The immunological and pharmacokinetic evaluation of Lipid-PLGA hybrid nanoparticle-based oxycodone vaccines.

The current opioid epidemic is one of the most profound public health crises facing the United States. Despite that it has been under the spotlight for years, available treatments for opioid use disorder (OUD) and overdose are limited to opioid receptor ligands such as the agonist methadone and the overdose reversing drugs such as naloxone. Vaccines are emerging as an alternative strategy to combat OUD and prevent relapse and overdose.

Effect of chlorpyrifos on VEGF gene expression.

Chlorpyrifos (CPF; 0,0-diethyl 0-(3,5,6-trichloro-2-pyridinyl)-phosphorothioate), a cholinesterase inhibitor, compromised the integrity of the blood-brain barrier (BBB) when used at low concentrations during our previous experiments in vitro. To determine if BBB leakage would also occur in vivo, we used FITC-dextrans to evaluate BBB permeability in CPF-dosed mice. Results indicated BBB leakages that were evident at 2 h after treatment with 70 mg/kg CPF ip.

Effects of chlorpyrifos on transient receptor potential channels.

The well-known toxicity of chlorpyrifos (CPF) occurs via inhibition of cholinesterase (ChE), but in recent years the detrimental effects of low-dose CPF exposure have been attributed to an unknown non-cholinergic mechanism of action. We previously showed that CPF can alter gene expression of transient receptor potential canonical (TRPC) channels in vitro. In this study, we analyzed the gene expression of TRPCs at various time points after CPF treatment in vivo.

Intracellular potassium depletion enhances apoptosis induced by staurosporine in cultured trigeminal satellite glial cells.

Purpose: Satellite glial cells (SGC) surrounding neurons in sensory ganglia can buffer extracellular potassium, regulating the excitability of injured neurons and possibly influencing a shift from acute to neuropathic pain. SGC apoptosis may be a key component in this process. This work evaluated induction or enhancement of apoptosis in cultured trigeminal SGC following changes in intracellular potassium [K]ic.

Formulation of Nanovaccines toward an Extended Immunity against Nicotine.

Nicotine vaccines have been investigated to assist with smoking cessation. Because smoking cessation is a long process, past nicotine vaccines required multiple injections to achieve long-term efficacy. It would be of great significance if extended efficacy can be achieved with fewer injections.

Effects of polyhydroxyfullerenes on organophosphate-induced toxicity in mice.

Two polyhydroxyfullerenes, which decrease organophosphate (OP)-induced acetylcholinesterase (AChE) inhibition in vitro, were administered by the intraperitoneal (ip) route or applied topically at doses of 0.9-24 mg/kg to protect adult male mice from enzyme-inhibiting and behavioral effects indicative of OP toxicity resulting from exposure to 1.7 - 2 mg/kg diphosphorofluoridate (DFP) ip or 2.

Studies Exploring the Interaction of the Organophosphorus Compound Paraoxon with Fullerenes.

In vitro experiments previously published demonstrated the ability of fullerenes to decrease the capability of organophosphorus (OP) compounds to inhibit acetylcholinesterase. Experiments described herein demonstrate molecular level affinity interactions between fullerenes and the OP test compound paraoxon with NMR spectroscopy. The calculated binding constant of 19 M indicates that this binding was not covalent.

Exploratory studies with NX-13: oral toxicity and pharmacokinetics in rodents of an orally active, gut-restricted first-in-class therapeutic for IBD that targets NLRX1.

Nucleotide-binding oligomerization domain, leucine rich repeat containing X1 (NLRX1) is an emerging therapeutic target for a spectrum of human diseases. NX-13 is a small molecule therapeutic designed to target and activate NLRX1 to induce immunometabolic changes resulting in lower inflammation and therapeutic responses in inflammatory bowel disease (IBD). This study investigates the safety of NX-13 in a seven-day, repeat-dose general toxicity study in male and female Sprague Dawley rats at oral doses of 500 and 1000 mg/kg.

Iridium piano stool complexes with activity against and MRSA: it is past time to truly think outside of the box.

A new class of piano-stool iridium complexes with 1,2-diaminoethane ligands are shown to be effective and safe antimicrobials with activity against , including various isolates of methicillin-resistant strains (MRSA). Comparison to other piano stool complexes with activity against mycobacteria are made along with a discussion of structure-activity relationships. The structures of one the most active complexes with the ligand -1,2-diaminocyclohexane and one of the least active complexes with the ligand -1,2-diaminocyclohexane are compared and discussed with respect to their drastically different activities.

Alum as an adjuvant for nanoparticle based vaccines: A case study with a hybrid nanoparticle-based nicotine vaccine.

The treatment efficacy of a nicotine vaccine largely relies on its ability to induce high titers of nicotine-specific antibodies. Due to its strong immune-potentiating effects, aluminum salt (Alum) has been commonly used as an adjuvant in various nicotine vaccine formulations. In this study, we attempted to improve the immunological performance of a hybrid nanoparticle-based nicotine vaccine (NanoNicVac) by co-administering it with Alum.

The Safety, Tolerability, and Pharmacokinetics Profile of BT-11, an Oral, Gut-Restricted Lanthionine Synthetase C-Like 2 Agonist Investigational New Drug for Inflammatory Bowel Disease: A Randomized, Double-Blind, Placebo-Controlled Phase I Clinical Trial.

BT-11 is a new oral, gut-restricted, first-in-class investigational drug for Crohn disease (CD) and ulcerative colitis (UC) that targets the lanthionine synthetase C-like 2 (LANCL2) pathway and immunometabolic mechanisms. Oral BT-11 was assessed for safety, tolerability, and pharmacokinetics (PK) in normal healthy volunteers (n = 70) in a randomized, double-blind, placebo-controlled trial. Subjects (n = 70) were randomly assigned to one of five single ascending dose cohorts (up to 100 mg/kg, p.

Effect of Adjuvant Release Rate on the Immunogenicity of Nanoparticle-Based Vaccines: A Case Study with a Nanoparticle-Based Nicotine Vaccine.

Adjuvants are a critical component for vaccines, especially for a poorly immunogenic antigen, such as nicotine. However, the impact of adjuvant release rate from a vaccine formulation on its immunogenicity has not been well illustrated. In this study, we fabricated a series of hybrid-nanoparticle-based nicotine vaccines to study the impact of adjuvant release rate on their immunological efficacy.

Nonclinical Toxicology and Toxicokinetic Profile of an Oral Lanthionine Synthetase C-Like 2 (LANCL2) Agonist, BT-11.

BT-11 is an orally active, gut-restricted investigational therapeutic targeting the lanthionine synthetase C-like 2 pathway with lead indications in ulcerative colitis (UC) and Crohn disease (CD), 2 manifestations of inflammatory bowel disease (IBD). In 5 mouse models of IBD, BT-11 is effective at oral doses of 8 mg/kg. BT-11 was also efficacious at nanomolar concentrations in primary human samples from patients with UC and CD.

Paradox of PEGylation in fabricating hybrid nanoparticle-based nicotine vaccines.

Polyethylene glycol (PEG) has long been used in nanoparticle-based drug or vaccine delivery platforms. In this study, nano-nicotine vaccines (NanoNicVac) were PEGylated to different degrees to investigate the impact of PEG on the immunological efficacy of the vaccine. Hybrid nanoparticles with various degrees of PEGylation (2.

Hybrid nanoparticle-based nicotine nanovaccines: Boosting the immunological efficacy by conjugation of potent carrier proteins.

A series of hybrid nanoparticle-based nicotine nanovaccines (NanoNicVac) were engineered in this work by conjugating potent carrier protein candidates (Keyhole limpet hemocyanin (KLH) multimer, KLH subunit, cross-reactive material 197 (CRM), or tetanus toxoid (TT)) for enhanced immunological efficacy. NanoNicVac with CRM or TT were processed by dendritic cells more efficiently than that with KLH multimer or subunit. NanoNicVac carrying CRM or TT exhibited a significantly higher immunogenicity against nicotine and a considerably lower immunogenicity against carrier proteins than NanoNicVac carrying KLH multimer or subunit in mice.

Synthesis and Evaluation of Doxorubicin-Loaded Gold Nanoparticles for Tumor-Targeted Drug Delivery.

Doxorubicin is an effective and widely used cancer chemotherapeutic agent, but its application is greatly compromised by its cumulative dose-dependent side effect of cardiotoxicity. A gold nanoparticle-based drug delivery system has been designed to overcome this limitation. Five novel thiolated doxorubicin analogs were synthesized and their biological activities evaluated.

Rational incorporation of molecular adjuvants into a hybrid nanoparticle-based nicotine vaccine for immunotherapy against nicotine addiction.

Current clinically-tested nicotine vaccines have yet shown enhanced smoking cessation efficacy due to their low immunogenicity. Achieving a sufficiently high immunogenicity is a necessity for establishing a clinically-viable nicotine vaccine. This study aims to facilitate the immunogenicity of a hybrid nanoparticle-based nicotine vaccine by rationally incorporating toll-like receptor (TLR)-based adjuvants, including monophosphoryl lipid A (MPLA), Resiquimod (R848), CpG oligodeoxynucleotide 1826 (CpG ODN 1826), and their combinations.

Rationalization of a nanoparticle-based nicotine nanovaccine as an effective next-generation nicotine vaccine: A focus on hapten localization.

A lipid-polymeric hybrid nanoparticle-based next-generation nicotine nanovaccine was rationalized in this study to combat nicotine addiction. A series of nanovaccines, which had nicotine-haptens localized on carrier protein (LPKN), nanoparticle surface (LPNK), or both (LPNKN), were designed to study the impact of hapten localization on their immunological efficacy. All three nanovaccines were efficiently taken up and processed by dendritic cells.

Cerium oxide nanoparticles in neuroprotection and considerations for efficacy and safety.

Cerium oxide nanoparticles have widespread use in the materials industry, and have recently come into consideration for biomedical use due to their potent regenerative antioxidant properties. Given that the brain is one of the most highly oxidative organs in the body, it is subject to some of the greatest levels of oxidative stress, particularly in neurodegenerative disease. Therefore, cerium oxide nanoparticles are currently being investigated for efficacy in several neurodegenerative disorders and have shown promising levels of neuroprotection.

The next-generation nicotine vaccine: a novel and potent hybrid nanoparticle-based nicotine vaccine.

Owing to the urgent need for more effective treatment against nicotine addiction, a hybrid nanoparticle-based nicotine vaccine (NanoNiccine) was developed in this study. NanoNiccine was composed of a poly(lactide-co-glycolide) acid (PLGA) core, keyhole limpet hemocyanin (KLH) as an adjuvant protein enclosed within the PLGA core, a lipid layer, and nicotine haptens conjugated to the outer surface of the lipid layer. In contrast to the traditional nicotine vaccine, NanoNiccine is not a nicotine-protein conjugate vaccine.

Exploratory Studies With BT-11: A Proposed Orally Active Therapeutic for Crohn's Disease.

Lanthionine synthetase cyclase-like receptor 2 (LANCL2) is a novel therapeutic target for Crohn's disease (CD). BT-11 is a small molecule that binds LANCL2, is orally active, and has demonstrated therapeutic efficacy in 3 validated mouse models of colitis at doses as low as 8 mg/kg/d. Exploratory experiments evaluated BT-11 in male Harlan Sprague Dawley rats with a single oral dose of 500 mg/kg and 80 mg/kg/d for 14 days (n = 10 rats dosed/group).

controlled release of antigen in dendritic cells using pH-sensitive liposome-polymeric hybrid nanoparticles.

A hybrid nanoparticle (NP) consisting of a pH sensitive lipid shell and a poly(lactic-co-glycolic) acid (PLGA) core was constructed. This hybrid NP has a mean size of 120.1 ± 8.