A5024730290- RNA Interference and Gene Delivery
- Lipid Membrane Structure and Behavior
- Cancer, Hypoxia, and Metabolism
- Nanoplatforms for cancer theranostics
- ATP Synthase and ATPases Research
- Cardiomyopathy and Myosin Studies
- Advanced biosensing and bioanalysis techniques
- Cancer Research and Treatments
- Muscle Physiology and Disorders
- Nanoparticle-Based Drug Delivery
- Cardiovascular Effects of Exercise
- RNA and protein synthesis mechanisms
- Mass Spectrometry Techniques and Applications
- Antimicrobial Peptides and Activities
- Radiopharmaceutical Chemistry and Applications
- Supramolecular Self-Assembly in Materials
- Glycosylation and Glycoproteins Research
- Chemical Synthesis and Analysis
- Quantum Chromodynamics and Particle Interactions
- Cellular Mechanics and Interactions
- Particle physics theoretical and experimental studies
- Bladder and Urothelial Cancer Treatments
- Monoclonal and Polyclonal Antibodies Research
- Medical Imaging Techniques and Applications
- Photoreceptor and optogenetics research
University of Rhode Island
2015-2024
Ludwig-Maximilians-Universität München
2023
Saint Petersburg State University of Economics
2019
Saint Petersburg State University of Aerospace and Instrumentation
2019
University of San Francisco
2019
Yale University
2006-2017
University of Illinois Chicago
2017
Louisiana State University Health Sciences Center Shreveport
2017
Moffitt Cancer Center
2017
MemorialCare Health System
2017
We have developed a way to measure cell surface pH by positioning pH-sensitive fluorescent dye, seminaphtharhodafluor (SNARF), conjugated the low insertion peptide (pHLIP). It has been observed that many diseased tissues are acidic and tumors especially so. A combination of effects acidifies tumor interiors, cells pump out lactic acid protons maintain intracellular pH, acidifying extracellular space. Overexpression carbonic anhydrases on surfaces further contributes acidification. Thus, near...
The pH-selective insertion and folding of a membrane peptide, pHLIP [pH (low) peptide], can be used to target acidic tissue in vivo, including foci tumors, kidneys, inflammatory sites. In mouse breast adenocarcinoma model, fluorescently labeled finds solid tumors with high accuracy accumulates them even at very early stage tumor development. fluorescence signal is stable for >4 days approximately five times higher than healthy counterpart tissue. rat antigen-induced arthritis preferentially...
We have previously observed the spontaneous, pH-dependent insertion of a water-soluble peptide to form helix across lipid bilayers [Hunt, J. F., Rath, P., Rothschild, K. & Engelman, D. M. (1997) Biochemistry 36, 15177-15192]. now use related peptide, pH (low) translocate cargo molecules attached its C terminus plasma membranes living cells. Translocation is selective for low pH, and various types by disulfides can be released reduction in cytoplasm, including nucleic acids, cyclic...
Cancer is a complex disease with range of genetic and biochemical markers within among tumors, but general tumor characteristic extracellular acidity, which associated growth development. Acidosis could be universal marker for cancer imaging the delivery therapeutic molecules, its promise as biomarker has not been fully realized in clinic. We have discovered unique approach targeting acidic tissue using pH-sensitive folding transmembrane insertion pH (low) peptide (pHLIP). The essence...
Solid tumors often develop an acidic environment due to the Warburg effect. The effectiveness of diagnosis and therapy may therefore be enhanced by design use pH-sensitive agents that target tumors. Recently, a novel technology was introduced using pH low insertion peptide (pHLIP), inserts across cell membranes as alpha-helix when extracellular (pH(e)) is acidic. In this study, we expanded application pHLIP include positron emission tomography imaging in prostate (64)Cu conjugated...
The pH low-insertion peptide (pHLIP) serves as a model system for insertion and folding across lipid bilayer. It has three general states: (I) soluble in water or (II) bound to the surface of bilayer an unstructured monomer, (III) inserted monomeric alpha-helix. We used fluorescence spectroscopy isothermal titration calorimetry study interactions pHLIP with palmitoyloleoylphosphatidylcholine (POPC) calculate transition energies between states. found that Gibbs free energy binding POPC at low...
What are the molecular events that occur when a peptide inserts across membrane or exits from it? Using pH-triggered insertion of pH low to enable kinetic analysis, we show occurs in several steps, with rapid (0.1 sec) interfacial helix formation, followed by much slower (100 pathway give transmembrane helix. The reverse process unfolding and exit bilayer core, which can be induced rise acidic basic, proceeds approximately 400 times faster than folding/insertion through different...
We find that pH-(low)-insertion-peptide (pHLIP)-facilitated translocation of phalloidin, a cell-impermeable polar toxin, inhibits the proliferation cancer cells in pH-dependent fashion. The monomeric pHLIP inserts its C terminus across membrane under slightly acidic conditions (pH 6–6.5), forming transmembrane helix. delivery construct carries phalloidin linked to inserting via disulfide bond is cleaved inside cells, releasing toxin. To facilitate agent, lipophilic rhodamine moiety also...
Progress in nanomedicine depends on the development of nanomaterials and targeted delivery methods. In this work, we describe a method for preferential targeting gold nanoparticles to tumor mouse model. The is based use pH Low Insertion Peptide (pHLIP), which targets various imaging agents acidic tumors. We compare by nonfunctionalized nanogold particles with nanogold–pHLIP conjugates, where covalently attached N terminus pHLIP. Our most important finding that both intratumoral i.v....
The acidic pH of tumors profoundly inhibits effector functions activated CD8 + T-cells. We hypothesize that this is a physiological process in immune regulation, and it occurs within lymph nodes (LNs), which are likely because low convective flow high glucose metabolism. Here we show by vivo fluorescence MR imaging, LN paracortical zones acidic. These niches absent athymic Nu/Nu lymphodepleted mice, implicating T-cells the acidifying process. T-cell glycolysis inhibited at observed LNs. due...
Significance Targeted delivery has been limited by reliance on tumor cell biomarkers. The emergence of the pH (low) insertion peptide (pHLIP) technology provides an alternative targeting a metabolic marker, surface acidity. We report several new pHLIPs, including concept, pHLIP bundles, and we evaluate these constructs alongside generation pHLIPs. also discuss challenges inherent to design accurate evaluation Our research elucidates strengths weaknesses existing proposes future modifications...
miRNA therapeutics have gained attention during the past decade. These oligonucleotide treatments can modulate expression of miRNAs in vivo and could be used to correct imbalance gene found human diseases such as obesity, metabolic syndrome, atherosclerosis. The efficacy current anti-miRNA technologies hindered by physiological cellular barriers delivery into targeted cells nature that allows one target an entire pathway may lead deleterious off-target effects. For these reasons, novel...
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in USA, accounting for ~40,000 deaths annually. The dismal prognosis PDAC largely due to its late diagnosis. Currently, most sensitive diagnosis requires invasive procedures, such as endoscopic ultrasonography, which has inherent risks and accuracy that highly operator dependent. Here we took advantage a general characteristic solid tumors, acidic microenvironment generated by-product metabolism, develop...
Significance Nanometer-sized gold particles are shown to increase the effectiveness of radiation in killing cancer cells. Improved allows less be used, reducing adverse effects patients. Alternatively, more could possible while using current doses. Here we used pH Low-Insertion Peptide (pHLIP) tether nanoparticles membranes This increases their because radiation/particle effect is very localized. We find that pHLIP significantly amount cells, as well cell death from radiation. methodology...
Toxins could be effective anticancer drugs, if their selective delivery into cancer cells achieved. We have shown that the energy of membrane-associated folding water-soluble membrane peptides pHLIP (pH low insertion peptide) family used to move cell-impermeable cargo across lipid bilayer cytoplasm cells. Here we present results a study pHLIP-mediated cellular polar toxin, α-amanitin, an inhibitor RNA polymerase II. show can deliver α-amanitin in pH-dependent fashion and induce cell death...
Significance Bladder cancer is the fifth most common cancer. Timely diagnosis and appropriate early management protocols are of paramount significance for improving patient outcomes. This study shows efficient pH-dependent near-infrared imaging bladder malignant tumors without targeting normal tissue. Our results demonstrate that indocyanine green pH low insertion peptide (pHLIP) construct suitable use as a predictive clinical marker, specifically staining human after intravesical...
Extracellular acidity is associated with tumor progression. Elevated glycolysis and acidosis promote the appearance of aggressive malignant cells enhanced multidrug resistance. Thus, targeting can open new avenues in diagnosis treatment tumors metastatic cancers within a tumor. pH (low) insertion peptides (pHLIPs) belong to class pH-sensitive agents capable delivering imaging and/or therapeutic cancer tumors. Here, we investigated highly 4T1 mammary spontaneous breast FVB/N-Tg...
Previous work has reported the important links between cellular bioenergetics and development of chronic kidney disease, highlighting potential for targeting metabolic functions to regulate disease progression. More recently, it been shown that alterations in fatty acid oxidation (FAO) can have an impact on progression disease. In this work, we demonstrate loss miR-33, regulator lipid metabolism, partially prevent repression FAO fibrotic kidneys reduce accumulation. These changes were...