Evaluating the rate of reversal of fentanyl-induced respiratory depression using a novel long-acting naloxone nanoparticle, cNLX-NP.

Introduction: Fentanyl and fentanyl analogs (F/FA) have become increasingly common adulterants in counterfeit prescription pills and illicit street drug mixtures due to their ease of synthesis and exceedingly high potency. The ongoing epidemic of fatal overdoses fueled by F/FA continues to highlight the need for longer-acting therapies than naloxone (NLX), the current gold-standard for reversing opioid overdoses, which shows limited efficacy to prevent renarcotization associated with F/FA toxicity. A novel opioid reversal agent based on covalent naloxone nanoparticles (cNLX-NP) has been shown to blunt fentanyl-induced respiratory depression out to 48 hr, demonstrating its potential therapeutic utility.

Multivalent Vaccination Strategies Protect against Exposure to Polydrug Opioid and Stimulant Mixtures in Mice and Rats.

Illicit drug mixtures containing opioids and stimulants have been responsible for the majority of fatal drug overdoses among occasional users, and those with either opioid use disorder (OUD) or substance use disorder (SUD). As a complementary strategy to current pharmacotherapies, active immunization with conjugate vaccines has been proposed as a viable intervention to treat OUD as well as other SUD for which there are either limited or no treatment options. Vaccination against opioids and stimulants could help address the limitations of current medications (e.

Anti-Strychnine Immunoconjugate Reduces the Effects of Strychnine-Induced Toxicity in Mice.

Strychnine poisoning induces seizures that result in loss of control of airway muscles, leading to asphyxiation and subsequent death. Current treatment options are limited, requiring hands-on medical care and isolation to low-stimulus environments. Anticonvulsants and muscle relaxants have shown limited success in cases of severe toxicity.

Temperature-Responsive Bottlebrush Polymers Deliver a Stress-Regulating Agent for Prolonged Plant Heat Stress Mitigation.

Anticipated increases in the frequency and intensity of extreme temperatures will damage crops. Methods that efficiently deliver stress-regulating agents to crops can mitigate these effects. Here, we describe high aspect ratio polymer bottlebrushes for temperature-controlled agent delivery in plants.

Preclinical Efficacy and Selectivity of Vaccines Targeting Fentanyl, Alfentanil, Sufentanil, and Acetylfentanyl in Rats.

The ongoing public health emergency of opioid use disorders (OUD) and overdose in the United States is largely driven by fentanyl and its related analogues and has resulted in over 75 673 deaths in 2021. Immunotherapeutics such as vaccines have been investigated as a potential interventional strategy complementary to current pharmacotherapies to reduce the incidence of OUD and opioid-related overdose. Given the importance of targeting structurally distinct fentanyl analogues, this study compared a previously established lead conjugate vaccine (F-CRM) to a series of novel vaccines incorporating haptens derived from alfentanil and acetylfentanyl (F), and evaluated their efficacy against drug-induced pharmacological effects in rats.

Dual pH-Responsive and Tumor-Targeted Nanoparticle-Mediated Anti-Angiogenesis siRNA Delivery for Tumor Treatment.

Purpose: In order to overcome the biological barriers at all levels and enhance the delivery efficiency of siRNA, we have prepared a multifunctional siRNA delivery system (CHCE/siRNA nanoparticles) through self-assembly of the carboxymethyl chitosan modified with histidine, cholesterol, and anti-EGFR antibody (CHCE).

Methods: The morphology of CHCE/siRNA NPs was detected by dynamic light scattering and scanning electron microscope. In vitro, we assessed the tumor-targeting, cellular uptake, and endosomal escape by flow cytometry and confocal laser scanning microscopy, confirming the CHCE/siRNA NPs functions in gene silencing and cell killing ability.

Grafting Polymer Brushes by ATRP from Functionalized Poly(ether ether ketone) Microparticles.

Poly(ether ether ketone) (PEEK) is a semi-crystalline thermoplastic with excellent mechanical and chemical properties. PEEK exhibits a high degree of resistance to thermal, chemical, and bio-degradation. PEEK is used as biomaterial in the field of orthopaedic and dental implants; however, due to its intrinsic hydrophobicity and inert surface, PEEK does not effectively support bone growth.

Covalent Attachment of P15 Peptide to Ti Alloy Surface Modified with Polymer to Enhance Osseointegration of Implants.

Titanium (Ti) and its alloys are used in orthopedic and dental implants due to their excellent physical properties and biocompatibility. Although Ti exhibits superior osteoconductive properties compared to those of polymer-based implants, improved bone-on growth properties are required for enhanced surgical outcomes and improved recovery surgical interventions. Herein, we demonstrate a novel surface modification strategy to enhance the osteoconductivity of Ti surfaces through the grafting-from procedure of a reactive copolymer via surface-initiated atom transfer radical polymerization (SI-ATRP).

Cationic Hyperbranched Polymers with Biocompatible Shells for siRNA Delivery.

Cationic hyperbranched polymers (HBP) were prepared by self-condensing vinyl polymerization of an atom transfer radical polymerization (ATRP) inimer containing a quaternary ammonium group. Two types of biocompatible shells, poly(oligoethylene glycol) methacrylate (polyOEGMA) and poly(2-(methylsulfinyl) ethyl methacrylate) (polyDMSO), were grafted respectively from HBP core to form core-shell structures with low molecular weight dispersity and high biocompatibility, polyOEGMA-HBP and polyDMSO-HBP. Both of the structures showed low cytotoxicity and good siRNA complexing ability.

Iron Oxide Nanoparticles with Grafted Polymeric Analogue of Dimethyl Sulfoxide as Potential Magnetic Resonance Imaging Contrast Agents.

Novel water-dispersible hybrid iron oxide nanoparticles grafted with a polymeric analogue of dimethyl sulfoxide (DMSO) were prepared. Superparamagnetic iron oxide nanoparticles with immobilized atom-transfer radical polymerization (ATRP) initiators were prepared via an in situ method using 12-(2-bromoisobutyramido)dodecanoic acid as a surface ligand/initiator. The initiator-functionalized particles were employed in a surface-initiated initiator for continuous activator regeneration ATRP to graft poly(2-(methylsulfinyl)ethyl acrylate) (a polyacrylate analogue of DMSO) from the surface.

Nanogel-Mediated RNAi Against Runx2 and Osx Inhibits Osteogenic Differentiation in Constitutively Active BMPR1A Osteoblasts.

Trauma-induced heterotopic ossification (HO) and fibrodysplasia ossificans progressiva (FOP) are acquired and genetic variants of pathological bone formation occurring in soft tissues. Conventional treatment modalities target the inflammatory processes preceding bone formation. We investigated the development of a prophylaxis for heterotopic bone formation by addressing the biological basis for HO - dysregulation in the bone morphogenetic protein (BMP) signaling pathway.

Synthesis of poly(meth)acrylates with thioether and tertiary sulfonium groups by ARGET ATRP and their use as siRNA delivery agents.

The field of RNA interference depends on the development of safe and efficient carriers for short interfering ribonucleic acid (siRNA) delivery. Conventional cationic monomers for siRNA delivery have utilized the nitrogen heteroatom to produce cationic charges. Here, we polymerized cationic sulfonium (meth)acrylate by activators regenerated by electron transfer (ARGET) atom transfer radical polymerization (ATRP) to form polymers with narrow molecular weight distributions for siRNA delivery.

Cationic nanostructured polymers for siRNA delivery in murine calvarial pre-osteoblasts.

The endogenous RNA interference (RNAi) pathway enables control of pathologies caused by the dysregulation of proteins. Several biological molecules are active in RNAi including short interfering ribonucleic acid (siRNA). The effective utilization of siRNA as a therapeutic agent has been marked with distinct challenges, namely in intracellular delivery and achieving a sufficient dosage to affect protein expression.

Solid-phase incorporation of an ATRP initiator for polymer-DNA biohybrids.

The combination of polymers with nucleic acids leads to materials with significantly advanced properties. To obviate the necessity and complexity of conjugating two macromolecules, a polymer initiator is described that can be directly covalently linked to DNA during solid-phase synthesis. Polymer can then be grown from the DNA bound initiator, both in solution after the DNA-initiator is released from the solid support as well as directly on the solid support, simplifying purification.

Autotransfecting short interfering RNA through facile covalent polymer escorts.

Short interfering ribonucleic acids (siRNAs) are important agents for RNA interference (RNAi) that have proven useful in gene function studies and therapeutic applications. However, the efficacy of exogenous siRNAs for gene knockdown remains hampered by their susceptibility to cellular nucleases and impermeability to cell membranes. We report here new covalent polymer-escort siRNA constructs that address both of these constraints simultaneously.

Star polymers with a cationic core prepared by ATRP for cellular nucleic acids delivery.

Poly(ethylene glycol) (PEG)-based star polymers with a cationic core were prepared by atom transfer radical polymerization (ATRP) for in vitro nucleic acid (NA) delivery. The star polymers were synthesized by ATRP of 2-(dimethylamino)ethyl methacrylate (DMAEMA) and ethylene glycol dimethacrylate (EGDMA). Star polymers were characterized by gel permeation chromatography, zeta potential, and dynamic light scattering.

Preparation of cationic nanogels for nucleic acid delivery.

Cationic nanogels with site-selected functionality were designed for the delivery of nucleic acid payloads targeting numerous therapeutic applications. Functional cationic nanogels containing quaternized 2-(dimethylamino)ethyl methacrylate and a cross-linker with reducible disulfide moieties (qNG) were prepared by activators generated by electron transfer (AGET) atom transfer radical polymerization (ATRP) in an inverse miniemulsion. Polyplex formation between the qNG and nucleic acid exemplified by plasmid DNA (pDNA) and short interfering RNA (siRNA duplexes) were evaluated.

A protein-polymer hybrid mediated by DNA.

Protein-polymer hybrids (PPHs) represent an important and rapidly expanding class of biomaterials. Typically in these hybrids the linkage between the protein and the polymer is covalent. Here we describe a straightforward approach to a noncovalent PPH that is mediated by DNA.