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Nanoparticle-based oral drug delivery systems have the potential to target inflamed regions in the gastrointestinal tract by specifically accumulating at disrupted colonic epithelium. But, delivery of intact protein drugs at the targeted site is a major challenge due to the harsh gastrointestinal environment and the protective mucus layer. Biocompatible nanoparticles engineered to target the inflamed colonic tissue and efficiently penetrate the mucosal layer can provide a promising approach for orally delivering monoclonal antibodies to treat inflammatory bowel disease. The study aims to develop mucus-penetrating nanoparticles composed of poly(lactic-co-glycolic acid, PLGA) polymers with two different polyethylene glycol (PEG) chain lengths (2 kDa and 5kDa) to encapsulate monoclonal antibody against tumor necrosis factor-α (TNF-α). The impact of different PEG chain lengths on the efficacy of the nanosystems was evaluated in vitro, ex vivo, and in vivo. Both PLGA-PEG2k and PLGA-PEG5k nanoparticles successfully encapsulated the antibody and significantly reduced TNF-α secretion from activated macrophages and intestinal epithelial cells. However, only antibody-loaded PLGA-PEG2k nanoparticles were able to alleviate the experimental acute colitis in mice demonstrated by improved colon weight/length ratio, histological score, and reduced tissue-associated myeloperoxidase activity and expression of proinflammatory cytokine TNF-α levels compared with the control group. The results suggest that despite having no significant differences in the in vitro cell-based assays, PEG chain length has a significant impact on the in vivo performance of the mucus penetrating nanoparticles. Overall, PLGA-PEG2k nanoparticles were presented as a promising oral delivery system for targeted antibody delivery to treat inflammatory bowel disease. STATEMENT OF SIGNIFICANCE: There is an unmet therapeutic need for oral drug delivery systems for safe and effective antibody therapy of inflammatory bowel disease. Therefore, we have developed PEGylated PLGA-based nanoparticulate drug delivery systems for oral targeted delivery of anti-TNF-α antibody as a potential alternative treatment strategy. The PEG chain length did not affect encapsulation efficiency or interaction with mucin in vitro but resulted in differences in in vitro release profile and in vivo efficacy study. We demonstrated the superiority of anti-TNF-α mAb-PLGA-PEG2k over mAb-PLGA-PEG5k nanoparticles to effectively exhibit anti-inflammatory responses in an acute murine colitis model. These nanoparticle-based formulations may be adjusted to encapsulate other drugs that could be applied to a number of disorders at different mucosal surfaces.

The potential of nanoemulsions for the oral administration of peptides is still in its early stage. The aim of the present work was to rationally design, develop, and fully characterize a new nanoemulsion (NE) intended for the oral administration of hydrophobically modified insulin (HM-insulin). Specific components of the NE were selected based on their enhancing permeation properties as well as their ability to improve insulin association efficiency (Miglyol 812, sodium taurocholate), stability in the intestinal fluids, and mucodiffusion (PEGylated phospholipids and poloxamer 407). The results showed that the NE co-existed with a population of micelles, forming a mixed system that exhibited a 100% of HM-insulin association efficiency. The nanosystem showed good stability and miscibility in different bio-relevant media and displayed an acceptable mucodiffusive behavior in porcine mucus. In addition, it exhibited a high interaction with cell mono-cultures (Caco -2 and C2BBe1 human colon carcinoma Caco-2 clone cells) and co-cultures (C2BBe1 human colon carcinoma Caco-2 clone/HT29-MTX cells). The internalization in Caco-2 monolayers was also confirmed by confocal microscopy. Finally, the promising in vitro behavior of the nanosystem in terms of overcoming the biological barriers of the intestinal tract was translated into a moderate, although significant, hypoglycemic response (≈ 20–30%), following intestinal administration to both healthy and diabetic rat models. Overall, this information underlines the crucial steps to address when designing peptide-based nanoformulations to successfully overcome the intestinal barriers associated to the oral modality of administration. Graphical abstract

The warm mixed asphalt (WMA) technology has gained a lot of interests in the recent years in academia, state agencies and industries. WMA technology allows reductions in production and compaction temperatures guaranteeing relevant environmental and cost saving benefits. The purpose of the present study was to study and evaluate the performance of a typical additive in WMA pavement with Reclaimed Asphalt Pavement (RAP) on rutting, fatigue cracking and thermal cracking resistance on RI Route 102. In the present study, the asphalt binder was tested at different dosages of additive using Dynamic Shear Rheometer (DSR), Rolling Thin Film Oven (RTFO), Pressure Aging Vessel (PAV), Multiple Stress Creep Recovery (MSCR) and Bending Beam Rheometer (BBR). From the overall test, it was found that 0.7% additive would lessen pavement damage due to rutting, fatigue cracking and thermal cracking. Based on the results of binder test, Hot Mix Asphalt (HMA) and WMA specimens containing 20 % RAP were prepared using PG 58-28 asphalt binder and Superpave Gyratory Compactor (SGC). From the volumetric analysis of both HMA and WMA specimens, it was determined that the optimum binder content (OBC) for HMA with 20% RAP was 5.3 percent and the OBC for WMA (0.7% additive with RAP was 5.6%. It was found that the required amount of neat regular asphalt binder for WMA specimen was higher than the one required by HMA. HMA and WMA Specimens with each containing 20% RAP were prepared at OBC and indirect tensile (IDT) strength test were conducted on that specimen. The test indicated that the performance of HMA mixtures was better than WMA with same amount of RAP. RI Route 102 was used as case study in this research study. Route 102 was rehabilitated through Full Depth Reclamation (FDR) in 2015. First half road of RI Route 102 was built with HMA base and surface layer and the other half was built with WMA base and surface layer using a typical additive. It was found that both sections have similar value in Pavement Serviceability Index (PSI) and in International Roughness Index (IRI) at this time. Four specimens were prepared to predict the performance of asphalt pavement using the dynamic modulus and the master curve. Two HMA specimens each were prepared with and without RAP. Similarly, other two WMA specimens were prepared with and without RAP. These four specimens were tested with the Asphalt Mixture Performance Tester (AMPT) machine and developed the master curves for each specimen. The results of the material testing were used to predict the performance of each test sections by using AASHTOWare Pavement ME Design (PavementME) software. It was found that the WMA-RAP performed better in fatigue cracking resistance but was found to perform poor in rutting resistance than HMA and HMA-RAP. This indicated that fatigue cracking was not a problem with WMA-RAP mixtures whereas rutting resistance still requires further investigation and improvement.

Consumption of a high-energy Western diet triggers mild adaptive β cell proliferation to compensate for peripheral insulin resistance; however, the underlying molecular mechanism remains unclear. In the present study we show that the toll-like receptors TLR2 and TLR4 inhibited the diet-induced replication of β cells in mice and humans. The combined, but not the individual, loss of TLR2 and TLR4 increased the replication of β cells, but not that of α cells, leading to enlarged β cell area and hyperinsulinemia in diet-induced obesity. Loss of TLR2 and TLR4 increased the nuclear abundance of the cell cycle regulators cyclin D2 and Cdk4 in a manner dependent on the signaling mediator Erk. These data reveal a regulatory mechanism controlling the proliferation of β cells in diet-induced obesity and suggest that selective targeting of the TLR2/TLR4 pathways may reverse β cell failure in patients with diabetes.

Oral administration is the most commonly used route for drug delivery owing to its costeffectiveness,ease of administration, and high patient compliance. However, the absorption of orally delivered compounds is a complex process that greatly depends on the interplay between the characteristics of the drug/formulation and the gastrointestinal tract. In this contribution, we review the different preclinical models (in vitro, ex vivo and in vivo) from their development to application for studying the transport of drugs across intestinal barriers. This review also discusses the advantages and disadvantages of each model. Furthermore, the authors have reviewed the selection and validation of these models and how the limitations of the models can be addressed in future investigations. The correlation and predictability of the intestinal transport data from the preclinical models and human data are also explored. With the increasing popularity and prevalence of orally delivered drugs/formulations, the need of sophisticated preclinical models with higher predictive capacity for absorption of oral formulations used in clinical studies will be required. Keywords:Oral delivery

Type 1 and type 2 diabetes are associated with loss of β cell function. Optimal β cell function is linked to protein homeostasis in the endoplasmic reticulum (ER). Here, we review the roles of ER protein quality-control mechanisms, including the unfolded protein response (UPR), autophagy (specifically ER-phagy) and ER-associated degradation (ERAD), in β cells. We propose that different quality control mechanisms may control different aspects of β cell biology (i.e. function, survival, and identity), thereby contributing to disease pathogenesis.

Oral drug administration is one of the most preferred and simplest routes among both patients and formulation scientists. Nevertheless, orally delivery of some of the most widely used therapeutic agents (e.g., anticancer drugs, peptides, proteins and vaccines) is still a major challenge due to the limited oral bioavailability associated with them. The poor oral bioavailability of such drugs is attributed to one or many factors, such as poor aqueous solubility, poor permeability, and enzymatic degradation. Various technological strategies (such as permeation enhancers, prodrugs and nanocarriers) have been developed to enhance the bioavailability of these drugs after oral administration. Among the different approaches, advanced and innovative drug delivery systems, especially targeting-based strategies, have garnered tremendous attention. Furthermore, the presence of numerous types of cells and solute carrier transporters throughout the gastrointestinal tract represents numerous potential targeting sites for successful oral delivery that have not yet been exploited for their full potential. This review describes different targeting strategies towards different targeting sites in the gastrointestinal tract. Additionally, exciting improvements in oral drug delivery systems with different targeting strategies (e.g., M cells for oral vaccination and L cells for type 2 diabetes mellitus) are also discussed.

One of the long-standing challenges in materials science involves synthesizing biomaterials that recapitulate important features of native biological tissues. Even though, the number of available biomaterials at the moment are virtually limitless, few of them has unlocked all the secrets of the human body by mimicking the combinatorial-like material properties of our tissues and organs. Inspired by the human body, we have developed a polymeric gum, which combines stretchability, toughness, strength, flexibility, and self-healing. It also exhibits a high bioactivity that can target and eliminate bacterial infections fast and reliably. Notably, this material is moldable into almost any complex shape, and therefore suitable as a building block for wearables designed to conform directly with the curved and personalized anatomy of patients. It also exhibits excellent drug retention and release capacity, which altogether makes it suitable for applications in personalized wearable drug-delivery devices.

β Cell apoptosis and dedifferentiation are 2 hotly debated mechanisms underlying β cell loss in type 2 diabetes; however, the molecular drivers underlying such events remain largely unclear. Here, we performed a side-by-side comparison of mice carrying β cell–specific deletion of ER-associated degradation (ERAD) and autophagy. We reported that, while autophagy was necessary for β cell survival, the highly conserved Sel1L-Hrd1 ERAD protein complex was required for the maintenance of β cell maturation and identity. Using single-cell RNA-Seq, we demonstrated that Sel1L deficiency was not associated with β cell loss, but rather loss of β cell identity. Sel1L-Hrd1 ERAD controlled β cell identity via TGF-β signaling, in part by mediating the degradation of TGF-β receptor 1. Inhibition of TGF-β signaling in Sel1L-deficient β cells augmented the expression of β cell maturation markers and increased the total insulin content. Our data revealed distinct pathogenic effects of 2 major proteolytic pathways in β cells, providing a framework for therapies targeting distinct mechanisms of protein quality control.

The endoplasmic reticulum (ER) is broadly distributed throughout the cytoplasm of pancreatic beta cells, and this is where all proinsulin is initially made. Healthy beta cells can synthesize 6000 proinsulin molecules per second. Ordinarily, nascent proinsulin entering the ER rapidly folds via the formation of three evolutionarily conserved disulfide bonds (B7-A7, B19-A20, and A6-A11). A modest amount of proinsulin misfolding, including both intramolecular disulfide mispairing and intermolecular disulfide-linked protein complexes, is a natural by-product of proinsulin biosynthesis, as is the case for many proteins. The steady-state level of misfolded proinsulin-a potential ER stressor-is linked to (1) production rate, (2) ER environment, (3) presence or absence of naturally occurring (mutational) defects in proinsulin, and (4) clearance of misfolded proinsulin molecules. Accumulation of misfolded proinsulin beyond a certain threshold begins to interfere with the normal intracellular transport of bystander proinsulin, leading to diminished insulin production and hyperglycemia, as well as exacerbating ER stress. This is most obvious in mutant INS gene-induced Diabetes of Youth (MIDY; an autosomal dominant disease) but also likely to occur in type 2 diabetes owing to dysregulation in proinsulin synthesis, ER folding environment, or clearance.

Aims: To find out the prevalence of domestic violence in pregnant women attending Antenatal clinics (ANC) of B. P. Koirala Institute of Health Sciences, a tertiary centre in eastern Nepal.Methods: It was a hospital based cross-sectional study done at antenatal clinics of BPKIHS from 14th March 2015 to 30th August 2015. The total number of recruited antenatal patients was 470. Data were collected by face to face interview via pre-tested semi-structured questionnaire. Descriptive and inferential statistics were used for data analysis.Results: The prevalence of domestic violence among pregnant women was 53.2% of which prevalence of physical domestic violence was 9.6%. The most common person inflicting the domestic violence was husband (23.6%). Emotional abuse was the most common form of domestic violence experienced by the pregnant women (26.8%) and threatening for remarriage was most common emotional violence faced (43.2%). As the age of the pregnant women increases, they tend to have more domestic violence.Conclusions: The prevalence of Domestic Violence among pregnant women seemed alarmingly high in our society. Awareness to the family members and strengthening the women empowerment at community level might play a major role for reducing such violence. Pregnancy-related violence is a serious public health issue.

βcell survival and dedifferentiation are two hotly-debated mechanisms underlying βcell loss in type 2 diabetes; however, the underlying molecular mechanism remains largely unclear. Here we compare two principal protein quality control mechanisms, ER-associated protein degradation (ERAD) and autophagy and find that ERAD plays an important role in βcell dedifferentiation. Mice with βcell-specific Sel1L-Hrd1 deletion exhibit early-onset hyperglycemia and glucose intolerance as early as ~5 weeks of age. Surprisingly, in contrast to other tissue specific models of Sel1L-Hrd1 ERAD deficiency in which prohormones accumulate within the ER, Sel1L-Hrd1 ERAD deficiency impairs βcell function by attenuating insulin expression without an overt defect in proinsulin maturation and also triggers marked βcell dedifferentiation. There is, however, no overt activation of unfolded protein response (UPR) or proinsulin aggregation. In striking contrast to ERAD deficiency, loss of macroautophagy, a major mechanism for bulk protein degradation and organelle turnover, in βcells causes massive cell loss and hyperglycemia, but not βcell dedifferentiation. Thus, our data reveal a novel role of Sel1L-Hrd1 ERAD in the maintenance of βcell identify and demonstrate that impairment of ERAD contributes to the progression of type 2 diabetes in a manner distinct from that of autophagy. Disclosure N. Shrestha: None. X. Li: None. Y. Ji: None. R.B. Reinert: None. P. Arvan: None. L. Qi: None. Funding National Institutes of Health

Endoplasmic reticulum-associated degradation (ERAD) is a key component of cellular protein quality control, an essential process for pancreatic islet endocrine cells, which synthesize peptide prohormones in high quantities. Two highly conserved ER membrane proteins comprise the core ERAD machinery: HRD1, a ubiquitin ligase that retrotranslocates and ubiquitinates misfolded proteins for proteasomal degradation, and SEL1L, an adaptor protein that identifies ERAD target proteins and is required for HRD1 stability and function. Pancreatic alpha cells, intestinal L-cells, and certain neurons synthesize and differentially cleave proglucagon into tissue-specific hormones, including glucagon and glucagon-like peptide 1 (GLP-1). To investigate the role of ERAD in these cells, we targeted SEL1L deletion with the Cre-lox system, using mice expressing Cre recombinase under the proglucagon promoter. We found that Sel1LGcg mice showed normal growth and glucose homeostasis in vivo. Oral glucose tolerance was equally impaired by administration of the GLP-1 receptor antagonist exendin 9-39 in both Sel1LGcg and control mice, suggesting intact GLP-1 signaling in Sel1LGcg mice. Glucagon secretion in vivo was not significantly different following a 24 hour fast or insulin-induced hypoglycemia. Interestingly, pancreatic glucagon content was reduced by half in Sel1LGcg mice, despite unchanged pancreatic weight. By immunofluorescence, pancreatic islet morphology in Sel1LGcg mice was normal, though α-cells demonstrated increased expression of the ER chaperone BiP and ERAD-associated proteins OS9 and XTP3-B. By transmission electron microscopy, a large subset of α-cells showed significant ER dilation and fewer, smaller glucagon granules. Our data demonstrate that SEL1L-HRD1 ERAD is required for maintaining normal glucagon expression and ER morphology in pancreatic α-cells but does not entirely disrupt proglucagon signaling in vivo. Disclosure R.B. Reinert: None. N. Shrestha: None. Y. Ji: None. L. Qi: None. Funding National Institutes of Health (5T32DK007245)

Extracellular lysyl oxidases (LOX and LOXL1–LOXL4) are critical for collagen biosynthesis. LOXL2 is a marker of poor survival in oral squamous cell cancer. We investigated mechanisms by which tumor cell secreted LOXL2 targets proximal mesenchymal cells to enhance tumor growth and metastasis. This study identified the first molecular mechanism for LOXL2 in the promotion of cancer via its enzymatic modification of a non-collagenous substrate in the context of paracrine signaling between tumor cells and resident fibroblasts. The role and mechanism of active LOXL2 in promoting oral cancer was evaluated and employed a novel LOXL2 small molecule inhibitor, PSX-S1C, administered to immunodeficient, and syngeneic immunocompetent orthotopic oral cancer mouse models. Tumor growth, histopathology, and metastases were monitored. In vitro mechanistic studies with conditioned tumor cell medium treatment of normal human oral fibroblasts were carried out in the presence and absence of the LOXL2 inhibitor to identify signaling mechanisms promoted by LOXL2 activity. Inhibition of LOXL2 attenuated cancer growth and lymph node metastases in the orthotopic tongue mouse models. Immunohistochemistry data indicated that LOXL2 expression in and around tumors was decreased in mice treated with the inhibitor. Inhibition of LOXL2 activity by administration of PXS-S1C to mice reduced tumor cell proliferation, accompanied by changes in morphology and in the expression of epithelial to mesenchymal transition markers. In vitro studies identified PDGFRβ as a direct substrate for LOXL2, and indicated that LOXL2 and PDGF-AB together secreted by tumor cells optimally activated PDGFRβ in fibroblasts to promote proliferation and the tendency toward fibrosis via ERK activation, but not AKT. Optimal fibroblast proliferation in vitro required LOXL2 activity, while tumor cell proliferation did not. Thus, tumor cell-derived LOXL2 in the microenvironment directly targets neighboring resident cells to promote a permissive local niche, in addition to its known role in collagen maturation.

Poorly water-soluble drugs continue to be a problematic, yet important class of pharmaceutical compounds for treatment of a wide range of diseases. Their prevalence in discovery is still high, and their development is usually limited by our lack of a complete understanding of how the complex chemical, physiological and biochemical processes that occur between administration and absorption individually and together impact on bioavailability. This review defines the challenge presented by these drugs, outlines contemporary strategies to solve this challenge, and consequent in silico and in vitro evaluation of the delivery technologies for poorly water-soluble drugs. The next steps and unmet needs are proposed to present a roadmap for future studies for the field to consider enabling progress in delivery of poorly water-soluble compounds. ispartof: EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES vol:137 ispartof: location:Netherlands status: published

The potential of nanoemulsions for the oral administration of peptides is still in its early stage. The aim of the present work was to rationally design, develop, and fully characterize a new nanoemulsion (NE) intended for the oral administration of hydrophobically modified insulin (HM-insulin). Specific components of the NE were selected based on their enhancing permeation properties as well as their ability to improve insulin association efficiency (Miglyol 812, sodium taurocholate), stability in the intestinal fluids, and mucodiffusion (PEGylated phospholipids and poloxamer 407). The results showed that the NE co-existed with a population of micelles, forming a mixed system that exhibited a 100% of HM-insulin association efficiency. The nanosystem showed good stability and miscibility in different bio-relevant media and displayed an acceptable mucodiffusive behavior in porcine mucus. In addition, it exhibited a high interaction with cell mono-cultures (Caco -2 and C2BBe1 human colon carcinoma Caco-2 clone cells) and co-cultures (C2BBe1 human colon carcinoma Caco-2 clone/HT29-MTX cells). The internalization in Caco-2 monolayers was also confirmed by confocal microscopy. Finally, the promising in vitro behavior of the nanosystem in terms of overcoming the biological barriers of the intestinal tract was translated into a moderate, although significant, hypoglycemic response (≈ 20-30%), following intestinal administration to both healthy and diabetic rat models. Overall, this information underlines the crucial steps to address when designing peptide-based nanoformulations to successfully overcome the intestinal barriers associated to the oral modality of administration.

Autism spectrum disorder (ASD) is a highly prevalent and genetically heterogeneous brain disorder. Developing effective therapeutic interventions requires knowledge of the brain regions that malfunction and how they malfunction during ASD-relevant behaviors. Our study provides insights into brain regions activated by a novel social stimulus and how the activation pattern differs between mice that display autism-like disabilities and control littermates. Adenomatous polyposis coli (APC) conditional knockout (cKO) mice display reduced social interest, increased repetitive behaviors and dysfunction of the β-catenin pathway, a convergent target of numerous ASD-linked human genes. Here, we exposed the mice to a novel social vs. non-social stimulus and measured neuronal activation by immunostaining for the protein c-Fos. We analyzed three brain regions known to play a role in social behavior. Compared with control littermates, APC cKOs display excessive activation, as evidenced by an increased number of excitatory pyramidal neurons stained for c-Fos in the medial prefrontal cortex (mPFC), selectively in the infralimbic sub-region. In contrast, two other social brain regions, the medial amygdala and piriform cortex show normal levels of neuron activation. Additionally, APC cKOs exhibit increased frequency of miniature excitatory postsynaptic currents (mEPSCs) in layer 5 pyramidal neurons of the infralimbic sub-region. Further, immunostaining is reduced for the inhibitory interneuron markers parvalbumin (PV) and somatostatin (SST) in the APC cKO mPFC. Our findings suggest aberrant excitatory-inhibitory balance and activation patterns. As β-catenin is a core pathway in ASD, we identify the infralimbic sub-region of the mPFC as a critical brain region for autism-relevant social behavior.

Nanotechnology based drug delivery systems are anticipated to overcome the persistent challenges in oral protein and peptide administration, and lead to the development of long awaited non-invasive therapies. Herein, an advanced single-step aerosol flow reactor based technology was used to develop a multifunctional site specific dual protein-drug delivery nanosystem. For this purpose, mucoadhesive porous silicon (PSi) nanoparticles encapsulated into a pH-responsive polymeric nanomatrix was developed for advanced oral type 2 diabetes mellitus therapy with an antidiabetic peptide, glucagon like peptide-1 (GLP-1), and the enzyme inhibitor, dipeptidyl peptidase-4 (DPP4). Chitosan surface modification inherited the mucoadhesiveness to the nanosystem which led to enhanced cellular interactions and increased cellular compatibility. An advanced aerosol flow reactor technology was used to encapsulate the chitosan modified nanoparticles into an enteric polymeric nanomatrix. The pH-sensitive polymeric matrix simultaneously prevented the gastric degradation of the encapsulated peptide and also preserved the mucoadhesive functionality of the chitosan-modified PSi nanoparticles in the harsh stomach environment. The multidrug loaded nanosystem showed augmented intestinal permeability of GLP-1, evaluated in an in vitro cell-based intestinal epithelium model, attributed to the permeation enhancer effect of chitosan and inhibition of GLP-1 degradation by the DPP4 inhibitor. The applied technology resulted in the development of a dual-drug delivery nanosystem that synergizes the antidiabetic effect of the loaded peptide and the enzyme inhibitor, thereby indicating high clinical potential of the system and preparation technique.

Combination therapy via nanoparticulate systems has already been proposed as a synergistic approach for cancer treatment. Herein, undecylenic acid modified thermally hydrocarbonized porous silicon nanoparticles (UnTHCPSi NPs) loaded with sorafenib and surface-biofunctionalized with anti-CD326 antibody (Ab) were developed for cancer chemo-immunotherapy in MCF-7 and MDA-MB-231 breast cancer cells. The cytocompatibility study showed no significant toxicity for the bare and antibody-conjugated UnTHCPSi (Un-Ab) NPs at concentrations lower than 200 μg·mL−1. Compared to the bare UnTHCPSi, Un-Ab NPs loaded with sorafenib reduced the premature drug release in plasma, increasing the probability of proper drug targeting. In addition, high cellular interaction and subsequent internalization of the Un-Ab NPs into the cells expressing CD326 antigen demonstrated the possibility of improving antigen-mediated endocytosis via CD326 targeting. While an in vitro antitumor study revealed a higher inhibitory effect of the sorafenib-loaded Un-Ab NPs compared to the drug-loaded UnTHCPSi NPs in the CD326 positive MCF-7 cells, there was no difference in the anti-proliferation impact of both the abovementioned NPs in the CD326 negative MDA-MB-231 cells, suggesting CD326 as an appropriate receptor for Ab-mediated drug delivery. It was also shown that the anti-CD326 Ab can act as an immunotherapeutic agent by inducing antibody dependent cellular cytotoxicity and enhancing the interaction of effector immune and cancer cells for subsequent phagocytosis and cytokine secretion. Hence, the developed nanovectors can be applied for simultaneous tumor-selective drug targeting and immunotherapy.

EU’s main approach to sustainable housing is promoting green practices/products within the building construction sectors SCs. EU Switch Asia program financed research conducted in Nepal, 2015, to understand the organization of SCs, identify factors/barriers affecting SCM and existing relationships, the reasons to adopt green concepts/approaches and recommend support for SMEs to strengthen the sector’s management and sustainability. 109 companies, non-probabilistic snowball sampling and semi-closed questionnaires used in the survey. Conclusions: Companies create SCs to increase customer satisfaction, maintain long-term sales and retain clients. Size of company influences SCs organisation, SCM and using/producing green products/services; majority of participants had a person in the company to manage SC’s and had very good knowledge of SC, SCM and greening issues. SMEs need support with: information/communication technology, promotion and improvement/development of green products/services. Government should: increases awareness of green building products/

SUMMARY Type 1 diabetes mellitus (T1DM) is a global epidemic with an alarming number of patients suffering from the disease worldwide. The main goal of the therapy directed towards diabetes mellitus is achieving normal blood glucose levels. Gene therapy is one of the many approaches utilized to accomplish this in a safe, specific and efficient manner. Since the first cloning of insulin gene, the gene therapy approach for the treatment of T1DM has been widely investigated. Gene therapy for T1DM encompasses a broad area, from targeting noninsulin producing cells (e.g., hepatocytes, fibroblasts and myocytes) for stimulating the production and storage of insulin, and to genetically manipulate β cells to avoid autoimmune destruction. For this purpose, different types of viral and nonviral gene delivery vectors have been studied. This review aims mainly to discuss the most commonly gene delivery systems used for the treatment or prevention of T1DM. Several recent examples of viral and nonviral gene delivery ve...

Glucagon like peptide-1 (GLP-1) is an incretin hormone that is in the pipeline for type 2 diabetes mellitus (T2DM) therapy. However, oral administration of GLP-1 is hindered by the harsh conditions of the gastrointestinal tract and poor bioavailability. In this study, three nanosystems composed by three different biomaterials (poly(lactide-co-glycolide) polymer (PLGA), Witepsol E85 lipid (solid lipid nanoparticles, SLN) and porous silicon (PSi) were developed and loaded with GLP-1 to study their permeability in vitro. All the nanoparticles presented a size of approximately 200 nm. The nanoparticles' interaction with the mucus and the intestinal cells were enhanced after coating with chitosan (CS). PSi nanosystems presented the best association efficiency (AE) and loading degree (LD), even though a high AE was also observed for PLGA nanoparticles and SLN. Among all the nanosystems, PLGA and PSi were the only nanoparticles able to sustain the release of GLP-1 in biological fluids when coated with CS. This characteristic was also maintained when the nanosystems were in contact with the intestinal Caco-2 and HT29-MTX cell monolayers. The CS-coated PSi nanoparticles showed the highest GLP-1 permeation across the intestinal in vitro models. In conclusion, PLGA + CS and PSi + CS are promising nanocarriers for the oral delivery of GLP-1.

Porous silicon (PSi) based particulate systems are emerging as an important drug delivery system due to its advantageous properties such as biocompatibility, biodegradability and ability to tailor the particles' physicochemical properties. Here, annealed thermally hydrocarbonized PSi (AnnTHCPSi) and undecylenic acid modified AnnTHCPSi (AnnUnTHCPSi) microparticles were developed as a PSi-based platform for oral delivery of insulin. Chitosan (CS) was used to modify the AnnUnTHCPSi microparticles to enhance the intestinal permeation of insulin. Surface modification with CS led to significant increase in the interaction of PSi microparticles with Caco-2/HT-29 cell co-culture monolayers. Compared to pure insulin, the CS-conjugated microparticles significantly improved the permeation of insulin across the Caco-2/HT-29 cell monolayers, with ca. 20-fold increase in the amount of insulin permeated and ca. 7-fold increase in the apparent permeability (P(app)) value. Moreover, among all the investigated particles, the CS-conjugated microparticles also showed the highest amount of insulin associated with the mucus layer and the intestinal Caco-2 cells and mucus secreting HT-29 cells. Our results demonstrate that CS-conjugated AnnUnTHCPSi microparticles can efficiently enhance the insulin absorption across intestinal cells, and thus, they are promising microsystems for the oral delivery of proteins and peptides across the intestinal cell membrane.

The effect of adsorption and confinement on ibuprofen was studied by immersion loading the molecules into porous silicon (PSi) microparticles. The PSi microparticles were modified into thermally oxidized PSi (TOPSi) and thermally hydrocarbonized PSi (THCPSi) to evaluate the effects of the loading solvent and the surface chemistry on the obtainable drug payloads. The payloads, location, and the molecular state of the adsorbed drug were evaluated using thermal analysis. The results showed that after the adsorption of ∼800 mg/cm3 (wdrug/vpores) of drug into the mesopores, depending on the solvent used in the immersion, the drug began to rapidly recrystallize on the external surface of the particles. Moderate concentrations, however, enabled payloads of 800–850 mg/cm3 without excessive surface crystallization, and thus, there was no need for rinsing the samples to remove the externally crystallized portion. The results showed that the confined ibuprofen forms nanocrystals inside of the mesopores after approxi...

Nanoparticles are promising carrier systems for the oral delivery of proteins, a challenge in the pharmaceutical field., Oral delivery of proteins is still a challenge in the pharmaceutical field. Nanoparticles are among the most promising carrier systems for the oral delivery of proteins by increasing their oral bioavailability. However, most of the existent data regarding nanosystems for oral protein delivery is from in vitro studies, lacking in vivo experiments to evaluate the efficacy of these systems. Herein, a multifunctional composite system, tailored by droplet microfluidics, was used for dual delivery of glucagon like peptide-1 (GLP-1) and dipeptidyl peptidase-4 inhibitor (iDPP4) in vivo. Oral delivery of GLP-1 with nano- or micro-systems has been studied before, but the simultaneous nanodelivery of GLP-1 with iDPP4 is a novel strategy presented here. The type 2 diabetes mellitus (T2DM) rat model, induced through the combined administration of streptozotocin and nicotinamide, a non-obese model of T2DM, was used. The combination of both drugs resulted in an increase in the hypoglycemic effects in a sustained, but prolonged manner, where the iDPP4 improved the therapeutic efficacy of GLP-1. Four hours after the oral administration of the system, blood glucose levels were decreased by 44%, and were constant for another 4 h, representing half of the glucose area under the curve when compared to the control. An enhancement of the plasmatic insulin levels was also observed 6 h after the oral administration of the dual-drug composite system and, although no statistically significant differences existed, the amount of pancreatic insulin was also higher. These are promising results for the oral delivery of GLP-1 to be pursued further in a chronic diabetic model study.

A reliable microfluidic platform for the generation of stable and monodisperse multistage drug delivery systems is reported. A glass-capillary flow-focusing droplet generation device was used to encapsulate thermally hydrocarbonized porous silicon (PSi) microparticles into the aqueous cores of double emulsion drops, yielding the formation of a multistage PSi–lipid vesicle. This composite system enables a large loading capacity for hydrophobic drugs.

Poly(ethylene glycol) (PEG) hydrogels are being developed as cell delivery vehicles that have great potential to improve neuronal replacement therapies. Current research priorities include (1) characterizing neural cell growth within PEG hydrogels relative to standard culture systems and (2) generating neuronal-enriched populations within the PEG hydrogel environment. This study compares the percentage of neural precursor cells (NPCs), neurons, and glia present when dissociated neural cells are seeded within PEG hydrogels relative to standard monolayer culture. Results demonstrate that PEG hydrogels enriched the initial cell population for NPCs, which subsequently gave rise to neurons, then to glia. Relative to monolayer culture, PEG hydrogels maintained an increased percentage of NPCs and a decreased percentage of glia. This neurogenic advantage of PEG hydrogels is accentuated in the presence of basic fibroblast growth factor and epidermal growth factor, which more potently increase NPC and neuronal expression markers when applied to cells cultured within PEG hydrogels. Finally, this work demonstrates that glial differentiation can be selectively eliminated upon supplementation with a γ-secretase inhibitor. Together, this study furthers our understanding of how the PEG hydrogel environment influences neural cell composition and also describes select soluble factors that are useful in generating neuronal-enriched populations within the PEG hydrogel environment.