Characterization of Stealth Liposome-Based Nanoparticles Encapsulating the ACAT1/SOAT1 Inhibitor F26: Efficacy and Toxicity Studies In Vitro and in Wild-Type Mice.

Cholesterol homeostasis is pivotal for cellular function. Acyl-coenzyme A:cholesterol acyltransferase 1 (ACAT1), also abbreviated as SOAT1, is an enzyme responsible for catalyzing the storage of excess cholesterol to cholesteryl esters. ACAT1 is an emerging target to treat diverse diseases including atherosclerosis, cancer, and neurodegenerative diseases.

Pharmacokinetics and pharmacodynamics of Hedgehog pathway inhibitors used in the treatment of advanced or treatment-refractory basal cell carcinoma.

Introduction: Sonidegib and vismodegib are currently the only US Food and Drug Administration and European Medicines Agency-approved small-molecule Hedgehog pathway inhibitors (HHIs)for treating adults with advanced or refractory basal cell carcinoma (BCC) that is not amenable to conventional surgery or radiotherapy. At this time, there are no head-to-head clinical trials comparing these two HHIs for efficacy and safety to assist clinicians with determining which HHI may be best suited for their patients.

Areas Covered: This review briefly describes the pathogenesis of BCC, provides a detailed overview of the key pharmacokinetic profile differences between sonidegib and vismodegib, explains their pharmacodynamics, and highlights the therapeutic considerations when either HHI is used to treat special patient populations.

Stealth Liposomes Encapsulating a Potent ACAT1/SOAT1 Inhibitor F12511: Pharmacokinetic, Biodistribution, and Toxicity Studies in Wild-Type Mice and Efficacy Studies in Triple Transgenic Alzheimer's Disease Mice.

Cholesterol is essential for cellular function and is stored as cholesteryl esters (CEs). CEs biosynthesis is catalyzed by the enzymes acyl-CoA:cholesterol acyltransferase 1 and 2 (ACAT1 and ACAT2), with ACAT1 being the primary isoenzyme in most cells in humans. In Alzheimer's Disease, CEs accumulate in vulnerable brain regions.

A phase II study of alternating sunitinib and temsirolimus therapy in patients with metastatic renal cell carcinoma.

Background: Sunitinib is a multi-target tyrosine kinase inhibitor (TKI) that inhibits VEGF receptor 1, 2, 3 (VEGFRs), platelet-derived growth factor receptor (PDGFR), colony-stimulating factor receptor (CSFR), and the stem cell factor receptor c-KIT. Temsirolimus inhibits mammalian target of rapamycin (mTOR) through binding to intracellular protein FKBP-12. Both agents are approved for the treatment of metastatic renal cell carcinoma (mRCC), have different anticancer mechanisms, and non-overlapping toxicities.

Tumour, whole-blood, plasma and tissue concentrations of metformin in lung cancer patients.

Aim: Metformin is used for the management of type 2 diabetes mellitus (T2DM) and is being tested clinically as an anticancer agent. Metformin concentrations safely achievable in human solid tissues including tumours are unknown. This study was designed to determine metformin concentration in tissue compartments as a function of dose to inform rational dosing in preclinical models and interpretation of clinical results.

One-Sided Multidimensional Statistical Significance Testing: A New Method of Calculating the Statistical Significance of Spectra Used to Demonstrate Magnetic Nanoparticle Sensitivity.

Estimating statistical significance of the difference between two spectra or series is a fundamental statistical problem. Multivariate significance tests exist but the limitations preclude their use in many common cases; e.g.

Measuring protein biomarker concentrations using antibody tagged magnetic nanoparticles.

Under physiological conditions biomarker concentrations tend to rise and fall over time e.g. for inflammation.

Kynurenine-Induced Aryl Hydrocarbon Receptor Signaling in Mice Causes Body Mass Gain, Liver Steatosis, and Hyperglycemia.

Objective: The aryl hydrocarbon receptor (AHR) plays a key role in obesity. In vitro studies revealed that the tryptophan metabolite kynurenine (Kyn) activates AHR signaling in cultured hepatocytes. The objective of this study was to determine whether Kyn activated the AHR in mice to induce obesity.

The effect of sonidegib (LDE225) on the pharmacokinetics of bupropion and warfarin in patients with advanced solid tumours.

Aims: We evaluated the potential effect of sonidegib at an oral dose of 800 mg once daily (QD) on the pharmacokinetics (PK) of the probe drugs warfarin (CYP2C9) and bupropion (CYP2B6).

Methods: This was a multicentre, open-label study to evaluate the effect of sonidegib on the PK of the probe drugs warfarin and bupropion in patients with advanced solid tumours. Cohort 1 patients received a single warfarin 15-mg dose on Day 1 of the run-in period and on Cycle 2 Day 22 (C2D22) of sonidegib administration.

Identifying in vivo inflammation using magnetic nanoparticle spectra.

We are developing magnetic nanoparticle (NP) methods to characterize inflammation and infection in vivo. Peritoneal infection in C57BL/6 mice was used as a biological model. An intraperitoneal NP injection was followed by measurement of magnetic nanoparticle spectroscopy of Brownian rotation (MSB) spectra taken over time.

Harmonic phase angles used for nanoparticle sensing.

A series of techniques have been developed to use magnetic nanoparticles as biosensors to characterize their local microenvironment. Two approaches have been used to obtain quantitative information: model based approaches and scaling based approaches. We have favored scaling based approaches, because approximations made in models can lead to limitations in the accuracy.

Blood clot detection using magnetic nanoparticles.

Deep vein thrombosis, the development of blood clots in the peripheral veins, is a very serious, life threatening condition that is prevalent in the elderly. To deliver proper treatment that enhances the survival rate, it is very important to detect thrombi early and at the point of care. We explored the ability of magnetic particle spectroscopy (MSB) to detect thrombus via specific binding of aptamer functionalized magnetic nanoparticles with the blood clot.

Sensitivity Limits for ELISA Measurements of Molecular Biomarker Concentrations.

The extremely high sensitivity that has been suggested for magnetic particle imaging has its roots in the unique signal produced by the nanoparticles at the frequencies of the harmonics of the drive field. That sensitivity should be translatable to other methods that utilize magnetic nanoparticle probes, specifically towards magnetic nanoparticle spectroscopy that is used to measure molecular biomarker concentrations for an " ELISA" assay approach. In this paper, we translate the predicted sensitivity of magnetic particle imaging into a projected sensitivity limit for ELISA.