MR Molecular Imaging of Extradomain-B Fibronectin for Assessing Progression and Therapy Resistance of Prostate Cancer.

Accurate assessment and characterization of the progression and therapy response of prostate cancer are essential for precision healthcare of patients diagnosed with the disease. MRI is a clinical imaging modality routinely used for diagnostic imaging and treatment planning of prostate cancer. Extradomain B fibronectin (EDB-FN) is an oncofetal subtype of fibronectin highly expressed in the extracellular matrix of aggressive cancers, including prostate cancer.

Intravitreal Delivery of PEGylated-ECO Plasmid DNA Nanoparticles for Gene Therapy of Stargardt Disease.

Objective: Current gene therapy of inherited retinal diseases is achieved mainly by subretinal injection, which is invasive with severe adverse effects. Intravitreal injection is a minimally invasive alternative for gene therapy of inherited retinal diseases. This work explores the efficacy of intravitreal delivery of PEGylated ECO (a multifunctional pH-sensitive amphiphilic amino lipid) plasmid DNA (pGRK1-ABCA4-S/MAR) nanoparticles (PEG-ELNP) for gene therapy of Stargardt disease.

Pharmacokinetics and Tolerability of the Cancer-Targeting MRI Contrast Agent MT218 in Healthy Males.

Objective: The aim of this study was to evaluate the pharmacokinetics and safety profile of MT218, a peptide-targeted gadolinium-based contrast agent, in healthy males.

Materials And Methods: This was a double-blind, randomized, placebo-controlled, single-ascending-dose study including 30 healthy male subjects. In each dose group (0.

Evaluating Dual-Targeted ECO/siRNA Nanoparticles against an Oncogenic lncRNA for Triple Negative Breast Cancer Therapy with Magnetic Resonance Molecular Imaging.

Differentiation antagonizing noncoding RNA (DANCR) is recognized as an oncogenic long noncoding RNA (lncRNA) overexpressed in triple negative breast cancer (TNBC). We showed in a previous study that RNAi with targeted multifunctional ionizable lipid ECO/siRNA nanoparticles was effective to regulate this undruggable target for effective treatment of TNBC. In this study, we developed dual-targeted ECO/siDANCR nanoparticles by targeting a tumor extracellular matrix oncoprotein, extradomain B fibronectin (EDB-FN), and integrins overexpressed on cancer cells for enhanced delivery of siDANCR.

Stress resilience-enhancing drugs preserve tissue structure and function in degenerating retina via phosphodiesterase inhibition.

Chronic, progressive retinal diseases, such as age-related macular degeneration (AMD), diabetic retinopathy, and retinitis pigmentosa, arise from genetic and environmental perturbations of cellular and tissue homeostasis. These disruptions accumulate with repeated exposures to stress over time, leading to progressive visual impairment and, in many cases, legal blindness. Despite decades of research, therapeutic options for the millions of patients suffering from these disorders remain severely limited, especially for treating earlier stages of pathogenesis when the opportunity to preserve the retinal structure and visual function is greatest.

PET Imaging of Hepatocellular Carcinoma Using ZD2-(Ga-NOTA).

Purpose: We tested a recently developed short peptide radioligand for PET imaging of hepatocellular carcinoma (HCC) by targeting an oncoprotein, extra-domain B fibronectin (EDB-FN) in the tumor microenvironment.

Methods: The radioligand consists of a small linear peptide ZD2 with Ga-NOTA chelator, and specifically binds to EDB-FN. PET images were acquired dynamically for 1 hour after intravenously (i.

Effective gene therapy of Stargardt disease with PEG-ECO/ nanoparticles.

Stargardt disease (STGD) is the most common form of inherited retinal genetic disorders and is often caused by mutations in . Gene therapy has the promise to effectively treat monogenic retinal disorders. However, clinically approved adeno-associated virus (AAV) vectors do not have a loading capacity for large genes, such as .

Evaluation of Physicochemical Properties, Pharmacokinetics, Biodistribution, Toxicity, and Contrast-Enhanced Cancer MRI of a Cancer-Targeting Contrast Agent, MT218.

Objectives: Preclinical assessments were performed according to the US Food and Drug Administration guidelines to determine the physicochemical properties, pharmacokinetics, clearance, safety, and tumor-specific magnetic resonance (MR) imaging of MT218, a peptidic gadolinium-based MR imaging agent targeting to extradomain B fibronectin for MR molecular imaging of aggressive tumors.

Materials And Methods: Relaxivity, chelation stability, binding affinity, safety-related target profiling, and effects on CYP450 enzymes and transporters were evaluated in vitro. Magnetic resonance imaging was performed with rats bearing prostate cancer xenografts, immunocompetent mice bearing murine pancreatic cancer allografts, and mice bearing lung cancer xenografts at different doses of MT218.

Peptide Derivatives of Retinylamine Prevent Retinal Degeneration with Minimal Side Effects on Vision in Mice.

Safe and effective molecular therapeutics for prophylactic treatment of retinal degenerative diseases are greatly needed. Disruptions in the clearance of all--retinal (atRAL) by the visual (retinoid) cycle of the retina can lead to the accumulation of atRAL and its condensation products known to initiate progressive retinal dystrophy. Retinylamine (Ret-NH) and its analogues are known to be effective in lowering the concentration of atRAL within the eye and thus preventing retinal degeneration in mouse models of human retinopathies.

Formulation and efficacy of ECO/pRHO-ABCA4-SV40 nanoparticles for nonviral gene therapy of Stargardt disease in a mouse model.

It is still a challenge to develop gene replacement therapy for retinal disorders caused by mutations in large genes, such as Stargardt disease (STGD). STGD is caused by mutations in ABCA4 gene. Previously, we have developed an effective non-viral gene therapy using self-assembled nanoparticles of a multifunctional pH-sensitive amino lipid ECO and a therapeutic ABCA4 plasmid containing rhodopsin promoter (pRHO-ABCA4).

Magnetic Resonance Molecular Imaging of Extradomain B Fibronectin Improves Imaging of Pancreatic Cancer Tumor Xenografts.

The survival of pancreatic cancer patients can be greatly improved if their disease is detected at an early, potentially curable stage. Magnetic resonance molecular imaging (MRMI) of oncoproteins is a promising strategy for accurate, early detection of the disease. Here, we test the hypothesis that MRMI of extradomain-B fibronectin (EDB-FN), an abundant oncoprotein in the tumor extracellular matrix, can overcome the stromal barriers of pancreatic cancer to facilitate effective molecular imaging and detection of small tumors.

Synthesis and assessment of ZD2-(Ga-NOTA) specific to extradomain B fibronectin in tumor microenvironment for PET imaging of pancreatic cancer.

Patients diagnosed with pancreatic cancer at a late stage have a dismal survival rate. Accurate early detection of pancreatic cancer with a size of 10 mm or less could dramatically improve patient survival after timely treatments. We have developed a new PET probe ZD2-(Ga-NOTA) specific to extradomain-B fibronectin (EDB-FN), an oncoprotein in tumor microenvironment, for sensitive molecular imaging and early diagnosis of pancreatic cancer.

Non-viral Gene Therapy for Stargardt Disease with ECO/pRHO-ABCA4 Self-Assembled Nanoparticles.

Stargardt disease (STGD) is an autosomal recessive retinal disorder caused by a monogenic ABCA4 mutation. Currently, there is no effective therapy to cure Stargardt disease. The replacement of mutated ABCA4 with a functional gene remains an attractive strategy.

Preparation and Evaluation of ZD2 Peptide Cu-DOTA Conjugate as a Positron Emission Tomography Probe for Detection and Characterization of Prostate Cancer.

Positron emission tomography (PET) is a sensitive modality for cancer molecular imaging. We aim to develop a PET probe for sensitive detection and risk stratification of prostate cancer by targeting an abundant microenvironment oncoprotein, extradomain-B fibronectin (EDB-FN). The probe consists of a small ZD2 peptide specific to EDB-FN and a Cu-DOTA chelate.

Optimization of ZD2 Peptide Targeted Gd(HP-DO3A) for Detection and Risk-Stratification of Prostate Cancer with MRI.

The aim of this work is to optimize a peptide targeted macrocyclic MRI contrast agent for detection and risk-stratification of aggressive prostate cancer. The optimized agent was prepared using click chemistry in the presence of CuSO and ascorbate at room temperature. The T and T relaxivities of ZD2-N3-Gd(HP-DO3A) are 5.

Protective Effect of a Locked Retinal Chromophore Analog against Light-Induced Retinal Degeneration.

Continuous regeneration of the 11--retinal visual chromophore from all--retinal is critical for vision. Insufficiency of 11--retinal arising from the dysfunction of key proteins involved in its regeneration can impair retinal health, ultimately leading to loss of human sight. Delayed recovery of visual sensitivity and night blindness caused by inadequate regeneration of the visual pigment rhodopsin are typical early signs of this condition.

A novel small molecule chaperone of rod opsin and its potential therapy for retinal degeneration.

Rhodopsin homeostasis is tightly coupled to rod photoreceptor cell survival and vision. Mutations resulting in the misfolding of rhodopsin can lead to autosomal dominant retinitis pigmentosa (adRP), a progressive retinal degeneration that currently is untreatable. Using a cell-based high-throughput screen (HTS) to identify small molecules that can stabilize the P23H-opsin mutant, which causes most cases of adRP, we identified a novel pharmacological chaperone of rod photoreceptor opsin, YC-001.

Retinal-chitosan Conjugates Effectively Deliver Active Chromophores to Retinal Photoreceptor Cells in Blind Mice and Dogs.

The retinoid (visual) cycle consists of a series of biochemical reactions needed to regenerate the visual chromophore 11--retinal and sustain vision. Genetic or environmental factors affecting chromophore production can lead to blindness. Using animal models that mimic human retinal diseases, we previously demonstrated that mechanism-based pharmacological interventions can maintain vision in otherwise incurable genetic diseases of the retina.

New GABA modulators protect photoreceptor cells from light-induced degeneration in mouse models.

No clinically approved therapies are currently available that prevent the onset of photoreceptor death in retinal degeneration. Signaling between retinal neurons is regulated by the release and uptake of neurotransmitters, wherein GABA is the main inhibitory neurotransmitter. In this work, novel 3-chloropropiophenone derivatives and the clinical anticonvulsants tiagabine and vigabatrin were tested to modulate GABA signaling and protect against light-induced retinal degeneration.

A Combination of G Protein-Coupled Receptor Modulators Protects Photoreceptors from Degeneration.

Degeneration of retinal photoreceptor cells can arise from environmental and/or genetic causes. Since photoreceptor cells, the retinal pigment epithelium (RPE), neurons, and glial cells of the retina are intimately associated, all cell types eventually are affected by retinal degenerative diseases. Such diseases often originate either in rod and/or cone photoreceptor cells or the RPE.

Targeted Multifunctional Lipid ECO Plasmid DNA Nanoparticles as Efficient Non-viral Gene Therapy for Leber's Congenital Amaurosis.

Development of a gene delivery system with high efficiency and a good safety profile is essential for successful gene therapy. Here we developed a targeted non-viral delivery system using a multifunctional lipid ECO for treating Leber's congenital amaurosis type 2 (LCA2) and tested this in a mouse model. ECO formed stable nanoparticles with plasmid DNA (pDNA) at a low amine to phosphate (N/P) ratio and mediated high gene transfection efficiency in ARPE-19 cells because of their intrinsic properties of pH-sensitive amphiphilic endosomal escape and reductive cytosolic release (PERC).

Photocyclic behavior of rhodopsin induced by an atypical isomerization mechanism.

Vertebrate rhodopsin (Rh) contains 11--retinal as a chromophore to convert light energy into visual signals. On absorption of light, 11--retinal is isomerized to all--retinal, constituting a one-way reaction that activates transducin (G) followed by chromophore release. Here we report that bovine Rh, regenerated instead with a six-carbon-ring retinal chromophore featuring a C=C double bond locked in its conformation (Rh6mr), employs an atypical isomerization mechanism by converting 11- to an 11,13- configuration for prolonged G activation.

MicroRNA-processing Enzymes Are Essential for Survival and Function of Mature Retinal Pigmented Epithelial Cells in Mice.

Age-related macular degeneration (AMD) is a major cause of irreversible vision loss. The neovascular or "wet" form of AMD can be treated to varying degrees with anti-angiogenic drugs, but geographic atrophy (GA) is an advanced stage of the more prevalent "dry" form of AMD for which there is no effective treatment. Development of GA has been linked to loss of the microRNA (miRNA)-processing enzyme DICER1 in the mature retinal pigmented epithelium (RPE).

Synergistically acting agonists and antagonists of G protein-coupled receptors prevent photoreceptor cell degeneration.

Photoreceptor cell degeneration leads to visual impairment and blindness in several types of retinal disease. However, the discovery of safe and effective therapeutic strategies conferring photoreceptor cell protection remains challenging. Targeting distinct cellular pathways with low doses of different drugs that produce a functionally synergistic effect could provide a strategy for preventing or treating retinal dystrophies.