March 10, 2015
Drug-Polyester Nanoconjugates for Targeted Cancer Therapy and Diagnosis
Targeted cancer therapy mediated by nanoparticles (NPs) incorporating chemotherapeutic agents has not yet been successful in clinical translation. Most current NPs administered systemically resulted in non-specific uptake of the reticuloendothelial system (RES) and failed to localize in solid tumor tissues. Here we developed a novel translational polymeric NP system that can successfully evade non-specific RES uptake and facilitate targeted cancer diagnosis and therapy. By uniquely integrating well-established chemical reaction-controlled ring opening polymerization with NP formulation, the developed NP system allowed quantitative loading and controlled release of multiple anticancer drugs. More importantly, the developed NP could bind with albumin, a ubiquitous protein in the blood, to bypass the endothelium barrier and penetrate into tumor tissues more deeply and efficiently. Taking advantage of PET/CT imaging, these albumin-bound NPs showed significantly reduced accumulation in the RES and enhanced tumor accumulation in MCF-7 breast cancer xenograft model, and substantially inhibited tumor growth, compared to current widely used PEGylated NPs. In addition, the developed NP system is so versatile to readily incorporate x-ray computed tomography (CT) contrast agents to form multifunctional NPs with combined characteristics of diagnosis and targeted therapy. With substantially enhanced tumor accumulation and protracted tumor retention, the system largely facilitated personalized therapy by improving diagnosis accuracy, providing simultaneous site-specific treatment and monitoring therapeutic efficacy.
Behavioral and Pharmacological Evaluation of a Genetic Model of ADHD
It is difficult to model multifaceted clinical disorders in animals, which effectively limits our ability to fully understand disease etiology and progression. Selective breeding is a powerful tool that can be used to model such disorders, including attention-deficit/hyperactivity disorder (ADHD). We have been conducting a selective breeding experiment for increased levels of physical activity in the home cage for more than 17 generations. One line (high-active) is subjected to selection for increased total distance traveled in the home cage, while the other line (control) is randomly bred. Distance traveled in the home cage has increased from approximately 0.3 km/day in controls to 1.5 km/day in high-active. The goal of this study was to characterize the pharmacological responses of the high-active mice to d-amphetamine in the go/no-go task of motor impulsivity, as well as performance of high-active mice in the y-maze task for inattention. Both motor impulsivity and inattention are hallmark features of ADHD, and the present results suggest the high-active mice are a useful model for elucidating the underlying neurobiology, pharmacology, and genetic correlations between hyperactivity, inattention, and impulsivity.
Metabolism of the Endocannabinoids—Anandamide and 2-Arachidonoyl Glycerol—by CYP2J2 Nanodiscs
Endocannabinoids are neuromodulatory lipids that elicit the same psychoactive effects of cannabis. The dysregulation of the two most prevalent endocannabinoids—anandamide (AEA) and 2-arachidonoylglycerol (2-AG)—are implicated in cardiovascular disease as well as many neurological disorders. Both AEA and 2-AG have been shown to be substrates for the cytochrome P450 pathway, forming potent metabolites with unique signaling capabilities. Here we demonstrate that 2-AG and AEA are substrates for metabolism by CYP2J2 epoxygenase in the model membrane bilayers of nanodiscs. CYP2J2 is the primary cytochrome P450 in the human heart and is known to promote vasodilatory, anti-inflammatory, and anti-nociceptive effects. Notably, the incorporation of CYP2J2 into discoidal (~10 nm diameter) nanodiscs enabled biochemical and biophysical elucidation of the protein-ligand interactions. Incubations of CYP2J2 with AEA formed four AEA-epoxides, whereas incubations with 2-AG yielded detectable levels of only two 2-AG epoxides. The formation of the predominant AEA and 2-AG epoxides was confirmed using endoplasmic derived microsomes prepared from the left myocardium of porcine and bovine heart tissues.