Encapsulation and Delivery of the Kinase Inhibitor PIK-75 by Organic Core High-Density Lipoprotein-Like Nanoparticles Targeting Scavenger Receptor Class B Type 1.

PIK-75 (F7) is a potent multikinase inhibitor that targets p110α, DNA-PK, and p38γ. PIK-75 has shown potential as a therapy in preclinical cancer models, but it has not been used in the clinic, at least in part, due to limited solubility. We therefore developed a nanoparticle to encapsulate PIK-75 and enable targeted cellular delivery.

Conserved and divergent gene regulatory programs of the mammalian neocortex.

Divergence of cis-regulatory elements drives species-specific traits, but how this manifests in the evolution of the neocortex at the molecular and cellular level remains unclear. Here we investigated the gene regulatory programs in the primary motor cortex of human, macaque, marmoset and mouse using single-cell multiomics assays, generating gene expression, chromatin accessibility, DNA methylome and chromosomal conformation profiles from a total of over 200,000 cells. From these data, we show evidence that divergence of transcription factor expression corresponds to species-specific epigenome landscapes.

Spectrum of Apolipoprotein AI and Apolipoprotein AII Proteoforms and Their Associations With Indices of Cardiometabolic Health: The CARDIA Study.

Background ApoAI (apolipoproteins AI) and apoAII (apolipoprotein AII) are structural and functional proteins of high-density lipoproteins (HDL) which undergo post-translational modifications at specific residues, creating distinct proteoforms. While specific post-translational modifications have been reported to alter apolipoprotein function, the full spectrum of apoAI and apoAII proteoforms and their associations with cardiometabolic phenotype remains unknown. Herein, we comprehensively characterize apoAI and apoAII proteoforms detectable in serum and their post-translational modifications and quantify their associations with cardiometabolic health indices.

2'-3'-Cyclic Nucleotide 3'-Phosphodiesterase Inhibition by Organometallic Vanadium Complexes: A Potential New Paradigm for Studying CNS Degeneration.

The enzyme, 2'-3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) has been known for over fifty years. Nevertheless, the roles this membrane-bound enzyme play have yet to be described completely. Recently, there has been renewed interest in the study of this enzyme due to studies that suggest that CNPase plays a role in the mediation of cellular inflammatory responses in renal and nervous system tissues.

Targeted reduction of cholesterol uptake in cholesterol-addicted lymphoma cells blocks turnover of oxidized lipids to cause ferroptosis.

Normal human cells can either synthesize cholesterol or take it up from lipoproteins to meet their metabolic requirements. In some malignant cells, de novo cholesterol synthesis genes are transcriptionally silent or mutated, meaning that cholesterol uptake from lipoproteins is required for survival. Recent data suggest that lymphoma cells dependent upon lipoprotein-mediated cholesterol uptake are also subject to ferroptosis, an oxygen- and iron-dependent cell death mechanism triggered by accumulation of oxidized lipids in cell membranes unless the lipid hydroperoxidase, glutathione peroxidase 4 (GPX4), reduces these toxic lipid species.

Tri-ethylene glycol modified class B and class C CpG conjugated gold nanoparticles for the treatment of lymphoma.

CpG oligodeoxynucleotides (CpGs) can induce an anti-tumor immune response, but also uniquely cause direct lymphoma cytotoxicity. To improve the delivery and efficacy of CpGs, we utilized a tri-ethylene modified CpG conjugated gold nanoparticle (tmCpG NP) platform that is compatible with both class B and class C CpGs, to treat various types of lymphoma, including diffuse large B cell lymphoma, high-grade lymphoma, Burkitt's lymphoma, and mantle cell lymphoma. Both classes of tmCpG NPs reduced viability of human and murine lymphoma cells via apoptosis compared with free CpGs, while having no toxic effects on dendritic cells.

Electrical Stimulation of C6 Glia-Precursor Cells In Vitro Differentially Modulates Gene Expression Related to Chronic Pain Pathways.

Glial cells comprise the majority of cells in the central nervous system and exhibit diverse functions including the development of persistent neuropathic pain. While earlier theories have proposed that the applied electric field specifically affects neurons, it has been demonstrated that electrical stimulation (ES) of neural tissue modulates gene expression of the glial cells. This study examines the effect of ES on the expression of eight genes related to oxidative stress and neuroprotection in cultured rodent glioma cells.

Biomimetic Magnetic Nanostructures: A Theranostic Platform Targeting Lipid Metabolism and Immune Response in Lymphoma.

B-cell lymphoma cells depend upon cholesterol to maintain pro-proliferation and pro-survival signaling the B-cell receptor. Targeted cholesterol depletion of lymphoma cells is an attractive therapeutic strategy. We report here high-density lipoprotein mimicking magnetic nanostructures (HDL-MNSs) that can bind to the high-affinity HDL receptor, scavenger receptor type B1 (SR-B1), and interfere with cholesterol flux mechanisms in SR-B1 receptor positive lymphoma cells, causing cellular cholesterol depletion.

Supramolecular Assembly of High-Density Lipoprotein Mimetic Nanoparticles Using Lipid-Conjugated Core Scaffolds.

Synthetic high-density lipoprotein (HDL) mimics have emerged as promising therapeutic agents. However, approaches to date have been unable to reproduce key features of spherical HDLs, which are the most abundant human HDL species. Here, we report the synthesis and characterization of spherical HDL mimics using lipid-conjugated organic core scaffolds.

Effects of Phase Polarity and Charge Balance Spinal Cord Stimulation on Behavior and Gene Expression in a Rat Model of Neuropathic Pain.

Objective: To investigate the effect of phase polarity and charge balance of spinal cord stimulation (SCS) waveforms on pain behavior and gene expression in a neuropathic pain rodent model. We hypothesized that differing waveforms will result in diverse behavioral and transcriptomics expression due to unique mechanisms of action.

Materials And Methods: Rats were implanted with a four-contact cylindrical mini-lead and randomly assigned to two control (no-pain and pain model) and five test groups featuring monophasic, as well as charge-unbalanced and charge-balanced biphasic SCS waveforms.

Nitric Oxide-Delivering High-Density Lipoprotein-like Nanoparticles as a Biomimetic Nanotherapy for Vascular Diseases.

Disorders of blood vessels cause a range of severe health problems. As a powerful vasodilator and cellular second messenger, nitric oxide (NO) is known to have beneficial vascular functions. However, NO typically has a short half-life and is not specifically targeted.

HDL nanoparticles targeting sonic hedgehog subtype medulloblastoma.

Medulloblastoma is the most common paediatric malignant brain cancer and there is a need for new targeted therapeutic approaches to more effectively treat these malignant tumours, which can be divided into four molecular subtypes. Here, we focus on targeting sonic hedgehog (SHH) subtype medulloblastoma, which accounts for approximately 25% of all cases. The SHH subtype relies upon cholesterol signalling for tumour growth and maintenance of tumour-initiating cancer stem cells (CSCs).

Rational Targeting of Cellular Cholesterol in Diffuse Large B-Cell Lymphoma (DLBCL) Enabled by Functional Lipoprotein Nanoparticles: A Therapeutic Strategy Dependent on Cell of Origin.

Cancer cells have altered metabolism and, in some cases, an increased demand for cholesterol. It is important to identify novel, rational treatments based on biology, and cellular cholesterol metabolism as a potential target for cancer is an innovative approach. Toward this end, we focused on diffuse large B-cell lymphoma (DLBCL) as a model because there is differential cholesterol biosynthesis driven by B-cell receptor (BCR) signaling in germinal center (GC) versus activated B-cell (ABC) DLBCL.

Systemically administered collagen-targeted gold nanoparticles bind to arterial injury following vascular interventions.

Surgical and endovascular therapies for severe atherosclerosis often fail due to the development of neointimal hyperplasia and arterial restenosis. Our objective was to synthesize, characterize, and evaluate the targeting specificity and biocompatibility of a novel systemically injected nanoparticle. We hypothesize that surface-functionalization of gold nanoparticles (AuNPs) with a collagen-targeting peptide will be biocompatible and target specifically to vascular injury.

Lipoproteins and lipoprotein mimetics for imaging and drug delivery.

Lipoproteins are a set of natural nanoparticles whose main role is the transport of fats within the body. While much work has been done to develop synthetic nanocarriers to deliver drugs or contrast media, natural nanoparticles such as lipoproteins represent appealing alternatives. Lipoproteins are biocompatible, biodegradable, non-immunogenic and are naturally targeted to some disease sites.

Mosaic Interdigitated Structure in Nanoparticle-Templated Phospholipid Bilayer Supports Partial Lipidation of Apolipoprotein A-I.

Using gold nanoparticle-templated high-density lipoprotein-like particles as a model, the nanoparticle-templated phospholipid bilayer is studied from the bottom-up. Data support the phospholipids have a mosaic interdigitated structure. The discontinuous lipid milieu supports partial lipidation of apolipoprotein A-I, different from an ordinary phospholipid bilayer, suggesting that synergy between nanoparticle templates and bound phospholipid layers can modulate amphiphilic proteins for desired functions.

Knockdown of intraislet IKKβ by spherical nucleic acid conjugates prevents cytokine-induced injury and enhances graft survival.

Background: The efficiency of islet graft survival after intraportal implantation is compromised by host innate immune responses and the production of proinflammatory cytokines that cause acute cellular injury. This reaction activates intraislet nuclear factor-κB (NF-κB), causing production of gene products that have detrimental effects on β-cell survival and function. We hypothesized that small interfering RNA targeting of IKKβ, a crucial kinase in the NF-κB activation pathway, in islets before transplantation would ameliorate the detrimental effects of cytokines and improve islet survival after transplantation.

Update on current and potential nanoparticle cancer therapies.

Purpose Of Review: To summarize the most recent preclinical and clinical advancements in therapeutic nano-oncology.

Recent Findings: First-generation nanotherapies are well tolerated in humans and evidence shows that they are efficacious, while at the same time reducing the burden of side-effects. Most of these therapies are not specifically targeted, but take advantage of enhanced passive accumulation within tumors to preferentially deliver chemotherapies that demonstrate off-target toxicities when administered as free drugs.

Biomimetic, synthetic HDL nanostructures for lymphoma.

New therapies that challenge existing paradigms are needed for the treatment of cancer. We report a nanoparticle-enabled therapeutic approach to B-cell lymphoma using synthetic high density lipoprotein nanoparticles (HDL-NPs). HDL-NPs are synthesized using a gold nanoparticle template to control conjugate size and ensure a spherical shape.

Conditional and specific inhibition of NF-κB in mouse pancreatic β cells prevents cytokine-induced deleterious effects and improves islet survival posttransplant.

Background: Islets are susceptible to damage by proinflammatory cytokines via activation of transcription factor NF-κB. We hypothesized that inhibition of NF-κB activity will decrease cytokine-mediated β-cell injury and improve islet transplant functional outcome.

Methods: We created a transgenic mouse expressing a degradation resistant N-terminally deleted IκBα (ΔNIκBα) under the control of a commercially available tetracycline-controlled transcriptional activation system using a rat insulin promoter.

Transfection of pancreatic islets using polyvalent DNA-functionalized gold nanoparticles.

Background: Transplantation of pancreatic islets is an effective treatment for select patients with type 1 diabetes. Improved cellular therapy results may be realized by altering the gene expression profile of transplanted islets. Current viral and nonviral vectors used to introduce nucleic acids for gene regulation hold promise, but safety and efficacy shortcomings motivate the development of new transfection strategies.