Applications of pHLIP Technology for Cancer Imaging and Therapy

Wyatt, Linden C.; Lewis, Jason S.; Andreev, Oleg A.; Reshetnyak, Yana K.; Engelman, Donald M.

doi:10.1016/j.tibtech.2017.11.005

Cited by 16 publications

(15 citation statements)

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“…Paracortical zones are acidic niches inside the lymph node. The pHe of inguinal LNs in C57BL/6 (B6) mice was probed using pH-Low Insertion Peptide (pHLIP) a short peptide that undergoes a conformational change at low pH to make it membrane penetrant, where it can be persistent [17][18][19][20][21] . To visualize areas of pHLIP insertion 20 , the peptide was conjugated to the fluorophore Cy5.5, which emits in the far-red range for optimal signal-tobackground ratio.…”

Section: Resultsmentioning

confidence: 99%

T-cells produce acidic niches in lymph nodes to suppress their own effector functions

et al. 2020

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The acidic pH of tumors profoundly inhibits effector functions of activated CD8 + T-cells. We hypothesize that this is a physiological process in immune regulation, and that it occurs within lymph nodes (LNs), which are likely acidic because of low convective flow and high glucose metabolism. Here we show by in vivo fluorescence and MR imaging, that LN paracortical zones are profoundly acidic. These acidic niches are absent in athymic Nu/Nu and lymphodepleted mice, implicating T-cells in the acidifying process. T-cell glycolysis is inhibited at the low pH observed in LNs. We show that this is due to acid inhibition of monocarboxylate transporters (MCTs), resulting in a negative feedback on glycolytic rate. Importantly, we demonstrate that this acid pH does not hinder initial activation of naïve T-cells by dendritic cells. Thus, we describe an acidic niche within the immune system, and demonstrate its physiological role in regulating T-cell activation.

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Section: Resultsmentioning

confidence: 99%

T-cells produce acidic niches in lymph nodes to suppress their own effector functions

et al. 2020

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“…Studies of examples of spontaneous insertion and folding have inspired the design of synthetic peptides that are soluble in aqueous solution and spontaneously insert into membranes, and have been the subjects of biophysical investigations (Ladokhin and White, 2004). The discovery of peptides that respond to low pH by spontaneously inserting and folding across a membrane (Hunt et al, 1997) accelerated the development of these peptides for medical applications (Reshetnyak et al, 2006;Andreev et al, 2014;Wyatt et al, 2018a), as it emerged that low cell surface pH (or high acidity) is associated with several significant pathological conditions.…”

Section: Membrane-associated Foldingmentioning

confidence: 99%

“…pH Triggered Insertion Into Membrane and Folding pH (Low) Insertion Peptides (pHLIPs) utilize pH-triggered membrane insertion and folding to target acidic diseased tissues. The insertion can be used for the selective delivery of therapeutic and imaging agents (Wyatt et al, 2018a). pHLIPs constitute a large class of moderately hydrophobic membrane peptides that are soluble in aqueous solution at normal and high pHs.…”

Section: Phlip Technologymentioning

confidence: 99%

Targeting Acidic Diseased Tissues by pH-Triggered Membrane-Associated Peptide Folding

Reshetnyak

Moshnikova

Andreev

et al. 2020

Front. Bioeng. Biotechnol.

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The advantages of targeted therapy have motivated many efforts to find distinguishing features between the molecular cell surface landscapes of diseased and normal cells. Typically, the features have been proteins, lipids or carbohydrates, but other approaches are emerging. In this discussion, we examine the use of cell surface acidity as a feature that can be exploited by using pH-sensitive peptide folding to target agents to diseased cell surfaces or cytoplasms.

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“…pHLIP peptides target tumors with high precision, since high cell surface acidity or low pH (pH surf ) is a byproduct of the elevated glycolytic metabolism and of overactivated carbonic anhydrases (CAIX) at cancer and activated immune cells 4 – 7 . A variety of imaging and therapeutic agents are successfully delivered to tumors by pHLIP peptides (see review 8 and references within it). pHLIP peptides tumor targeting has been demonstrated in human cancerous tissues and more than 20 different human and murine cancer models including transgenic breast, prostate, pancreatic and skin models.…”

Section: Introductionmentioning

confidence: 99%

pHLIP ICG for delineation of tumors and blood flow during fluorescence-guided surgery

Crawford

Moshnikova

Roles

et al. 2020

Sci Rep

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Fluorescence imaging has seen enduring use in blood flow visualization and is now finding a new range of applications in image-guided surgery. In this paper, we report a translational study of a new fluorescent agent for use in surgery, pHLIP ICG, where ICG (indocyanine green) is a surgical fluorescent dye used widely for imaging blood flow. We studied pHLIP ICG interaction with the cell membrane lipid bilayer, the pharmacology and toxicology in vitro and in vivo (mice and dogs), and the biodistribution and clearance of pHLIP ICG in mice. The pHLIP ICG tumor targeting and imaging efficacy studies were carried out in several murine and human mouse tumor models. Blood vessels were imaged in mice and pigs. Clinical Stryker imaging instruments for endoscopy and open surgery were used in the study. Intravenously administered pHLIP ICG exhibits a multi-hour circulation half-life, offering protracted delineation of vasculature. As it clears from the blood, pHLIP ICG targets tumors and tumor stroma, marking them for surgical removal. pHLIP ICG is non-toxic, marks blood flow for hours after injection, and effectively delineates tumors for improved resection on the day after administration.

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Applications of pHLIP Technology for Cancer Imaging and Therapy

Cited by 16 publications

References 0 publications

T-cells produce acidic niches in lymph nodes to suppress their own effector functions

T-cells produce acidic niches in lymph nodes to suppress their own effector functions

Targeting Acidic Diseased Tissues by pH-Triggered Membrane-Associated Peptide Folding

pHLIP ICG for delineation of tumors and blood flow during fluorescence-guided surgery

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