCM and ACM, the transendothelial electrical resistance was enhanced to 319 ± 16.67 Ω × cm2 (225% increase) and the permeability coefficient of propidium iodide was reduced to 2.09 ± 0.5 × 10−6 cm/s (61% decrease). Analysis of three major barrier integrity modulators: transforming growth factor-β1 (TGF-β1), vascular endothelial growth factor (VEGF), and matrix metalloproteinases (MMPs), revealed a higher TGF-β1 expression and lower VEGF and MMP-9 expressions in a co-culture of HBMECs with HBVPs and HAs at a ratio of 1:2. Calcein-AM analysis showed higher P-glycoprotein (P-gp) activity in the model using PCM and ACM with HBVPs:HAs = 1:2 (100%) than that with HBVPs:HAs = 1:1 (55%) and HBVPs:HAs = 1:6 (49%). The effect of TGF-β1 receptor inhibitor SB431542, VEGF inhibitor asterric acid, and MMP-9 inhibitor CTT (H-Cys-Thr-Thr-His-Trp-Gly-Phe-Thr-Leu-Cys-OH) on the BBB model suggested that TGF-β1 up-regulates P-gp activity and VEGF down-regulates P-gp activity. In the presence of PCM and ACM, co-culturing of HBMECs with HBVPs and HAs at a ratio of 1:2 could approach the in vivo BBB in a well representative manner.

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.

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.

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 Aβ-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 Aβ-insulted neurons in the pharmacotherapy of Alzheimer’s disease.

Glioblastoma multiforme (GBM), a grade IV astrocytoma, is the most aggressive and formidable brain malignancy. It has a predictably poor prognosis and unique medical challenges. The high recurrence of GBM in clinical practice leads to an average survival of only 12–18 months after diagnosis. One of the critical issues in GBM treatment is the physiological restriction of antitumor drugs from traversing the blood–brain barrier (BBB). In recent years, the development of nanoparticles (NPs) has enhanced the ability of pharmaceuticals to cross the BBB for GBM treatment. In addition, the fabrication and design of nanoparticulate carriers determine the category of medicinal substance that the particles can carry, such as a high molecular weight hydrophobic/hydrophilic drug, a gene segment, or an imaging contrast agent. Surface modification of NPs also ameliorates the biocompatibility of numerous antitumor remedies. Thus, the capability of nanocarriers provides a high likelihood of managing GBM, by means of gene therapy, chemotherapy, anti-angiogenesis therapy or diagnosis. This review focuses on GBM treatment by inhibiting angiogenesis and using nanocarriers. Development of innovative drug delivery systems will also be highlighted in various aspects, including effective permeation of the BBB, and may provide inspiration for salvage chemotherapy and adjuvant care of patients with GBM in future clinical application.

Several million people in the world are affected by dementia, especially by Alzheimer's disease (AD), a frequently encountering neurodegenerative disorder in the brain, and it is predicted to double by every 20 years. The growing population of aging leads to an increase in the number of individuals at the risk of AD. Up to now, the epidemiological other than age and familial factors of AD remain elusive, although amyloid β peptide (extracellular neuritic plaque) and tau protein (intracellular neurofibrillary tangle) are regarded as the two major pathological features. In addition, a few critical issues emerge at the moment and are required to be ascertained. Is there any scheme for resolving the exact mechanism of AD? Are there any vaccines and drugs to completely reverse the AD progress? Is there any possibility for the early stage detection of AD? And, is there a permanent cure for AD? These questions are haunting researchers to identify the best pharmaceuticals and accurate pathways for AD-related evolution. This paper discusses about the etymology, pathology, therapeutic strategy and technology on recent advancement, facilitating scientists and medical practitioners to discover the physiological causes and therapeutic targets to improve AD treatment.

Nerve growth factor (NGF)-loaded heparinized cationic solid lipid nanoparticles (NGF-loaded HCSLNs) were developed using heparin-stearic acid conjugate, cacao butter, cholesterol, stearylamine (SA), and esterquat 1 (EQ 1). The effect of cationic lipids and lipid matrix composition on the particle size, particle structure, surface molecular composition, chemical structure, electrophoretic mobility, and zeta potential of HCSLNs was investigated. The effect of HCSLNs on the membrane charge of induced pluripotent stem cells (iPSCs) was also studied. The results indicated that the average diameter of HCSLNs was 90–240 nm and the particle size of HCSLNs with EQ 1 was smaller than that with SA. The zeta potential and electrophoresis analysis showed that HCSLNs with SA had a positively charged potential and HCSLNs with EQ 1 had a negatively charged potential at pH 7.4. The high-resolution transmission electron microscope confirmed the loading of NGF on the surface of HCSLNs. Differentiation of iPSCs using NGF-loaded HCSLNs with EQ 1 exhibited higher absolute values of the electrophoretic mobility and zeta potential than differentiation using NGF-loaded HCSLNs with SA. The immunochemical staining of neuronal nuclei revealed that NGF-loaded HCSLNs can be used for differentiation of iPSCs into neurons. NGF-loaded HCSLNs with EQ 1 had higher viability of iPSCs than NGF-loaded HCSLNs with SA. NGF-loaded HCSLNs with EQ 1 may be promising formulation to regulate the membrane charge of iPSCs during neuronal differentiation.

Differentiated somatic cells can be engineered into pluripotent stem cells, which have the ability to differentiate into any type of cell lineage; these are known as induced pluripotent stem cells (iPSC). Different techniques are used for the generation of iPSC from somatic cells. The discovery of iPSC has led to the opening of a wide variety of applications in the fields of regenerative medicine, tissue engineering, disease modeling, nanotechnology, and drug discovery. In this review, we discuss reprogramming techniques for the derivation of iPSC and the advantages of iPSC over embryonic stem cells, and mainly focus on the relevance to regenerative medicine of several types of biomaterial-guided differentiation of iPSC to different cell types. In recent years, the fabrication of biomaterial has grown from basic materials to the development of biomaterial scaffolds with the ability to guide processes like proliferation, differentiation and morphogenesis. Natural extracellular matrix offers a perfect microenvironment for biochemical, topographical and electric signals for cell attachment, proliferation and differentiation. Hence, there is a need to fabricate a biomaterial scaffold with the properties of immunologically inert, biodegradable, biochemical and physical cues with high biocompatibility for iPSC differentiation. This review outlines the rationale for using biomaterial-guided differentiation in tissue engineering and regenerative medicine through the use of appropriate biomaterial that can permit the iPSC to adhere, proliferate and finally differentiate into particular functional somatic cells.

Catanionic solid lipid nanoparticles (CASLNs) with surface wheat germ agglutinin (WGA) and lactoferrin (Lf) were formulated to entrap and release etoposide (ETP), cross the blood–brain barrier (BBB), and inhibit glioblastoma multiforme (GBM) growth. Microemulsified ETP-CASLNs were modified with WGA and Lf to permeate a cultured monolayer of human brain-microvascular endothelial cells (HBMECs) regulated by human astrocytes and to treat malignant U87MG cells. Experimental evidence revealed that an increase in the weight percentage of ETP from 1% to 4% decreased its encapsulation efficiency about 34-44%. In addition, the release rate of ETP from WGA-Lf-ETP-CASLNs decreased with an increase in the concentration of catanionic surfactant from 7.5 µM to 12.5 µM, and WGA-Lf-ETP-CASLNs at 12.5 µM of catanionic surfactant exhibited a feature of sustained release. WGA-Lf-ETP-CASLNs also reduced transendothelial electrical resistance from 245.5 Ω×cm 2 to 191.5 Ω×cm 2 , enhanced the permeability of propidium iodide from 3.62×10 −6 cm/s to 5.61×10 −6 cm/s, induced a minor cytotoxicity to HBMECs, increased the ability of ETP to cross the BBB by about 5.6 times, and improved the antiproliferative efficacy of U87MG cells. The grafting of WGA and Lf is crucial to control the medicinal property of ETP-CASLNs, and WGA-Lf-ETP-CASLNs can be promising colloidal carriers in GBM management.

Self-assembled microgel functionalized with peptides was developed and applied to regenerate neurons from induced pluripotent stem cells (iPSCs). Collagen (COL), hyaluronic acid (HA), and alginate (ALG) were modified with methacrylic anhydride (MA), photocrosslinked for patterned particles, grafted with GRGDSP and Ln5-P4, and self-assembled to integrate the microgel into three-dimensional scaffolds. Physicochemical assessments revealed that the ternary microgel scaffolds had an optimal chemical composition at COLMA:HAMA:ALGMA=1:2:1. In fabricating cell-laden constructs, modified GRGDSP/Ln5-P4 in linear self-assembled scaffolds could significantly improve the entrapment efficiency and viability of iPSCs. In addition, GRGDSP/Ln5-P4 in the microgel constructs triggered the differentiation of iPSCs toward neurons, since the percentage of neurite-like cells could be higher than 98% after induction of nerve growth factor. Self-assembled microgel comprising COLMA, HAMA, ALGMA, and GRGDSP/Ln5-P4 may be promising in producing mature neural lineage from iPSCs, to provide better treatment for damaged nervous tissue.

Polyacrylamide (PAAM) and chitosan were fabricated by inverted colloidal crystal (ICC) method for scaffolds comprising regular pores. The hybrid PAAM-chitosan ICC scaffolds were grafted with poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) for a rougher pore surface and grafted with transactivator of transcription von Hippel-Lindau (TATVHL) peptide for a better differentiation of induced pluripotent stem (iPS) cells toward neural lineage. By scanning electron microscopy, we found that iPS cells cultured in PAAM-chitosan ICC scaffolds with PLGA NPs at 1.0 mg/mL and TATVHL peptide at 15 μg/mL elongated the axonal length to 15 μm. A combination of PLGA NPs and TATVHL peptide favored the adhesion of iPS cells, reduced the embryonic phenotype after cultivation, and guided the production of βIII tubulin-positive cells in PAAM-chitosan ICC scaffolds. In addition to the differentiation toward neurite-like cells, an increase in the content of TATVHL peptide in PAAM-chitosan ICC scaffolds inhibited the differentiation of iPS cells toward astrocytes. ICC scaffolds composed of PAAM, chitosan, PLGA NPs, and TATVHL peptide can be an efficacious matrix to differentiate iPS cells toward neurons and retard the glial formation for nerve regeneration.

Yung-Chih Kuo,1 Che-Yu Lin,1 Jay-Shake Li,2 Yung-I Lou3 1Department of Chemical Engineering, 2Department of Psychology, National Chung Cheng University, Chia-Yi, 3Department of Accounting, Providence University, Taichung, Taiwan, Republic of China Abstract: Curcumin (CRM) and nerve growth factor (NGF) were entrapped in liposomes (LIP) with surface wheat germ agglutinin (WGA) to downregulate the phosphorylation of kinases in Alzheimer’s disease (AD) therapy. Cardiolipin (CL)-conjugated LIP carrying CRM (CRM-CL/LIP) and also carrying NGF (NGF-CL/LIP) were used with AD models of SK-N-MC cells and Wistar rats after an insult with β-amyloid peptide (Aβ). We found that CRM-CL/LIP inhibited the expression of phosphorylated p38 (p-p38), phosphorylated c-Jun N-terminal kinase (p-JNK), and p-tau protein at serine202 and prevented neurodegeneration of SK-N-MC cells. In addition, NGF-CL/LIP could enhance the quantities of p-neurotrophic tyrosine kinase receptor type 1 and p-extracellular signal-regulated kinase 5 for neuronal rescue. Moreover, WGA-grafted CRM-CL/LIP and WGA-grafted NGF-CL/LIP significantly improved the permeation of CRM and NGF across the blood–brain barrier, reduced Aβ plaque deposition and the malondialdehyde level, and increased the percentage of normal neurons and cholinergic activity in the hippocampus of AD rats. Based on the marker expressions and in vivo evidence, current LIP carriers can be promising drug delivery systems to protect nervous tissue against Aβ-induced apoptosis in the brain during the clinical management of AD. Keywords: liposome, Alzheimer’s disease, β-amyloid, neurodegeneration, blood–brain barrier, wheat germ agglutinin

Of late, cancer has become a terrible disease affecting people throughout the world. Keeping this in mind, we tried to design drugs that are more lipophilic, target-specific, water-soluble, cytoselective and fluorescent. In this regard, we reported novel ruthenium(II)-p-cymene imidazophenanthroline scaffolds as effective DNA targeting agents. The planarity of imidazophenanthroline ligands caused the Ru(II) complex to be a good intercalator. An extended π-electronic conjugation was introduced in the imidazophenanthroline moieties through the Suzuki and Sonogashira coupling reactions. Here, we synthesized nine Ru(II) complexes (16a–b, 17a–d, and 19a–c). Among these, [(η6-p-cymene)RuCl(K2-N,N-2-(4′-methyl-[1,1′-BIphenyl]-4-yl)-1H-imidazo[4,5-f][1,10]phenanthroline)]·PF6 (16b) exhibited the best potency and selectivity with excellent cellular uptake; [(η6-p-cymene)RuCl(K2-N,N-2-(4-(phenylethynyl)phenyl)-1H-imidazo[4,5-f][1,10]phenanthroline)]·PF6 (17a) acted as a cytoselective probe for live cell imaging.

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 β-tubulin III to 93.72% in cultured cells. Strong affinity of Ln5-P4/NGF-RA-ASLNs to α3β1 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.

Solid lipid nanoparticles (SLNs) conjugated with aprotinin (Apr) and melanotransferrin antibody (Anti-MTf) were used to carry doxorubicin (Dox) across the blood–brain barrier (BBB) for glioblastoma multiforme (GBM) chemotherapy. Dox-entrapped SLNs with grafted Apr and Anti-MTf (Apr-Anti-MTf-Dox-SLNs) were applied to a cellular monolayer comprising human brain-microvascular endothelial cells (HBMECs) with a regulation of human astrocyte (HAs) and to a proliferated colony of U87MG cells. Based on the average particle diameter, zeta potential, entrapping efficiency of Dox, and grafting efficiency of Apr and Anti-MTf, we found that 1,2-dipalmitoyl-sn-glycero-3-phosphocholine of 40% (w/w) in lipids was appropriate for fabricating Apr-Anti-MTf-Dox-SLNs. In addition, Apr-Anti-MTf-Dox-SLNs could prevent Dox from fast dissolution and did not induce a serious cytotoxicity to HBMECs and HAs when compared with free Dox. Moreover, the treatment with Apr-Anti-MTf-Dox-SLNs enhanced the ability of Dox to infuse the BBB and to inhibit the growth of GBM. The current Apr-Anti-MTf-Dox-SLNs can be a promising pharmacotherapeutic preparation to penetrate the BBB for malignant brain tumor management.

Solid lipid nanoparticles (SLNs) conjugated with tamoxifen (TX) and lactoferrin (Lf) were applied to carry anticancer carmustine (BCNU) across the blood-brain barrier (BBB) for enhanced antiproliferation against glioblastoma multiforme (GBM). BCNU-loaded SLNs with modified TX and Lf (TX-Lf-BCNU-SLNs) were used to penetrate a monolayer of human brain-microvascular endothelial cells (HBMECs) and human astrocytes and to target malignant U87MG cells. The surface TX and Lf on TX-Lf-BCNU-SLNs improved the characteristics of sustained release for BCNU. When compared with BCNU-loaded SLNs, TX-Lf-BCNU-SLNs increased the BBB permeability coefficient for BCNU about ten times. In addition, TX-BCNU-SLNs considerably promoted the fluorescent intensity of intracellular acetomethoxy derivative of calcein (calcein-AM) in HBMECs via endocytosis. However, the conjugated Lf could only slightly increase the fluorescence of calcein-AM. Moreover, the order of formulation in the inhibition to U87MG cells was TX-Lf-BCNU-SLNs>TX-BCNU-SLNs>Lf-BCNU-SLNs>BCNU-SLNs. TX-Lf-BCNU-SLNs can be effective in infiltrating the BBB and delivering BCNU to GBM for future chemotherapy application.

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.

Polymeric nanoparticles (NPs) combined with lipids can have profound effects on treatment efficacy in patients with neurological disorders such as Alzheimer's disease (AD). We developed polyacrylamide (PAAM)-cardiolipin (CL)-poly(lactide-co-glycolide) (PLGA) NPs grafted with surface 83-14 monoclonal antibody (MAb) to carry rosmarinic acid (RA) and curcumin (CUR). This drug delivery system was used to cross the blood-brain barrier (BBB) and enhance the viability of SK-N-MC cells insulted with β-amyloid (Aβ) deposits. Experimental evidence revealed that an increase in the concentration of 83-14 MAb enhanced the permeability coefficient of RA and CUR using the nanocarriers. The levels of phosphorylated p38 and phosphorylated tau protein at serine 202 in degenerated SK-N-MC cells were in the order: Aβ > (Aβ + RA-CUR) > (Aβ + 83-14 MAb-RA-CUR-PAAM-PLGA NPs) > (Aβ + 83-14 MAb-RA-CUR-PAAM-CL-PLGA NPs) ≈ control. The viability of SK-N-MC cells reduced with time and CL in 83-14 MAb-RA-CUR-PAAM-CL-PLGA NPs advantaged Aβ-targeted delivery of RA-CUR. These results evidenced that the current 83-14 MAb-RA-CUR-PAAM-CL-PLGA NPs can be a promising pharmacotherapy to permeate the BBB and reduce the fibrillar Aβ-induced neurotoxicity.