Development of Liposome Systems for Enhancing the PK Properties of Bivalent PROTACs.

Proteolysis-Targeting Chimeras (PROTACs) are a promising new technology in drug development. They have rapidly evolved in recent years, with several of them in clinical trials. While most of these advances have been associated with monovalent protein degraders, bivalent PROTACs have also entered clinical trials, although progression to market has been limited. One of the reasons is the complex physicochemical properties of the heterobifunctional PROTACs. A promising strategy to improve pharmacokinetics of highly lipophilic compounds, such as PROTACs, is encapsulation in liposome systems. Here we describe liposome systems for intravenous administration to enhance the PK properties of two bivalent PROTAC molecules, by reducing clearance and increasing systemic coverage. We developed and characterized a PROTAC-in-cyclodextrin liposome system where the drug was retained in the liposome core. In PK studies at 1 mg/kg for GNE-01 the PROTAC-in-cyclodextrin liposome, compared to the solution formulation, showed a 80- and a 380-fold enhancement in AUC for mouse and rat studies, respectively. We further investigated the same PROTAC-in-cyclodextrin liposome system with the second PROTAC (GNE-02), where we monitored both lipid and drug concentrations in vivo. Similarly, in a mouse PK study of GEN-02, the PROTAC-in-cyclodextrin liposome system exhibited enhancement in plasma concentration of a 23× increase over the conventional solution formulation. Importantly, the lipid CL correlated with the drug CL. Additionally, we investigated a conventional liposome approach for GNE-02, where the PROTAC resides in the lipid bilayer. Here, a 5× increase in AUC was observed, compared to the conventional solution formulation, and the drug CL was faster than the lipid CL. These results indicate that the different liposome systems can be tailored to translate across multiple PROTAC systems to modulate and improve plasma concentrations. Optimization of the liposomes could further improve tumor concentration and improve the overall therapeutic index (TI). This delivery technology may be well suited to bring novel protein targeted PROTACs into clinics.

Electrocatalytic hydrogen evolution from water by a series of iron carbonyl clusters.

The development of efficient hydrogen evolving electrocatalysts that operate near neutral pH in aqueous solution remains of significant interest. A series of low-valent iron clusters have been investigated to provide insight into the structure-function relationships affecting their ability to promote formation of cluster-hydride intermediates and to promote electrocatalytic hydrogen evolution from water. Each of the metal carbonyl anions, [Fe4N(CO)12](-) (1(-)), [Fe4C(CO)12](2-) (2(2-)), [Fe5C(CO)15](2-) (3(2-)), and [Fe6C(CO)18](2-) (4(2-)) were isolated as their sodium salt to provide the necessary solubility in water. At pH 5 and -1.25 V vs SCE the clusters afford hydrogen with Faradaic efficiencies ranging from 53-98%. pH dependent cyclic voltammetry measurements provide insight into catalytic intermediates. Both of the butterfly shaped clusters, 1(-) and 2(2-), stabilize protonated adducts and are effective catalysts. Initial reduction of butterfly shaped 1(-) is pH-independent and subsequently, successive protonation events afford H1(-), and then hydrogen. In contrast, butterfly shaped 2(2-) undergoes two successive proton coupled electron transfer events to form H22(2-) which then liberates hydrogen. The higher nuclearity clusters, 3(2-) and 4(2-), do not display the same ability to associate with protons, and accordingly, they produce hydrogen less efficiently.

Olfactory sulcal depth and olfactory bulb volume in patients with schizophrenia: an MRI study.

The current report used structural magnetic resonance imaging (MRI) to objectively measure olfactory bulb volume and olfactory sulcal depth in patients diagnosed with chronic schizophrenia and healthy controls. Additional measures were obtained to assess olfactory function. The olfactory bulb and sulcus were manually traced on structural 3T MRIs for 25 right-handed male patients diagnosed with chronic schizophrenia and 25 matched male healthy controls. A sub-set of subjects received the University of Pennsylvania Smell Identification Test (UPSIT). Olfactory bulb volume was significantly decreased in patients with schizophrenia compared to healthy controls, as was their performance on the UPSIT. Additionally, a positive correlation was seen in patients between right bulb volume and UPSIT scores. Overall, our findings support earlier research studies showing morphometric and functional changes in the olfactory system in patients with schizophrenia.

Risk factors associated with fecal Salmonella shedding among hospitalized horses with signs of gastrointestinal tract disease.

OBJECTIVE: To estimate prevalence of and identify risk factors for fecal Salmonella shedding among hospitalized horses with signs of gastrointestinal tract disease. DESIGN: Cross-sectional study. ANIMALS: 465 hospitalized horses with gastrointestinal tract disease. PROCEDURE: Horses were classified as positive or negative for fecal Salmonella shedding during hospitalization by means of standard aerobic bacteriologic methods. The relationship between investigated exposure factors and fecal Salmonella shedding was examined by means of logistic regression. RESULTS: The overall prevalence of fecal Salmonella shedding was 13%. Salmonella serotype Newport was the most commonly isolated serotype (12/60 [20%]), followed by Anatum (8/60 [13%]), Java (13%), and Saint-paul (13%). Foals with gastrointestinal tract disease were 3.27 times as likely to be shedding Salmonella organisms as were adult horses with gastrointestinal tract disease. Adult horses that had been treated with antimicrobial drugs prior to hospitalization were 3.09 times as likely to be shedding Salmonella organisms as were adult horses that had not been treated with antimicrobial drugs prior to hospitalization. Adult horses that underwent abdominal surgery were 2.09 times as likely to be shedding Salmonella organisms as were adult horses that did not undergo abdominal surgery. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that a history of exposure to antimicrobial drugs prior to hospitalization and abdominal surgery during hospitalization were associated with Salmonella shedding in adult horses with gastrointestinal tract disease. Foals with gastrointestinal tract disease were more likely to shed Salmonella organisms than were adult horses with gastrointestinal tract disease.