Islatravir Dimer: Crystal Form Dependence of a Radiation-Induced Degradation Product.

A rare example of crystal form-dependent, gamma radiation-induced degradation is presented. Islatravir is known to exist in several polymorphic forms, but only one of these forms shows the generation of a specific dimer degradation product under gamma irradiation. Extended gamma irradiation studies demonstrated that only one of the known crystalline forms shows an appreciable rate of dimer formation. Additionally, this dimer is not observed to form under other forced stress conditions. We present the structural elucidation of this dimer impurity and rationalize its form-dependent generation based on the analysis of the underlying crystal structure.

Expansile Nanoparticles Encapsulate Factor Quinolinone Inhibitor 1 and Accumulate in Murine Liver upon Intravenous Administration.

Expansile nanoparticles (eNPs) are a promising pH-responsive polymeric drug delivery vehicle, as demonstrated in multiple intraperitoneal cancer models. However, previous delivery routes were limited to intraperitoneal injection and to a single agent, paclitaxel. In this study, we preliminarily evaluate the biodistribution and in vivo toxicity of eNPs in mice after intravenous injection. The eNPs localize predominantly to the liver, without detectable acute toxicity in the liver or other key organs. On the basis of these results, we encapsulated FQI1, a promising lead compound for treatment of hepatocellular carcinoma, in eNPs. eNPs are taken up by cancerous and noncancerous human liver cells in vitro, although at different rates. FQI1-loaded eNPs release FQI1 in a pH-dependent manner and limit proliferation equivalently to unencapsulated FQI1 in immortalized hepatocytes in vitro. eNPs are a versatile platform delivery system for therapeutic compounds and have potential utility in the treatment of liver disease.

Poly(Alkyl Glycidate Carbonate)s as Degradable Pressure-Sensitive Adhesives.

Insertion of CO2 into the polyacrylate backbone, forming poly(carbonate) analogues, provides an environmentally friendly and biocompatible alternative. The synthesis of five poly(carbonate) analogues of poly(methyl acrylate), poly(ethyl acrylate), and poly(butyl acrylate) is described. The polymers are prepared using the salen cobalt(III) complex catalyzed copolymerization of CO2 and a derivatized oxirane. All the carbonate analogues possess higher glass-transition temperatures (Tg =32 to -5 °C) than alkyl acrylates (Tg =10 to -50 °C), however, the carbonate analogues (Td ≈230 °C) undergo thermal decomposition at lower temperatures than their acrylate counterparts (Td ≈380 °C). The poly(alkyl carbonates) exhibit compositional-dependent adhesivity. The poly(carbonate) analogues degrade into glycerol, alcohol, and CO2 in a time- and pH-dependent manner with the rate of degradation accelerated at higher pH conditions, in contrast to poly(acrylate)s.

Synthesis and Characterization of Hybrid Polymer/Lipid Expansile Nanoparticles: Imparting Surface Functionality for Targeting and Stability.

The size, drug loading, drug release kinetics, localization, biodistribution, and stability of a given polymeric nanoparticle (NP) system depend on the composition of the NP core as well as its surface properties. In this study, novel, pH-responsive, and lipid-coated NPs, which expand in size from a diameter of approximately 100 to 1000 nm in the presence of a mildly acidic pH environment, are synthesized and characterized. Specifically, a combined miniemulsion and free-radical polymerization method is used to prepare the NPs in the presence of PEGylated lipids. These PEGylated-lipid expansile NPs (PEG-L-eNPs) combine the swelling behavior of the polymeric core of expansile NPs with the improved colloidal stability and surface functionality of PEGylated liposomes. The surface functionality of PEG-L-eNPs allows for the incorporation of folic acid (FA) and folate receptor-targeting. The resulting hybrid polymer/lipid nanocarriers, FA-PEG-L-eNPs, exhibit greater in vitro uptake and potency when loaded with paclitaxel compared to nontargeted PEG-L-eNPs.

Ultra-high drug loading improves nanoparticle efficacy against peritoneal mesothelioma.

Peritoneal mesothelioma is an aggressive disease with a median survival of under three years, due to a lack of effective treatment options. Mesothelioma is traditionally considered a "chemoresistant" tumor; however, low intratumoral drug levels coupled with the inability to administer high systemic doses suggests that therapeutic resistance may be due to poor drug delivery rather than inherent biology. While patient survival may improve with repetitive local intraperitoneal infusions of chemotherapy throughout the perioperative period, these regimens carry associated toxicities and significant peri-operative morbidity. To circumvent these issues, we describe ultra-high drug loaded nanoparticles (NPs) composed of a unique poly(1,2-glycerol carbonate)-graft-succinate-paclitaxel (PGC-PTX + PTX) conjugate. PGC-PTX + PTX NPs are cytotoxic, localize to tumor in vivo, and improve survival in a murine model of human peritoneal mesothelioma after a single intraperitoneal (IP) injection compared to multiple weekly doses of the clinically utilized formulation PTX-C/E. Given their unique pharmacokinetics, a second intraperitoneal dose of PGC-PTX + PTX NPs one month later more than doubles the overall survival compared to the clinical control (122 versus 58 days). These results validate the clinical potential of prolonged local paclitaxel to treat intracavitary malignancies such as mesothelioma using a tailored polymer-mediated nanoparticle formulation.

Polymer-drug conjugate therapeutics: advances, insights and prospects.

Polymer-drug conjugates have long been a mainstay of the drug delivery field, with several conjugates successfully translated into clinical practice. The conjugation of therapeutic agents to polymeric carriers, such as polyethylene glycol, offers several advantages, including improved drug solubilization, prolonged circulation, reduced immunogenicity, controlled release and enhanced safety. In this Review, we discuss the rational design, physicochemical characteristics and recent advances in the development of different classes of polymer-drug conjugates, including polymer-protein and polymer-small-molecule drug conjugates, dendrimers, polymer nanoparticles and multifunctional systems. Current obstacles hampering the clinical translation of polymer-drug conjugate therapeutics and future prospects are also presented.

Reinforcement of polymeric nanoassemblies for ultra-high drug loadings, modulation of stiffness and release kinetics, and sustained therapeutic efficacy.

The optimization of current polymeric nanoparticle therapies is restricted by low drug loadings and limited tunability of core properties. To overcome these shortcomings, a novel self-association approach is utilized to fabricate a dual-loaded poly(1,2-glycerol carbonate)-graft-succinic acid-paclitaxel (PGC-PTX) conjugate nanoparticle (NP) in which the physical entrapment of free paclitaxel (PTX) affords unprecedented ultra-high drug loadings >100 wt%, modulation of mechanical stiffness, and tunable release kinetics. Despite high incorporation of free PTX (up to 50 wt%), the dual-loaded PGC-PTX nanocarriers (i.e., PGC-PTX + PTX NPs) exhibit controlled and sustained drug release over 15 days, without burst release effects. Importantly, optimization of drug/material efficiency concomitantly affords improved in vitro efficacy. In vivo, PGC-PTX + PTX NPs are safely administered at doses exceeding the median lethal dose of standard PTX, while a single high dose significantly extends survival relative to weekly PTX administrations in a murine model of peritoneal carcinomatosis.

Synthesis of poly(1,2-glycerol carbonate)-paclitaxel conjugates and their utility as a single high-dose replacement for multi-dose treatment regimens in peritoneal cancer.

Current chemotherapeutic dosing strategies are limited by the toxicity of anticancer agents and therefore rely on multiple low-dose administrations. As an alternative, we describe a novel sustained-release, biodegradable polymeric nanocarrier as a single administration replacement of multi-dose paclitaxel (PTX) treatment regimens. The first synthesis of poly(1,2-glycerol carbonate)-graft-succinic acid-paclitaxel (PGC-PTX) is described, and its use enables high, controlled PTX loadings of up to 74 wt%. Moreover, the polymer backbone is composed of biocompatible building blocks-glycerol and carbon dioxide. When formulated as nanoparticles (NPs), PGC-PTX NPs exhibit PTX concentrations >15 mg mL-1, sub-100 nm diameters, narrow dispersity, storage stability for up to 6 months, and sustained and controlled PTX release kinetics over an extended period of 70 days. A safely administered single dose of PGC-PTX NPs contains more PTX than the median lethal dose of standard PTX. In murine models of peritoneal carcinomatosis, in which the clinical implementation of multi-dose intraperitoneal (IP) treatment regimens is limited by catheter-related complications, PGC-PTX NPs exhibit improved safety at high doses, tumor localization, and efficacy even after a single IP injection, with comparable curative effect to PTX administered as a multi-dose IP treatment regimen.

Coordinated regulation of acid resistance in Escherichia coli.

BACKGROUND: Enteric Escherichia coli survives the highly acidic environment of the stomach through multiple acid resistance (AR) mechanisms. The most effective system, AR2, decarboxylates externally-derived glutamate to remove cytoplasmic protons and excrete GABA. The first described system, AR1, does not require an external amino acid. Its mechanism has not been determined. The regulation of the multiple AR systems and their coordination with broader cellular metabolism has not been fully explored. RESULTS: We utilized a combination of ChIP-Seq and gene expression analysis to experimentally map the regulatory interactions of four TFs: nac, ntrC, ompR, and csiR. Our data identified all previously in vivo confirmed direct interactions and revealed several others previously inferred from gene expression data. Our data demonstrate that nac and csiR directly modulate AR, and leads to a regulatory network model in which all four TFs participate in coordinating acid resistance, glutamate metabolism, and nitrogen metabolism. This model predicts a novel mechanism for AR1 by which the decarboxylation enzymes of AR2 are used with internally derived glutamate. This hypothesis makes several testable predictions that we confirmed experimentally. CONCLUSIONS: Our data suggest that the regulatory network underlying AR is complex and deeply interconnected with the regulation of GABA and glutamate metabolism, nitrogen metabolism. These connections underlie and experimentally validated model of AR1 in which the decarboxylation enzymes of AR2 are used with internally derived glutamate.