Targeting acidity in diseased tissues: Mechanism and applications of the membrane-inserting peptide, pHLIP

Deacon, John C.; Engelman, Donald M.; Barrera, Francisco N.

doi:10.1016/j.abb.2014.11.002

Cited by 59 publications

(77 citation statements)

References 85 publications

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“…Additional delivery systems to selectively reach and target the acidic core of cancers have been developed. Among them, pH-sensitive liposomes, that release chemotherapeutical substances at an acidic pH [65], and the pH low insertion peptides (pHLIP), that consist of soluble peptides able to bind cell membrane in a pH-dependent way [66]. Another interesting strategy is to target the plasticity of cancer metabolic reprogramming with anti-metabolic drugs.…”

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confidence: 99%

Acidity of Microenvironment as a Further Driver of Tumor Metabolic Reprogramming

Peppicelli¹,

Andreucci²,

Ruzzolini³

et al. 2017

J Clin Cell Immunol

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In the last decade, experimental research has intensely focused on metabolic reprogramming of tumor cells, which contributes to cancer cell adaptation and survival in different and hostile microenvironments. Metabolic reprogramming consists of the switch of tumor cells from aerobic or anaerobic glycolysis to oxidative phosphorylation. A comprehensive vision of the metabolic scenario involving functionally different tumor cell subpopulations was proposed as a necessary premise to the design of new strategies of diagnosis and therapy. Special focus has been put on the role of acidosis of certain tumor regions, a very important although frequently neglected aspect.Despite the progresses in cancer therapy, the escaping of tumor cancer cells from host defense and relapse of disease still represent main issues in tumor-bearing patients. Indeed, malignant cells are provided with a tremendous plasticity that they exploit to survive, replicate and invade in stressed microenvironments. Such plasticity allows cancer cells to easily modify their properties, including metabolism, switching back and forth from aerobic or anaerobic glycolysis to oxidative phosphorylation (OxPhos). It is well ascertained that a suitable metabolic profile of cancer cells is necessary to sustain tumor growth, local invasion and distant colonization. Thus, cancer metabolism needs to be considered in view of the design of new strategies to control tumor progression.Keywords: "Warburg effect"; Glucose level; Hypoxia; Hypoxiainducible factor-1α; Acidosis; Oxidative phosphorylation Tumor Microenvironment and Metabolic Reprogramming of Tumor Cells Warburg effectProliferating tumor cells have been largely shown to adopt "aerobic glycolysis" as the main metabolic profile, the so-called "Warburg effect" [1]. Indeed, most cancer cells use huge amounts of glucose even when oxygen tension is high enough to sustain mitochondrial respiration in normal cells. A link between oncogenesis and glucose metabolism is the activating mutations in phosphoinositide 3-kinase (PI3K) or overexpression of the AKT oncogenes, promoting expression and localization of the high affinity glucose transporters on the plasma membrane [2]. This is followed by lactic acid fermentation in the cytosol and lactate export from the cell [3]. This alteration of glucose metabolism acquired practical importance in clinical settings following the development of 18-fluorodeoxyglucose-positron emission tomography imaging [4,5]. Furthermore, it is well recognized that a high serum level of lactate dehydrogenase (LDH) represents a biomarker of poor prognosis in different cancers [6].When Warburg metabolism is favored, a relatively low level of pyruvate is metabolized in the mitochondria and the energy gain is only 2 ATP per molecule of glucose. Thus, fermentation of glucose to lactic acid is an inefficient pathway, but, very important, it is a fast energy supplier (about 100 folds faster than OxPhos). Moreover, the aerobic glycolytic phenotype confers a significant proliferative advantage a...

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mentioning

confidence: 99%

Acidity of Microenvironment as a Further Driver of Tumor Metabolic Reprogramming

Peppicelli¹,

Andreucci²,

Ruzzolini³

et al. 2017

J Clin Cell Immunol

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“…For example, pHLIPs have been found to target acidic conditions in vivo including ischemic heart muscles and localized rheumatoid arthritis [136]. Of course, the simple secret again lies in the difference between targeted tissues with non-targeted areas.…”

Section: Discussionmentioning

confidence: 99%

“…GALA peptide was chosen mostly for its endosomal disruptive capacity; while pHLIPs were usually applied in tumor extracellular pH-targeting [129,[132][133][134][135] for they were active at pH 6.0~6.5 (depend on pHLIP sequence [136]), which was within the range of tumor environmental pH. Also, it has been ascertained that the insertion of pHLIP only relied on physical properties of the membrane instead of the active process from cells, displaying a simple path for pHLIP to cross the cellular membrane ( Fig.7) [136]. Conjugated with fluorescent probes, pHLIP could accumulate within various types of tumors for imaging which was directly dependent on the extra cellular acidity of tumor environment [134].…”

Section: Ph Low Insertion Peptides (Phlips)mentioning

confidence: 99%

Taming Cell Penetrating Peptides: Never Too Old To Teach Old Dogs New Tricks

Zhang

Gao

2015

Mol. Pharmaceutics

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Cell penetrating peptides (CPPs) have received substantial attention due to their intrinsic property to cross plasma membranes or even as helpers to facilitate the cellular entry of drug molecules, macromolecules, and nanoparticles. Although CPPs and CPP-like peptides provided versatile platforms for drug delivery, their nonselectivity or lack of delivery efficiency is stirring up debates as to the tactics for the optimizing the CPPs themselves. The good news is that, as spurred by the recent progress in the understanding of tumor microenvironment as well as biochemistry and material sciences, we have made attempts in working on perfecting or even "taming" CPPs and CPP-functionalized drug vectors for tumor delivery, and some of them afforded gratifying results. Due to the fact that these peptides are mainly short peptides made up of amino acids (5-30 amino acids), the addition, modification, or replacement of amino acids might lead to surprisingly improved performance. Several novel environment-responsive CPPs or CPP-like peptides have also been discovered. In this review we will discuss the measures taken to harness the power of CPPs and the discovery of environment-responsive peptides with CPP properties.

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“…(14, 15) Targeting and imaging of tumor acidity is an attractive strategy, as acidity typically is a general property of the tumor microenvironment. Acidosis results during tumor development at both early and advanced stages from a combination of factors such as hypoxia, anaerobic glycolysis (Warburg effect) and carbonic anhydrase activity.…”

Section: Discussionmentioning

confidence: 99%

“…(14–15) Ischemia and acidosis frequently accompany tumor progression from early to advanced stages, related to factors such as hypoxia, the Warburg effect, and carbonic anhydrases. (16) Therefore, compared to specific molecular markers, tumor acidity may provide a more universal target for imaging and therapy.…”

Section: Introductionmentioning

confidence: 99%

Targeting Acidity in Pancreatic Adenocarcinoma: Multispectral Optoacoustic Tomography Detects pH-Low Insertion Peptide Probes In Vivo

Kimbrough

Khanal

Zeiderman

et al. 2015

Clinical Cancer Research

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Background pH-low Insertion Peptides (pHLIPs) can serve as a targeting moiety that enables pH-sensitive probes to detect solid tumors. Using these probes in conjunction with multispectral optoacoustic tomography (MSOT) is a promising approach to improve imaging for pancreatic cancer. Methods A pH-sensitive pHLIP (V7) was conjugated to 750 NIR fluorescent dye and evaluated as a targeted probe for pancreatic adenocarcinoma. The pH-insensitive K7 pHLIP served as an untargeted control. Probe binding was assessed in vitro at pH 7.4, 6.8, and 6.6 using human pancreatic cell lines S2VP10 and S2013. Using MSOT, semi-quantitative probe accumulation was then assessed in vivo with a murine orthotopic pancreatic adenocarcinoma model. Results In vitro, the V7–750 probe demonstrated significantly higher fluorescence at pH 6.6 compared to pH 7.4 (S2VP10, p=0.0119; S2013, p=0.0160), while no difference was observed with the K7–750 control (S2VP10, p=0.8783; S2013, p=0.921). In the in vivo S2VP10 model, V7–750 probe resulted in 782.5 MSOT a.u. signal compared to 5.3 MSOT a.u. in K7–750 control in tumor (p= 0.0001). Similarly, V7–750 probe signal was 578.3 MSOT a.u. in the S2013 model compared to K7–750 signal at 5.1 MSOT a.u. (p=0.0005). There was minimal off-target accumulation of the V7–750 probe within the liver or kidney, and probe distribution was confirmed with ex vivo imaging. Conclusion Compared to pH-insensitive controls, V7–750 pH-sensitive probe specifically targets pancreatic adenocarcinoma, and has minimal off-target accumulation. The non-invasive detection of pH-targeted probes by means of MSOT represents a promising modality to improve the detection and monitoring of pancreatic cancer.

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Targeting acidity in diseased tissues: Mechanism and applications of the membrane-inserting peptide, pHLIP

Cited by 59 publications

References 85 publications

Acidity of Microenvironment as a Further Driver of Tumor Metabolic Reprogramming

Acidity of Microenvironment as a Further Driver of Tumor Metabolic Reprogramming

Taming Cell Penetrating Peptides: Never Too Old To Teach Old Dogs New Tricks

Targeting Acidity in Pancreatic Adenocarcinoma: Multispectral Optoacoustic Tomography Detects pH-Low Insertion Peptide Probes In Vivo

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