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Background/aim: Salmonella typhimurium A1-R has been shown to target and inhibit many types of cancers in mouse models without continuous infection of normal tissue. The objective of the present study was to determine the effective dose of orally-administered Salmonella typhimurium A1-R, expressing-green fluorescent protein (GFP), on an HT1080 human-fibrosarcoma nude-mouse model., Materials and Methods: The HT1080-human- fibrosarcoma nude-mouse models were randomized into the following three groups: G1: untreated control; G2: Oral Salmonella typhimurium A1-R (5×10 7 colony forming units [CFU]/body, twice a week, 2 weeks); G3: Oral Salmonella typhimurium A1-R (3.3×10 8 CFU/body, twice a week, 2 weeks). Each group comprised five mice. Body weight and tumor volume were measured twice a week. The number of colonies of Salmonella typhimurium A1-R-GFP in excised tumors and excised livers in groups G2 and G3 were determined on day 3, day 7 and 14 by growth on agar plates. Tukey-Kramer analysis was used to examine the relationships between variables. Statistically-significant results are defined as those with p≤0.05., Results: Salmonella typhimurium A1-R was administered orally at a dose of 3.3×10 8 CFU, which successfully regressed the HT1080 tumor in nude mice. However, this effect was not observed at a lower dose of 5×10 7 CFU. After administering Salmonella typhimurium A1-R at 3.3×10 8 CFU, tumors and liver tissues were harvested, homogenized, and cultured on days 3, 7 and 14. Resulting GFP-expressing Salmonella typhimurium A1-R colonies were then counted. The number of GFP-bacterial colonies derived from excised tumors at intervals of 3, 7, and 14 days increased over time post-administration of oral GFP-Salmonella typhimurium. Conversely, the number of GFP-Salmonella typhimurium A1-R colonies that could be grown from excised livers decreased over time, following oral administration of GFP-Salmonella typhimurium. Additionally, the GFP-bacterial colonies grown from the excised tumors were significantly larger than those grown from the excised livers., Conclusion: The present study showed that an aggressive fibrosarcoma could be regressed by orally-administered Salmonella typhimurium A1-R which accurately targeted tumors without continuous growth in normal organs. The present results suggested the potential of orally-administered Salmonella typhimurium A1-R as a probiotic to treat aggressive soft-tissue sarcoma., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Abiraterone acetate (AbA) is a progesterone derivative indicated for the treatment of metastatic prostate cancer. This BCS (Biopharmaceutics Classification System) Class IV molecule has an extremely poor oral bioavailability (<10 %), notably due to its very low water solubility and intestinal permeability. Among the few existing galenic strategies to improve AbA's oral bioavailability, lipid nanoparticles such as Solid Lipid Nanoparticles (SLN) and Nanostructured Lipid Carriers (NLC) are relevant nanovectors. The objective of this study is to develop and compare SLN and NLC for oral delivery of abiraterone acetate. Both SLN and NLC are biocompatible, biodegradable and produced by high pressure homogenization (HPH), an ecological-friendly manufacturing process, organic solvent-free and easily scalable. The HPH process allowed the formation of AbA-loaded SLN and NLC with particle size lower than 160 nm and high encapsulation efficiencies. The addition of a liquid lipid significantly reduced the mean diameter of the nanoparticles, reflecting the greater benefit of the NLC formulation compared to SLN. Both SLN and NLC formulations offered an important protection of AbA in intestinal media, with a better stability for NLC. When encapsulated in SLN or NLC, the AbA is strongly retained by the nanoparticles, whatever the dissolution medium, which means that both formulas are able to protect and retain the drug in the intestinal tract, right up to its delivery to the enterocytes surface. High concentrations of nanoparticles were administered without cytotoxicity, especially for the NLC, which provides a real added value in terms of biocompatibility with Caco-2 cells. Finally, the nanoparticles were able to penetrate into enterocytes by the transcellular route, demonstrating an intense cellular internalization., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

This study investigated the potential of self-nanoemulsifying drug delivery systems (SNEDDS) to optimize the oral bioavailability of insulin. Insulin complexes with phospholipids and enzymatically-modified phospholipids were developed and incorporated into the SNEDDS using Lauroglycol FCC as the oily phase and Cremophor EL and Labrafil M1944CS as the surfactant and co-surfactant, respectively. Additionally, mucoadhesive polysaccharides (sodium alginate and guar gum) were added further to enhance the bioavailability of insulin in these systems. The objective was to increase the bioavailability and bioactivity of an insulin-modified phosphatidylcholine complex by incorporating mucoadhesives into the SNEDDS. After polymer inclusion, the resulting nanoemulsions exhibited droplet diameters ranging from 57 to 83 nm. Cytotoxicity and apparent permeability tests were conducted on Caco-2 and NIH 3 T3 cell lines, revealing that toxicity was related to the concentrations of insulin and surfactant in the nanosystems-formulations containing guar gum as a mucoadhesive showed better tolerance to cell death in the Caco-2 line. In a murine diabetes model, the SNEDDS were observed to reduce glucose levels by up to 61.63 %, with a relative bioavailability of 2.25 % compared to subcutaneously administered insulin. These results suggest that SNEDDS incorporating mucoadhesives could represent a promising strategy for improving oral insulin delivery., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Extracellular vesicles (EVs) have emerged as valuable biological materials for treating intractable diseases. Extensive studies are conducted on EVs derived from various cellular sources. In this study, EVs derived from Lactobacillus reuteri (L. reuteri), a probiotic, exhibit remarkable cancer therapeutic efficacy when administered orally is reported. These L. reuteri-derived EVs (REVs) demonstrate stability in the gastrointestinal tract and exert significant anti-tumor effects. Using A549 cells and murine models, we confirmed that REVs mediate their therapeutic effects by modulating apoptotic signaling pathways. Furthermore, the combination of REV with drugs enhances tumor ablation and induces immunogenic cell death. In a mouse model, oral administration of REVs encapsulating indocyanine green followed by photothermal therapy led to complete tumor elimination within 32 days. REVs represent a promising biological therapeutic platform for cancer treatment, either independently or in combination with other therapies, depending on the treatment objectives., (© 2024 The Author(s). Small published by Wiley‐VCH GmbH.)

The incidence of inflammatory bowel disease (IBD), a chronic gastrointestinal disorder, is rapidly increasing worldwide. Unfortunately, the current therapies for IBD are often hindered by premature drug release and undesirable side effects. With the advancement of nanotechnology, the innovative targeted nanotherapeutics are explored to ensure the accurate delivery of drugs to specific sites in the colon, thereby reducing side effects and improving the efficacy of oral administration. The emphasis of this review is to summarize the potential pathogenesis of IBD and highlight recent breakthroughs in carbohydrate-based nanoparticles for IBD treatment, including their construction, release mechanism, potential targeting ability, and their therapeutic efficacy. Specifically, we summarize the latest knowledge regarding environmental-responsive nano-systems and active targeted nanoparticles. The environmental-responsive drug delivery systems crafted with carbohydrates or other biological macromolecules like chitosan and sodium alginate, exhibit a remarkable capacity to enhance the accumulation of therapeutic drugs in the inflamed regions of the digestive tract. Active targeting strategies improve the specificity and accuracy of oral drug delivery to the colon by modifying carbohydrates such as hyaluronic acid and mannose onto nanocarriers. Finally, we discuss the challenges and provide insight into the future perspectives of colon-targeted delivery systems for IBD treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Acetyl tributyl citrate (ATBC) and acetyl triethyl citrate (ATEC) are widely used as plasticizers, but their metabolites as exposure biomarkers for biomonitoring, as well as approximate human metabolic pathways, are not well understood. This study addresses this knowledge gap by conducting suspect screening to propose specific metabolites in human urine as potential biomarkers of exposure and explore their kinetic profiles. Ten volunteers were administered deuterium labeled ATBC (ATBC-d 3 ) and seven received ATEC or deuterium labeled ATEC (ATEC-d 3 ), with urine samples collected over 48 h post-administration. Employing ultra-performance liquid chromatography coupled to quadrupole-time-of-flight mass spectrometry (UPLC-qTOF/MS), six metabolites of ATBC were consistently detected, including (OH) 3 -ATBC-d 3 , ADBC-d 3 , OH-ADBC-d 3 , DBC, OH-DBC, and OH-DBA. For ATEC, four metabolites were identified: ADEC-d 3 , AMEC-d 3 , OH-ADEC-d 3 , and DEC. Based on their high detection frequency, relative response, and specificity to their parent compounds, ADBC-d 3 and OH-ADBC-d 3 were identified as promising candidate biomarkers for ATBC exposure, while ADEC-d 3 emerged as a suitable biomarker for ATEC. Estimated urinary elimination half-lives ranged from 1.0 to 9.9 h for ATBC metabolites and 1.6 to 3.0 h for ATEC metabolites. One-compartment kinetic modeling provided preliminary insights into metabolite kinetics. This research advances the understanding of ATBC and ATEC metabolism in humans, providing a foundation for future exposure assessments and toxicological studies. The identified biomarkers and preliminary metabolic profiles offer valuable starting points for biomonitoring and risk assessment of these alternative plasticizers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The biosafety concerns associated with fecal microbiota transplant (FMT) limit their clinical application in treating ulcerative colitis (UC). Gut microbiota secrete abundant extracellular vesicles (Gm-EVs), which play a critical role in bacteria-to-bacteria and bacteria-to-host communications. Herein, intestinal microbiota are trained using tea leaf lipid/pluronic F127-coated curcumin nanocrystals (CN@Lp 127 s), which can maintain stability during transit through the gastrointestinal tract. Compared with FMT, Gm-EVs derived from healthy mice significantly improve treatment outcomes against UC by reducing colonic inflammatory responses, restoring colonic barrier function, and rebalancing intestinal microbiota. Strikingly, Gm-EVs obtained from CN@Lp 127 -trained healthy mice exhibit a superior therapeutic effect on UC compared to groups receiving FMT from healthy mice, Gm-EVs from healthy mice, and FMT from CN@Lp 127 -trained healthy mice. Oral administration of Gm-EVs from CN@Lp 127 -trained healthy mice not only alleviates colonic inflammation, promotes mucosal repair, and regulates gut microbiota but also regulates purine metabolism to decrease the uric acid level, resulting in a robust improvement in the UC. This study demonstrates the UC therapeutic efficacy of Gm-EVs derived from nanomedicine-trained gut microbiota in regulating the immune microenvironment, microbiota, and purine metabolism of the colon. These EVs provide an alternative platform to replace FMT as a treatment for UC., (© 2024 Wiley‐VCH GmbH.)

Ensuring precise drug release at target sites is crucial for effective treatment. Here, pH-responsive nanoparticles for oral administration of mycophenolate mofetil, an alternative therapy for patients with inflammatory bowel disease unresponsive to conventional treatments is developed. However, its oral administration presents challenges due to its low solubility in the small intestine and high solubility and absorption in the stomach. Therefore, this aim is to design a drug delivery system capable of maintaining drug solubility compared to the free drug while delaying absorption from the stomach to the intestine. Successful synthesis and assembly of a block copolymer incorporating a pH-responsive functional group is achieved. Dynamic light scattering indicated a significant change in hydrodynamic size when the pH exceeded 6.5, confirming successful incorporation of the pH-responsive group. Encapsulation and controlled release of mycophenolate mofetil are efficiently demonstrated, with 90% release observed at intestinal pH. In vitro cell culture studies confirmed biocompatibility, showing no toxicity or adverse effects on Caco-2 cells. In vivo oral rat studies indicated reduced drug absorption in the stomach and enhanced absorption in the small intestine with the developed formulation. This research presents a promising drug delivery system with potential applications in the treatment of inflammatory bowel disease., (© 2024 The Author(s). Small published by Wiley‐VCH GmbH.)

Background: Oral insulin delivery is considered a revolutionary alternative to daily subcutaneous injection. However, the oral bioavailability of insulin is very low due to the poor oral absorption into blood circulation. Methods: To promote penetration across the intestinal epithelium and achieve enhanced and safe glucose-responsive oral insulin delivery, pH and H 2 O 2 dual-sensitive nanoparticles (NPs) were constructed. The NPs were loaded of glucose oxidase (GOx) and insulin by pH and H 2 O 2 dual-sensitive amphiphilic polymer incorporated with phenylboronic ester-conjugated poly(2-hydroxyethyl methacrylate) and poly(carboxybetaine) (PCB). The dual-sensitive NPs were utilized for the treatment of type 1 diabetes mellitus (T1DM) after oral administration. Results: The dual-sensitive NPs could enhance the transport of insulin across the intestinal epithelium into blood facilitated by zwitterionic PCB. By virtue of the generated low pH and high H 2 O 2 with GOx in hyperglycemic environment, the pH and H 2 O 2 dual-sensitive NPs were disassembled to achieve rapid and sustained release of insulin. After oral administration of the dual-sensitive NPs in enteric capsules into T1DM mouse model, the oral bioavailability of insulin reached 20.24%, and the NPs achieved hypoglycemic effect for a few hours longer than subcutaneously injected insulin. Importantly, the pH and H 2 O 2 dual-sensitive NPs could ameliorate the local decline of pH and rise of H 2 O 2 to avoid the toxic side effect. Conclusion: Therefore, this work would provide a promising platform for the enhanced and safe treatment of diabetes mellitus., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background/aim: In a previous report, our group showed that oral administration of lipopolysaccharides (LPS) from Pantoea agglomerans can prevent the progression of streptozotocin (STZ)-induced diabetes-related cognitive dysfunction (DRCD) in mice without causing significant side-effects. However, the treatment effects of oral administration of LPS to DRCD remain unknown., Materials and Methods: We modified our previous animal experimental model to investigate whether oral administration of LPS can recover cognitive function after DRCD onset., Results: The Morris water maze (MWM) revealed a significant decrease in learning and memory abilities at 13 days after intracerebroventricular administration of STZ, thereby providing evidence of the occurrence of DRCD in the animal model. Oral administration of LPS (1 mg/kg per day) started after cognitive impairment was observed. After 28 days of treatment, mice receiving LPS via the oral route showed significant recovery of spatial learning ability, a symptom of early dementia, while only a trend toward recovery was seen for spatial memory compared to the untreated group., Conclusion: These results, limited to MWM, suggest that oral administration of LPS is a promising therapeutic strategy for restoring decreased spatial learning ability., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Byung Chull An,1 Yeo-Sang Yoon,1 Ho Jin Park,1 Sangkyun Park,1 Tai Yeub Kim,1 Jun Young Ahn,1 Daebeom Kwon,1 Oksik Choi,1 Jin Young Heo,1 Yongku Ryu,1 Joong-Hyun Kim,2 Heejong Eom,2 Myung Jun Chung1 1R&D Center, Cell Biotech, Co., Ltd., Gimpo-si, Gyeonggi-do, Korea; 2Laboratory Animal Center, Osong Medical Innovation Foundation, Chungbuk, Cheongju, 28160, KoreaCorrespondence: Myung Jun Chung Tel +82-31-987-6205Fax +82-31-987-6216Email ceo@cellbiotech.comPurpose: This study aimed to toxicological evaluate a probiotics-based delivery system for p8 protein as an anti-colorectal cancer drug.Introduction: Lactic acid bacteria (LAB) have been widely ingested for many years and are regarded as very safe. Recently, a Pediococcus pentosaceus SL4 (PP) strain that secretes the probiotic-derived anti-cancer protein P8 (PP-P8) has been developed as an anti-colorectal cancer (CRC) biologic by Cell Biotech. We initially identified a Lactobacillus rhamnosus (LR)-derived anti-cancer protein, P8, that suppresses CRC growth. We also showed that P8 penetrates specifically into CRC cells (DLD-1 cells) through endocytosis. We then confirmed the efficacy of PP-P8, showing that oral administration of this agent significantly decreased tumor mass (∼ 42%) relative to controls in a mouse CRC xenograft model. In terms of molecular mechanism, PP-P8 induces cell-cycle arrest in G2 phase through down-regulation of Cyclin B1 and Cdk1. In this study, we performed in vivo toxicology profiling to obtain evidence that PP-P8 is safe, with the goal of receiving approval for an investigational new drug application (IND).Methods: Based on gene therapy guidelines of the Ministry of Food and Drug Safety (MFDS) of Korea, the potential undesirable effects of PP-P8 had to be investigated in intact small rodent or marmoset models prior to first-in-human (FIH) administration. The estimated doses of PP-P8 for FIH are 1.0× 1010 – 1.0× 1011 CFU/person (60 kg). Therefore, to perform toxicological investigations in non-clinical animal models, we orally administered PP-P8 at doses of 3.375 × 1011, 6.75 × 1011, and 13.5× 1011 CFU/kg/day; thus the maximum dose was 800– 8000-fold higher than the estimated dose for FIH.Results: In our animal models, we observed no adverse effects of PP-P8 on clinicopathologic findings, relative organ weight, or tissue pathology. In addition, we observed no inflammation or ulceration during pathological necropsy.Conclusion: These non-clinical toxicology studies could be used to furnish valuable data for the safety certification of PP-P8.Keywords: biologics, therapeutic protein, probiotics derived anti-cancer protein P8, Pediococcus pentosaceus SL4, Lactobacillus rhamnosus, colorectal cancer, drug delivery system, protein secretion system, oral administration, non-clinical trial, toxicology finding

This study provides a snapshot of the current vaccine business ecosystem, including practices, challenges, beliefs, and expectations of vaccine providers. Our team focused on providers’ firsthand experience with administering vaccines to determine if an oral vaccine (e.g. pill or oral-drop) would be well-received. We interviewed 135 healthcare providers and vaccine specialists across the US, focusing questions on routine vaccinations, not COVID-19 vaccines. Improving workflow efficiency is a top concern among vaccine providers due to shrinking reimbursement rates—determined by pharmacy benefit managers (PBMs)—and the time-intensiveness of injectable vaccines. Administering injectable vaccines takes 23 minutes/patient on average, while dispensing pills takes only 5 minutes/patient. An average of 24% of patients express needle-fear, which further lengthens the processing time. Misaligned incentives between providers and PBMs could reduce the quality and availability of vaccine-related care. The unavailability of single-dose orders prevents some rural providers from offering certain vaccines. Most interviewees (74%) believe an oral vaccine would improve patient–provider experience, patient-compliance, and workflow efficiency, while detractors (26%) worry about the taste, vaccine absorption, and efficacy. Additional research could investigate whether currently non-vaccinating pharmacies would be willing to offer oral vaccines, and the impact of oral vaccines on vaccine acceptance.

Namibia is ethnically diverse and rich in indigenous knowledge on the medicinal uses of plants. However, this knowledge in treating gastrointestinal conditions is not well documented despite its contributions to the healthcare system in Namibia. This study aimed at documenting the ethnomedicinal uses of plants used to treat gastrointestinal conditions in the Iikokola village and validating their use through phytochemical analysis. A survey was conducted using semi-structured questionnaires with consenting knowledge holders. Voucher specimens were collected and deposited with the National Herbarium of Namibia for botanical nomenclature. Among the 26 knowledge holders approached 23 participated in the study, of which 16 were females and 7 were males. A total of 19 plant species belonging to 10 plant families were reported to treat at least one gastrointestinal condition and 14 other ailments. Most species belong to Fabaceae and Combretaceae families (FIV=100). The gastrointestinal use of 32% of the plants documented in this study has not been reported elsewhere. Diarrhea, vomiting, and stomach pain are frequently managed using medicinal plants. Decoctions from roots of Grewia tenax, Terminalia sericea, Corchorus tridens, Albizia anthelmintica, and Lantana camara, were mostly used for gastrointestinal ailments. Oral administration was the only route used in the administration of gastrointestinal remedies, among all age groups. Phytochemical compounds such as coumarins, flavonoids, saponins, and tannins which have been linked to the antidiarrheal activity of plants, were detected in organic and aqueous extracts. Organic extracts of T. sericea and G. tenax showed higher total phenolic and flavonoid contents ≤ 169.46 and ≤ 74.03 mg QE/g respectively. These phytochemical properties add value to their ethnomedicinal use is rational although antimicrobial properties and safety profile should be determined. The traditional uses of medicinal plants reported in this study will help safeguard and guide future research aiming at developing plant-based treatments for gastrointestinal conditions.

Enteral administration is the most convenient route despite the gastrointestinal physiological barriers. Nanostructured lipid carriers (NLCs) have emerged as a promising strategy for improving therapeutic compound oral bioavailability, not only due to nanomaterial advantages, but also due to lipid ingredients themselves, such as preventing enzyme degradation, taste masking, and especially favorable uptake by chylomicron pathways to the lymphatic drainage system. Therefore, NLCs have been employed for systemic absorption improvement, site-specific treatment of the digestive system, and especially targeting delivery to the liver, brain, cancer ulcer, and so on through oral uptake. Lipids, surfactants, and other materials like lipophilic counter ions or coating polymers are considered for oral NLCs formulation design. A variety of NLCs fabrication methods and stability enhancement techniques by transforming NLCs into powder form or hydrophobic -ion pairing are discussed. Hence, this review aims to provide an overview of the current state of the art of NLCs and their modern techniques and applications in oral drug administration, which will advocate their extended use in the future.

Inhibition of the NEDD8-activating enzyme (NAE), the key E1 enzyme in the neddylation cascade, has been considered an attractive anticancer strategy with the discovery of the first-in-class NAE inhibitor, MLN4924. In this study, we identified SOMCL-19-133 as a highly potent, selective, and orally available NAE inhibitor, which is an analog to AMP. It effectively inhibited NAE with an IC50 value of 0.36 nM and exhibited more than 2855-fold selectivity over the closely related Ubiquitin-activating enzyme (UAE). It is worth noting that treatment with SOMCL-19-133 prominently inhibited Cullin neddylation and delayed the turnover of a panel of Cullin-RING ligases (CRLs) substrates (e.g., Cdt1, p21, p27, and Wee1) at lower effective concentrations than that of MLN4924, subsequently caused DNA damage and Chk1/Chk2 activation, and thus triggered cell cycle arrest and apoptosis. Moreover, SOMCL-19-133 exhibited potent antiproliferative activity against a broad range of human tumor cell lines (mean IC50 201.11 nM), which was about 5.31-fold more potent than that of MLN4924. In vivo, oral delivery treatments with SOMCL-19-133, as well as the subcutaneous injection, led to significant tumor regression in mouse xenograft models. All of the treatments were well tolerated on a continuous daily dosing schedule. Compared with MLN4924, SOMCL-19-133 had a 5-fold higher peak plasma concentration, lower plasma clearance, and a 4-fold larger area under the curve (AUClast). In conclusion, SOMCL-19-133 is a promising preclinical candidate for treating cancers owing to its profound in vitro and in vivo efficacy and favorable pharmacokinetic properties.

Although therapeutic cancer vaccines have been gaining substantial ground, the development of cancer vaccines is impeded because of the undegradability of delivery systems, ineffective delivery of tumor antigens and weak immunogenicity of adjuvants. Here, we made use of a whole glucan particle (WGP) to encapsulate ovalbumin (OVA), thereby formulating a novel cancer vaccine. Results from in vitro experiments showed that WGP-OVA not only induced the activation of bone marrow-derived macrophages (BMDMs) including driving M0 BMDM polarization to the M1 phenotype, upregulating the costimulatory molecules and inducing the generation of cytokines, but also facilitated antigen presentation. After oral administration of the WGP-OVA formulation to mice with OVA-expressing tumors, these particles can increase tumor-infiltrating OVA-specific CD8+ CTLs and repolarize tumor-associated macrophages (TAMs) toward M1-like phenotype, which led to delayed tumor progression. These findings revealed that WGP could serve as both an antigen delivery system and an adjuvant system for promising cancer vaccines. [ABSTRACT FROM AUTHOR]

Edaravone has been widely used in the treatment of acute ischemic stroke. However, there has been no oral preparation of edaravone in the clinic. In this study, we assessed the effect and possible mechanisms of oral edaravone on the middle cerebral artery occlusion (MCAO) model in rats. Highly bioavailable form of novel edaravone formulation developed using self-nanomicellizing solid dispersion strategy which showed up to 16.1-fold improved oral bioavailability was considered oral edaravone. The male rats (n = 84) were randomly divided into sham; model; oral edaravone in low dose (10 mg/kg), medium dose (20 mg/kg), and high dose (30 mg/kg); and edaravone by intraperitoneal administration group (IP group, 10 mg/kg). Rats were treated with different drugs 5 h after the operation, twice a day for 7 days. The behavioral data were dose-dependently improved by oral edaravone and sensorimotor functions of the high dose group were similar to those of the edaravone by IP route group. Furthermore, oral edaravone significantly reduced cerebral infarction area and downregulated the levels of caspase-3, GFAP, Iba1, 3-NT, and 4-HNE, whereas upregulated those of Vamp-2 and Map-2 in a dose-dependent manner. Especially effect of the high dose on these molecules was equal to that of edaravone by IP administration. Taken together, our data suggest that the improvement of sensorimotor deficits by oral edaravone in high doses after ischemia is similar to that in edaravone by IP administration. Neuroprotection of oral edaravone is at least partial by minimizing oxidative stress, the overactivation of glial cells, and the levels of the apoptosis-associated proteins, and alleviating synaptic damage in a dose-dependent manner. [ABSTRACT FROM AUTHOR]

Bromelain (Br), a mixture of proteolytic enzymes from pineapple (Ananas comosus), has various therapeutic potentials; however, its low bioavailability has limited the clinical applications specifically in oral delivery as the most common convenient used route of administration. In the present study, a lipopolymeric nanoparticle (NP) containing Br was developed to enhance its stability and oral delivery efficiency. Firstly, Br was loaded into poly (D, L-lactide-co-glycolide acid) (PLGA) and PLGA-phosphatidylcholine (PLGA-PC) NPs using double emulsion solvent evaporation technique. Then, Br integrity and activity were investigated using SDS-PAGE and gelatin test. The stability and release profile of Br from synthetized NPs were evaluated at different pH values of the digestive system. Furthermore, cytotoxicity, cellular uptake, and the amount of Br passage from Caco-2 cells were explored. The results showed PLGA-PC-Br NPs had higher encapsulation efficiency (83%) compared to PLGA-Br NPs (50%). In addition, this NP showed more Br released in neutral (20.36%) and acidic (34%) environments compared to PLGA-Br NPs after 5 days. The delay in the release of Br from PLGA-PC-Br NPs versus the faster release of Br from PLGA-Br formulation could assure that an appropriate concentration of Br has reached the intestine. Intestinal absorption study demonstrated that lipid polymer NPs were able to pass through Caco-2 cells about 1.5 times more (98.4%) than polymeric NPs (70%). In conclusion, PLGA-PC NPs would be considered as a promising lipid-polymer nanocarrier for effective intestinal absorption of Br. [ABSTRACT FROM AUTHOR]

Both sublingual (SL) and oral vaccine administration modalities are convenient, easy, and safe. Here, we have investigated the differences in vaccine efficacy that are induced by oral and sublingual immunization with live influenza virus (A/Hong Kong/1/1968, H3N2) in mice. Intranasally administering a lethal dose of the influenza virus resulted in the deaths of the mice, whereas viral replication in the lungs did not occur upon SL or oral administration. At 30 days post-immunization through the SL or oral route, the mice were intranasally challenge-infected with the lethal dose of the homologous influenza virus. Both SL and oral immunizations with the influenza virus elicited significantly higher levels of virus-specific IgG and IgA antibody responses, as well as HAI titers in the sera. Upon challenge infection, the SL immunization elicited higher levels of pulmonary IgG antibody and CD8+ T cell responses than the oral immunization. Enhanced splenic germinal center B (GC B) and B cell proliferation were also detected from the SL immunization, both of which were significantly greater than those of the oral immunization. Importantly, compared to oral immunization, significantly lessened lung viral loads and bodyweight reductions were observed from the SL immunization and these parameters contributed to prolonging the survival of the immunized mice. These results indicate that both SL and oral administration could be effective routes in inducing protective immunity against influenza virus infection, with SL immunization being the better of the two delivery routes. [ABSTRACT FROM AUTHOR]

Kiteplatin, [PtCl2(cis-1,4-DACH)] (DACH = diaminocyclohexane), contains an isomeric form of the oxaliplatin diamine ligand trans-1R,2R-DACH and has been proposed as a valuable drug candidate against cisplatin- and oxaliplatin-resistant tumors, in particular, colorectal cancer. To further improve the activity of kiteplatin, it has been transformed into a Pt(IV) prodrug by the addition of two benzoato groups in the axial positions. The new compound, cis,trans,cis-[PtCl2(OBz)2(cis-1,4-DACH)] (1; OBz = benzoate), showed cytotoxic activity at nanomolar concentration against a wide panel of human cancer cell lines. Based on these very promising results, the investigation has been extended to the in vivo activity of compound 1 in a Lewis Lung Carcinoma (LLC) model and its suitability for oral administration. Compound 1 resulted to be remarkably stable in acidic conditions (pH 1.5 to mimic the stomach environment) undergoing a drop of the initial concentration to ~60% of the initial one only after 72 h incubation at 37 °C; thus resulting amenable for oral administration. Interestingly, in a murine model (2·106 LLC cells implanted i.m. into the right hind leg of 8-week old male and female C57BL mice), a comparable reduction of tumor mass (~75%) was observed by administering compound 1 by oral gavage and the standard drug cisplatin by intraperitoneal injection, thus indicating that, indeed, there is the possibility of oral administration for this dibenzoato prodrug of kiteplatin. Moreover, since the mechanism of action of Pt(IV) prodrugs involves an initial activation by chemical reduction to cytotoxic Pt(II) species, the reduction of 1 by two bioreductants (ascorbic acid/sodium ascorbate and glutathione) was investigated resulting to be rather slow (not complete after 120 h incubation at 37 °C). Finally, the neurotoxicity of 1 was evaluated using an in vitro assay. [ABSTRACT FROM AUTHOR]

Hepatocyte growth factor (HGF) has been investigated as a regulator for immune reactions caused by transplantation and autoimmune diseases and other biological functions. Previous studies demonstrated that cDNA-encoding HGF administration could inhibit acute graft-versus-host disease (GVHD) after treatment via hematopoietic stem cell transplantation. This study aimed to show the preparation of HGF protein on yeast cell surfaces to develop a tool for the oral administration of HGF to a GVHD mouse model. In this study, full-length HGF and the heavy chain of HGF were genetically fused with α-agglutinin and were successfully displayed on the yeast cell surface. This study suggested that yeast cell surface display engineering could provide a novel administration route for HGF. [ABSTRACT FROM AUTHOR]

Obesity-related diseases are always the major health problems that concern the whole world. Serial studies have reported that obesity development is closely related to the out-of-control leptin encoded by the obesity gene (ob). The latest report declaimed "Less Is More," a model explaining that partial leptin reduction triggers leptin sensitization and contributes to obesity control. Here, we came up with a novel concept, in vivo protein interference (iPRTi), an interesting protein knock-down strategy for in vivo partial leptin reduction. First, the specific immune response against leptin induced by the oral administration of ob recombinant yeast was confirmed. Subsequentally, leptin resistance was observed in diet-induced obese mice, and oral administration with ob recombinant yeast declined the circulating leptin and reduced significantly the body weight gain. To further investigate whether the iPRTi strategy is capable of obesity management, the diet-induced obese mice were administrated with ob recombinant yeast. All the indexes examined including the circulating leptin, triglyceride, and total cholesterol, as well as food intake and weight gain, demonstrated a positive effect of the iPRTi strategy on obesity control. In short, this study provides a novel strategy for the potential application of recombinant yeast for the therapy of obese individuals with leptin resistance. Oral administration of ob recombinant yeast mediated partial leptin reduction for diet-induced obesity control. When the whole yeast is uptaken by phagocytic cells in the gut, for example, dendritic cells, it is supposed to be lysed within the cells. The recombinant DNA vaccine cassette can be released, expressed, and further presented to lymphocytes, thereby activating the immune response. [ABSTRACT FROM AUTHOR]

A facile and robust microfluidic method to produce nanoparticle-in-microparticle systems (Trojan systems) is reported as a delivery vector for the oral administration of active pharmaceutical ingredients. The microfluidic system is based on two coaxial capillaries that produce monodisperse water-in-oil-in-water (W/O/W) double emulsions in a highly controlled fashion with precise control over the resulting particle structure, including the core and shell dimensions. The influence of the three phase flow rates, pH and drying process on the formation and overall size is evaluated. These droplets are then used as templates for the production of pH-sensitive Trojan microparticles after solvent evaporation. The shell of Trojan microparticles is made of Eudragit®, a methacrylic acid-ethyl acrylate copolymer that would enable the Trojan microparticle payload to first pass through the stomach without being degraded and then dissolve in the intestinal fluid, releasing the inner payload. The synthesis of the pH-sensitive Trojan microparticles was also compared with a conventional batch production method. The payloads considered in this work were different in nature: (1) fluorescein, to validate the feasibility of the polymeric shell to protect the payload under gastric pH; (2) poly(D,L-lactic acid/glycolic acid)-PLGA nanoparticles loaded with the antibiotic rifampicin. These PLGA nanoparticles were produced also using a microfluidic continuous process and (3) PLGA nanoparticles loaded with Au nanoparticles to trace the PLGA formulation under different environments (gastric and intestinal), and to assess whether active pharmaceutical ingredient (API) encapsulation in PLGA is due efficiently. We further showed that Trojan microparticles released the embedded PLGA nanoparticles in contact with suitable media, as confirmed by electron microscopy. Finally, the results show the possibility of developing Trojan microparticles in a continuous manner with the ability to deliver therapeutic nanoparticles in the gastrointestinal tract. [ABSTRACT FROM AUTHOR]