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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>Cy5.5-labeled pH low insertion peptide (pHLIP) - Molecular Imaging and Contrast Agent Database (MICAD) - NCBI Bookshelf</title>
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<meta name="citation_inbook_title" content="Molecular Imaging and Contrast Agent Database (MICAD) [Internet]">
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<meta name="citation_title" content="Cy5.5-labeled pH low insertion peptide (pHLIP)">
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<meta name="citation_publisher" content="National Center for Biotechnology Information (US)">
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<meta name="citation_date" content="2009/11/12">
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<meta name="citation_author" content="Liang Shan">
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<meta name="citation_pmid" content="20641819">
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<meta name="DC.Title" content="Cy5.5-labeled pH low insertion peptide (pHLIP)">
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<meta name="description" content="The pH low insertion peptide (pHLIP) is a peptide of 37 amino acids that inserts across the cell membrane as an α-helix when the extracellular pH (pHe) is acidic (1-4). pHLIP labeled with the near-infrared (NIR) fluorescent marker Cy5.5 (pHLIP-Cy5.5) was developed by Andreev et al. for optical mapping of areas (tumor and arthritis) of elevated acidity in the small animals (1).">
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<meta name="og:description" content="The pH low insertion peptide (pHLIP) is a peptide of 37 amino acids that inserts across the cell membrane as an α-helix when the extracellular pH (pHe) is acidic (1-4). pHLIP labeled with the near-infrared (NIR) fluorescent marker Cy5.5 (pHLIP-Cy5.5) was developed by Andreev et al. for optical mapping of areas (tumor and arthritis) of elevated acidity in the small animals (1).">
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id="jr-fip-info-p"><a id="jr-fip-prev" class="wsprkl btn" title="Jump to previuos match">◀</a><button id="jr-fip-matches">no matches yet</button><a id="jr-fip-next" class="wsprkl btn" title="Jump to next match">▶</a></nav></nav></div><div id="jr-epub-interstitial" class="hidden"></div><div id="jr-content"><article data-type="main"><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK23623_"><span class="title" itemprop="name">Cy5.5-labeled pH low insertion peptide (pHLIP)</span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">pHLIP-Cy5.5</div><p class="contribs">Shan L.</p><p class="fm-aai"><a href="#_NBK23623_pubdet_">Publication Details</a></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figPHLIPCy5T1"><a href="/books/NBK23623/table/PHLIP-Cy5.T1/?report=objectonly" target="object" title="Table" class="img_link icnblk_img" rid-ob="figobPHLIPCy5T1"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="PHLIP-Cy5.T1"><a href="/books/NBK23623/table/PHLIP-Cy5.T1/?report=objectonly" target="object" rid-ob="figobPHLIPCy5T1">Table</a></h4><p class="float-caption no_bottom_margin">
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<i>In vitro</i>
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Rodents
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</p></div></div><div id="PHLIP-Cy5.Background"><h2 id="_PHLIP-Cy5_Background_">Background</h2><p>[<a href="/sites/entrez?cmd=PureSearch&db=pubmed&term=pHLIP" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PubMed</a>]</p><p>The pH low insertion peptide (pHLIP) is a peptide of 37 amino acids that inserts across the cell membrane as an α-helix when the extracellular pH (pH<sub>e</sub>) is acidic (<a class="bibr" href="#PHLIP-Cy5.REF.1" rid="PHLIP-Cy5.REF.1 PHLIP-Cy5.REF.2 PHLIP-Cy5.REF.3 PHLIP-Cy5.REF.4">1-4</a>). pHLIP labeled with the near-infrared (NIR) fluorescent marker Cy5.5 (pHLIP-Cy5.5) was developed by Andreev et al. for optical mapping of areas (tumor and arthritis) of elevated acidity in the small animals (<a class="bibr" href="#PHLIP-Cy5.REF.1" rid="PHLIP-Cy5.REF.1">1</a>).</p><p>Tumor microenvironment is characterized by low pH<sub>e</sub> (<a class="bibr" href="#PHLIP-Cy5.REF.5" rid="PHLIP-Cy5.REF.5 PHLIP-Cy5.REF.6">5, 6</a>). Almost all solid tumors have a neutral to alkaline intracellular pH (pH<sub>i</sub>), but they develop an acidic pH<sub>e</sub> (known as the Warburg effect, <a href="http://nobelprize.org/nobel_prizes/medicine/laureates/1931/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Nobel Prize in 1931</a>). The average pH<sub>e</sub> could be as low as 6.0 (<a class="bibr" href="#PHLIP-Cy5.REF.7" rid="PHLIP-Cy5.REF.7 PHLIP-Cy5.REF.8 PHLIP-Cy5.REF.9">7-9</a>). A pH gradient (pH<sub>i</sub> > pH<sub>e</sub>) exists across the cell membrane in tumors. This gradient is contrary to that found in normal tissues, in which pH<sub>i</sub> is lower than pH<sub>e</sub> (7.2–7.4) (<a class="bibr" href="#PHLIP-Cy5.REF.7" rid="PHLIP-Cy5.REF.7 PHLIP-Cy5.REF.8 PHLIP-Cy5.REF.9">7-9</a>). Diffusion of the H<sup>+</sup> ions along concentration gradients from tumors into adjacent normal tissues creates a peritumoral acid gradient (<a class="bibr" href="#PHLIP-Cy5.REF.10" rid="PHLIP-Cy5.REF.10">10</a>). The mechanisms responsible for the low pH<sub>e</sub> include anaerobic glycolysis because of hypoxia, aerobic glycolysis (the Warburg effect), increased metabolic CO<sub>2</sub> production associated with uncontrolled cell growth, and increased activity of ion pumps on the cell membrane (<a class="bibr" href="#PHLIP-Cy5.REF.5" rid="PHLIP-Cy5.REF.5 PHLIP-Cy5.REF.7">5, 7</a>).</p><p>Low pH<sub>e</sub> affects many aspects of tumor physiology. It is one of the driving forces in the clonal selection leading to invasive and metastatic diseases (<a class="bibr" href="#PHLIP-Cy5.REF.11" rid="PHLIP-Cy5.REF.11 PHLIP-Cy5.REF.12">11, 12</a>). Rofstad et al. have shown that lowering culture pH to 6.8 results in a promotion of <i>in vivo</i> metastasis of treated human melanoma cells compared with controls (cultured at pH 7.4) after tail vein injection of the cells in mice (<a class="bibr" href="#PHLIP-Cy5.REF.13" rid="PHLIP-Cy5.REF.13">13</a>). Exposure of tumor cells to an acidic environment leads to increased expression of various factors that contribute to tumor progression (<a class="bibr" href="#PHLIP-Cy5.REF.12" rid="PHLIP-Cy5.REF.12">12</a>). Tumor cells are able to maintain a high proliferation rate in the acidic environment, whereas the peritumoral acid gradient limits immune response to tumor antigens and induces normal cell apoptosis, extracellular matrix degradation, and angiogenesis (<a class="bibr" href="#PHLIP-Cy5.REF.7" rid="PHLIP-Cy5.REF.7 PHLIP-Cy5.REF.11">7, 11</a>). The passage of noncarrier-mediated weak drugs through the cell membranes is also influenced by the acidic pH<sub>e</sub> (<a class="bibr" href="#PHLIP-Cy5.REF.14" rid="PHLIP-Cy5.REF.14 PHLIP-Cy5.REF.15 PHLIP-Cy5.REF.16">14-16</a>). Typically, the drugs in an uncharged state (lipophilic form) pass more efficiently through the cell membranes. This leads to the hypothesis of ‘ion-trapping’ that weakly basic drugs will concentrate in more acidic compartments (<a class="bibr" href="#PHLIP-Cy5.REF.14" rid="PHLIP-Cy5.REF.14 PHLIP-Cy5.REF.15">14, 15</a>). The acid pH<sub>e</sub> of tumors will therefore hinder weakly basic drugs from reaching their intracellular targets, thereby reducing cytotoxicity (<a class="bibr" href="#PHLIP-Cy5.REF.16" rid="PHLIP-Cy5.REF.16">16</a>). Conversely, the acid pH<sub>e</sub> of tumors will improve uptake of weak acids into the relatively neutral intracellular space (<a class="bibr" href="#PHLIP-Cy5.REF.17" rid="PHLIP-Cy5.REF.17">17</a>). The currently used chemotherapeutic drugs such as mitoxantrone, doxorubicin, daunorubicin, anthracyclines, anthraquinones and vinca alkaloids are all weak bases (pKa 5.5–6.8), while cyclophosphamide, 5-fluorouracil and chlorambucil are weak acids (pKa 7.8–8.8) (<a class="bibr" href="#PHLIP-Cy5.REF.15" rid="PHLIP-Cy5.REF.15">15</a>). Both <i>in vitro</i> and <i>in vivo</i> studies have shown that the activities of those weak bases are inhibited by the low pH<sub>e</sub> (<a class="bibr" href="#PHLIP-Cy5.REF.14" rid="PHLIP-Cy5.REF.14 PHLIP-Cy5.REF.15 PHLIP-Cy5.REF.16">14-16</a>). On the contrary, the actions of the weak acids are enhanced by the low pH<sub>e</sub>. The pH gradient in tumors exerts a protective effect upon the cells from weak-base drugs as well as acts to potentiate the action of weak acid drugs (<a class="bibr" href="#PHLIP-Cy5.REF.17" rid="PHLIP-Cy5.REF.17">17</a>). Studies have consistently shown that selective tumor alkalinization <i>in vivo</i> is likely to result in an enhancement in the anti-tumor activity of weakly basic chemotherapeutic drugs (<a class="bibr" href="#PHLIP-Cy5.REF.18" rid="PHLIP-Cy5.REF.18 PHLIP-Cy5.REF.19">18, 19</a>). Low pH<sub>e</sub> has also been shown to impair the effectiveness of some drugs such as paclitaxel in that their chemical structures do not predict pH-dependent ionization (<a class="bibr" href="#PHLIP-Cy5.REF.7" rid="PHLIP-Cy5.REF.7">7</a>). In addition, radiation therapies are known to be significantly less effective at the hypoxic and acidic regions of tumor (<a class="bibr" href="#PHLIP-Cy5.REF.20" rid="PHLIP-Cy5.REF.20">20</a>).</p><p>An understanding of the mechanisms involved in tumor-specific low pH<sub>e</sub> leads to the development of targeted therapeutic approaches (<a class="bibr" href="#PHLIP-Cy5.REF.6" rid="PHLIP-Cy5.REF.6 PHLIP-Cy5.REF.7">6, 7</a>). Low pH<sub>e</sub> is also considered a promising marker for tumor targeting detection (<a class="bibr" href="#PHLIP-Cy5.REF.4" rid="PHLIP-Cy5.REF.4 PHLIP-Cy5.REF.8">4, 8</a>). The pHLIP interacts with the surface of membranes as an unstructured peptide at neutral pH<sub>e</sub>, but at acidic pH<sub>e</sub> (<7.0) it inserts across the membrane and forms a stable transmembrane α-helix (<a class="bibr" href="#PHLIP-Cy5.REF.1" rid="PHLIP-Cy5.REF.1 PHLIP-Cy5.REF.2 PHLIP-Cy5.REF.21 PHLIP-Cy5.REF.22">1, 2, 21, 22</a>). The pHLIP affinity for membranes at low pH (5.0) is 20 times higher than that at high pH (8.0). Studies by Zoonens et al. showed that the pHLIP could translocate cell-impermeable cargo molecules across a cell membrane and release them in the cytoplasm (<a class="bibr" href="#PHLIP-Cy5.REF.23" rid="PHLIP-Cy5.REF.23">23</a>). The process is mediated by the formation of a transmembrane α-helix because of increased peptide hydrophobicity associated with the protonation of Asp residues at low pH (<a class="bibr" href="#PHLIP-Cy5.REF.1" rid="PHLIP-Cy5.REF.1 PHLIP-Cy5.REF.22">1, 22</a>). Replacement of the two key Asp residues located in the transmembrane part of pHLIP with Lys or Asn leads to the loss of pH-sensitive membrane insertion (<a class="bibr" href="#PHLIP-Cy5.REF.3" rid="PHLIP-Cy5.REF.3">3</a>). Andreev et al. labeled the pHLIP with Cy5.5 and tested its feasibility for optical mapping of tumor and arthritis which were characterized by elevated acidity (<a class="bibr" href="#PHLIP-Cy5.REF.1" rid="PHLIP-Cy5.REF.1">1</a>).</p><p>Optical fluorescence imaging is increasingly being used to monitor biological functions of specific targets in small animals (<a class="bibr" href="#PHLIP-Cy5.REF.24" rid="PHLIP-Cy5.REF.24 PHLIP-Cy5.REF.25 PHLIP-Cy5.REF.26">24-26</a>). However, the intrinsic fluorescence of biomolecules poses a problem when fluorophores that absorb visible light are used. Near-infrared (NIR) fluorescence detection avoids the natural background fluorescence interference of biomolecules, providing a high contrast between target and background tissues in small animals. NIR fluorophores have a wider dynamic range and minimal background fluorescence as a result of reduced scattering compared with visible fluorescence detection. NIR fluorophores also have high sensitivity, attributable to low background fluorescence, and high extinction coefficients, which provide high quantum yields. The NIR region is also compatible with solid-state optical components, such as diode lasers and silicon detectors. NIR fluorescence imaging is a non-invasive alternative to radionuclide imaging in small animals (<a class="bibr" href="#PHLIP-Cy5.REF.27" rid="PHLIP-Cy5.REF.27 PHLIP-Cy5.REF.28">27, 28</a>).</p></div><div id="PHLIP-Cy5.Synthesis"><h2 id="_PHLIP-Cy5_Synthesis_">Synthesis</h2><p>[<a href="/entrez/query.fcgi?cmd=PureSearch&db=pubmed&details_term=pHLIP" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PubMed</a>]</p><p>Four peptides (L-pHLIP, D-pHLIP, N-pHLIP, and K-pHLIP) were designed by Andreev et al. (1). L-pHLIP and D-pHLIP were synthesized with the same sequence but from L- and <span class="small-caps">D</span>-amino acids, respectively. The pHLIP peptide sequence was ACEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTG. N-pHLIP and K-pHLIP were used as controls. In N-pHLIP and K-pHLIP, Asn and Lys replaced Asp residues, which are protonated at low pH and drives pHLIP insertion into membrane. All peptides were prepared with solid-phase peptide synthesis using standard 9-fluorenylmethyloxycarbonyl chemistry and purified with reverse-phase chromatography. NIR fluorescent dye Cy5.5 was conjugated with Cys or Lys residues placed on the pHLIP N terminus, which remains outside the cell when the peptide inserts across the lipid bilayer. The detailed purity and degree of labeling of the pHLIP-Cy5.5 conjugate were not reported.</p></div><div id="PHLIP-Cy5.In_Vitro_Studies_Tes"><h2 id="_PHLIP-Cy5_In_Vitro_Studies_Tes_"><i>In Vitro</i> Studies: Testing in Cells and Tissues</h2><p>[<a href="/entrez/query.fcgi?cmd=PureSearch&db=pubmed&details_term=pHLIP" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PubMed</a>]</p><p>Andreev et al. analyzed the molecular mechanism of pHLIP insertion <i>in vitro</i> using liposomes and human red blood cells (RBCs) (<a class="bibr" href="#PHLIP-Cy5.REF.1" rid="PHLIP-Cy5.REF.1">1</a>). In the presence of liposomes, pHLIP inserted into the lipid bilayer with perpendicular orientation and formed transmembrane α-helix at low pH (4.5) (<a class="bibr" href="#PHLIP-Cy5.REF.1" rid="PHLIP-Cy5.REF.1 PHLIP-Cy5.REF.29">1, 29</a>). The control K-pHLIP did not show secondary structure changes and remained outside the membrane at pH 4.5 and pH 8.0. N-pHLIP formed an α-helical structure and was found primarily in the membrane over a wide pH range (4.0–8.0). With concentrations up to 10 µM, pHLIP did not cause lysis of the human RBCs at pH 6.0 or pH 7.4 after incubation with RBCs for 1 h at room temperature. Morphologically, incubation of the RBCs (1% suspension) with pHLIP (5 μM) for 15 min resulted in the appearance of spicules on the surface of 67% of the cells at normal pH (7.4), but only on 13% of the cells at low pH (6.0). K-pHLIP (5 μM) induced formation of echinocytes at both pH levels (57% of cells at pH 7.4 and 55% of cells at pH 6.0), and N-pHLIP (5 μM) did not induce shape changes in RBCs (74% and 83% of the cells were discocytes at the respective pH levels). The results indicate that pHLIP inserts into the membrane at low pH (6.0), whereas K-pHLIP weakly binds to the membrane surface and N-pHLIP interacts with lipid vesicles and forms α-helical structure at both pH levels.</p></div><div id="PHLIP-Cy5.Animal_Studies"><h2 id="_PHLIP-Cy5_Animal_Studies_">Animal Studies</h2><div id="PHLIP-Cy5.Rodents"><h3>Rodents</h3><p>[<a href="/entrez/query.fcgi?cmd=PureSearch&db=pubmed&details_term=pHLIP" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PubMed</a>]</p><p>Andreev et al. tested the ability of pHLIP-Cy5.5 to accumulate in tumors with low pH<sub>e</sub> and inflammatory arthritis as another model of low pH (<a class="bibr" href="#PHLIP-Cy5.REF.1" rid="PHLIP-Cy5.REF.1">1</a>). Mouse tumors were established with subcutaneous injection of murine breast adenocarcinoma cells (CRL-2116) in the right flank of female C3D2F1 mice (number of animals not reported). pHLIP-Cy5.5 (500 µg/kg) was given as a single intraperitoneal injection into the left side of the mice. Optical imaging showed that pHLIP-Cy5.5 was redistributed and concentrated in tumors within 20 h after injection. pHLIP-Cy5.5 was able to mark tumors of various sizes with high accuracy. The fluorescent signal in tumors was stable for 4 days and was ~5 times higher than in the healthy counterpart tissue (<i>n</i> > 20 animals). No specific accumulations were observed in tumors for Cy5.5 dye alone, K-pHLIP-Cy5.5, and N-pHLIP-Cy5.5. Arthritis was induced in the right knee joints with the use of methylated bovine serum albumin and Freund's complete adjuvant. After intraperitoneal injection of pHLIP-Cy5.5 (30 µg/kg), pHLIP-Cy5.5 targeted the inflammatory site in the right leg with no accumulation in the left (control) leg. The fluorescent signal was 4–5 times higher in the right than in the left knee joints.</p><p>No significant difference was observed between the accumulation of L-pHLIP-Cy5.5 and D-pHLIP-Cy5.5 in tumor, inflammatory foci, and kidney, indicating that the peptide insertion process does not depend on amino acid chirality. Buffering the feed water to pH 8.2 resulted in ~50% reduction of the fluorescent signal in the kidneys of mice (number of animals not reported) There was no significant accumulation in the liver or other organs. A preliminary toxicity study showed no physiological or behavioral changes within 2 months after intravenous injection of <span class="small-caps">L</span>-pHLIP and <span class="small-caps">D</span>-pHLIP (4 mg/kg) in 4-week-old female and male mice (number of animals not reported).</p><p>Andreev et al. concluded that pHLIP nanotechnology offers an approach for mapping areas of elevated acidity in the body, possibly enabling the study of pathological processes, diagnosis of diseases, treatment by delivery of molecules to affected areas, and monitoring of therapeutic outcomes. The authors have reported similar results by labeling pHLIP with NIR dye Alexa750 (detailed data not shown) (<a class="bibr" href="#PHLIP-Cy5.REF.1" rid="PHLIP-Cy5.REF.1">1</a>). Vāvere et al. labeled the same peptide with <sup>64</sup>Cu (<a href="/bookshelf/corehtml/pmc/homepages/bookshelf/micad.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri"><sup>64</sup>Cu-DOTA-pHLIP</a>) and used it for positron emission tomography imaging of low pH<sub>e</sub> in prostate tumor xenografts (<a class="bibr" href="#PHLIP-Cy5.REF.4" rid="PHLIP-Cy5.REF.4">4</a>).</p></div><div id="PHLIP-Cy5.Other_NonPrimate_Mam"><h3>Other Non-Primate Mammals</h3><p>[<a href="/entrez/query.fcgi?cmd=PureSearch&db=pubmed&details_term=pHLIP+pH+imaging" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PubMed</a>]</p><p>No references are currently available.</p></div><div id="PHLIP-Cy5.NonHuman_Primates"><h3>Non-Human Primates</h3><p>[<a href="/entrez/query.fcgi?cmd=PureSearch&db=pubmed&details_term=pHLIP+pH+imaging" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PubMed</a>]</p><p>No references are currently available.</p></div></div><div id="PHLIP-Cy5.Human_Studies"><h2 id="_PHLIP-Cy5_Human_Studies_">Human Studies</h2><p>[<a href="/entrez/query.fcgi?cmd=PureSearch&db=pubmed&details_term=pHLIP+pH+imaging" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PubMed</a>]</p><p>No references are currently available.</p></div><div id="PHLIP-Cy5.NIH_Support"><h2 id="_PHLIP-Cy5_NIH_Support_">NIH Support</h2><p>P20RR016457, GM070895, GM073857</p></div><div id="PHLIP-Cy5.References"><h2 id="_PHLIP-Cy5_References_">References</h2><dl class="temp-labeled-list"><dl class="bkr_refwrap"><dt>1.</dt><dd><div class="bk_ref" id="PHLIP-Cy5.REF.1">Andreev O.A., Dupuy A.D., Segala M., Sandugu S., Serra D.A., Chichester C.O., Engelman D.M., Reshetnyak Y.K.
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<em>Mechanism and uses of a membrane peptide that targets tumors and other acidic tissues in vivo.</em>
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<span><span class="ref-journal">Proc Natl Acad Sci U S A. </span>2007;<span class="ref-vol">104</span>(19):7893–8.</span> [<a href="/pmc/articles/PMC1861852/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1861852</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/17483464" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17483464</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>2.</dt><dd><div class="bk_ref" id="PHLIP-Cy5.REF.2">Reshetnyak Y.K., Andreev O.A., Lehnert U., Engelman D.M.
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<em>Translocation of molecules into cells by pH-dependent insertion of a transmembrane helix.</em>
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<span><span class="ref-journal">Proc Natl Acad Sci U S A. </span>2006;<span class="ref-vol">103</span>(17):6460–5.</span> [<a href="/pmc/articles/PMC1435408/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1435408</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/16608910" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16608910</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>3.</dt><dd><div class="bk_ref" id="PHLIP-Cy5.REF.3">Reshetnyak Y.K., Segala M., Andreev O.A., Engelman D.M.
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<em>A monomeric membrane peptide that lives in three worlds: in solution, attached to, and inserted across lipid bilayers.</em>
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<span><span class="ref-journal">Biophys J. </span>2007;<span class="ref-vol">93</span>(7):2363–72.</span> [<a href="/pmc/articles/PMC1965453/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1965453</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/17557792" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17557792</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>4.</dt><dd><div class="bk_ref" id="PHLIP-Cy5.REF.4">Vavere A.L., Biddlecombe G.B., Spees W.M., Garbow J.R., Wijesinghe D., Andreev O.A., Engelman D.M., Reshetnyak Y.K., Lewis J.S.
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<em>A novel technology for the imaging of acidic prostate tumors by positron emission tomography.</em>
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<span><span class="ref-journal">Cancer Res. </span>2009;<span class="ref-vol">69</span>(10):4510–6.</span> [<a href="/pmc/articles/PMC2690701/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2690701</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19417132" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19417132</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>5.</dt><dd><div class="bk_ref" id="PHLIP-Cy5.REF.5">Fukumura D., Jain R.K.
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<em>Tumor microenvironment abnormalities: causes, consequences, and strategies to normalize.</em>
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<span><span class="ref-journal">J Cell Biochem. </span>2007;<span class="ref-vol">101</span>(4):937–49.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17171643" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17171643</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>6.</dt><dd><div class="bk_ref" id="PHLIP-Cy5.REF.6">Izumi H., Torigoe T., Ishiguchi H., Uramoto H., Yoshida Y., Tanabe M., Ise T., Murakami T., Yoshida T., Nomoto M., Kohno K.
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<em>Cellular pH regulators: potentially promising molecular targets for cancer chemotherapy.</em>
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<span><span class="ref-journal">Cancer Treat Rev. </span>2003;<span class="ref-vol">29</span>(6):541–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/14585264" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14585264</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>7.</dt><dd><div class="bk_ref" id="PHLIP-Cy5.REF.7">Cairns R., Papandreou I., Denko N.
|
|
<em>Overcoming physiologic barriers to cancer treatment by molecularly targeting the tumor microenvironment.</em>
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|
<span><span class="ref-journal">Mol Cancer Res. </span>2006;<span class="ref-vol">4</span>(2):61–70.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16513837" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16513837</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>8.</dt><dd><div class="bk_ref" id="PHLIP-Cy5.REF.8">Pathak A.P., Gimi B., Glunde K., Ackerstaff E., Artemov D., Bhujwalla Z.M.
|
|
<em>Molecular and functional imaging of cancer: advances in MRI and MRS.</em>
|
|
<span><span class="ref-journal">Methods Enzymol. </span>2004;<span class="ref-vol">386</span>:3–60.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15120245" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15120245</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>9.</dt><dd><div class="bk_ref" id="PHLIP-Cy5.REF.9">Penet M.F., Glunde K., Jacobs M.A., Pathak A.P., Bhujwalla Z.M.
|
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<em>Molecular and functional MRI of the tumor microenvironment.</em>
|
|
<span><span class="ref-journal">J Nucl Med. </span>2008;<span class="ref-vol">49</span>(5):687–90.</span> [<a href="/pmc/articles/PMC3075060/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3075060</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18413382" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18413382</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>10.</dt><dd><div class="bk_ref" id="PHLIP-Cy5.REF.10">Gatenby R.A., Gawlinski E.T., Gmitro A.F., Kaylor B., Gillies R.J.
|
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<em>Acid-mediated tumor invasion: a multidisciplinary study.</em>
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<span><span class="ref-journal">Cancer Res. </span>2006;<span class="ref-vol">66</span>(10):5216–23.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16707446" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16707446</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>11.</dt><dd><div class="bk_ref" id="PHLIP-Cy5.REF.11">Lunt S.J., Chaudary N., Hill R.P.
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<em>The tumor microenvironment and metastatic disease.</em>
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<span><span class="ref-journal">Clin Exp Metastasis. </span>2009;<span class="ref-vol">26</span>(1):19–34.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18543068" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18543068</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>12.</dt><dd><div class="bk_ref" id="PHLIP-Cy5.REF.12">Joyce J.A., Pollard J.W.
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<em>Microenvironmental regulation of metastasis.</em>
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|
<span><span class="ref-journal">Nat Rev Cancer. </span>2009;<span class="ref-vol">9</span>(4):239–52.</span> [<a href="/pmc/articles/PMC3251309/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3251309</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19279573" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19279573</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>13.</dt><dd><div class="bk_ref" id="PHLIP-Cy5.REF.13">Rofstad E.K., Mathiesen B., Kindem K., Galappathi K.
|
|
<em>Acidic extracellular pH promotes experimental metastasis of human melanoma cells in athymic nude mice.</em>
|
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<span><span class="ref-journal">Cancer Res. </span>2006;<span class="ref-vol">66</span>(13):6699–707.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16818644" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16818644</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>14.</dt><dd><div class="bk_ref" id="PHLIP-Cy5.REF.14">Raghunand N., Mahoney B.P., Gillies R.J.
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<em>Tumor acidity, ion trapping and chemotherapeutics. II. pH-dependent partition coefficients predict importance of ion trapping on pharmacokinetics of weakly basic chemotherapeutic agents.</em>
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<span><span class="ref-journal">Biochem Pharmacol. </span>2003;<span class="ref-vol">66</span>(7):1219–29.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/14505801" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14505801</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>15.</dt><dd><div class="bk_ref" id="PHLIP-Cy5.REF.15">Mahoney B.P., Raghunand N., Baggett B., Gillies R.J.
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<em>Tumor acidity, ion trapping and chemotherapeutics. I. Acid pH affects the distribution of chemotherapeutic agents in vitro.</em>
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<span><span class="ref-journal">Biochem Pharmacol. </span>2003;<span class="ref-vol">66</span>(7):1207–18.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/14505800" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14505800</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>16.</dt><dd><div class="bk_ref" id="PHLIP-Cy5.REF.16">Gerweck L.E., Kozin S.V., Stocks S.J.
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<em>The pH partition theory predicts the accumulation and toxicity of doxorubicin in normal and low-pH-adapted cells.</em>
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<span><span class="ref-journal">Br J Cancer. </span>1999;<span class="ref-vol">79</span>(5-6):838–42.</span> [<a href="/pmc/articles/PMC2362684/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2362684</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/10070878" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10070878</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>17.</dt><dd><div class="bk_ref" id="PHLIP-Cy5.REF.17">Kozin S.V., Shkarin P., Gerweck L.E.
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<em>The cell transmembrane pH gradient in tumors enhances cytotoxicity of specific weak acid chemotherapeutics.</em>
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<span><span class="ref-journal">Cancer Res. </span>2001;<span class="ref-vol">61</span>(12):4740–3.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11406545" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11406545</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>18.</dt><dd><div class="bk_ref" id="PHLIP-Cy5.REF.18">Silva A.S., Yunes J.A., Gillies R.J., Gatenby R.A.
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<em>The potential role of systemic buffers in reducing intratumoral extracellular pH and acid-mediated invasion.</em>
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<span><span class="ref-journal">Cancer Res. </span>2009;<span class="ref-vol">69</span>(6):2677–84.</span> [<a href="/pmc/articles/PMC3718046/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3718046</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19276380" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19276380</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>19.</dt><dd><div class="bk_ref" id="PHLIP-Cy5.REF.19">Swietach P., Vaughan-Jones R.D., Harris A.L.
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<em>Regulation of tumor pH and the role of carbonic anhydrase 9.</em>
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<span><span class="ref-journal">Cancer Metastasis Rev. </span>2007;<span class="ref-vol">26</span>(2):299–310.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17415526" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17415526</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>20.</dt><dd><div class="bk_ref" id="PHLIP-Cy5.REF.20">Vaupel P.
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<em>Tumor microenvironmental physiology and its implications for radiation oncology.</em>
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<span><span class="ref-journal">Semin Radiat Oncol. </span>2004;<span class="ref-vol">14</span>(3):198–206.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15254862" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15254862</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>21.</dt><dd><div class="bk_ref" id="PHLIP-Cy5.REF.21">Tang J., Gai F.
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<em>Dissecting the membrane binding and insertion kinetics of a pHLIP peptide.</em>
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<span><span class="ref-journal">Biochemistry. </span>2008;<span class="ref-vol">47</span>(32):8250–2.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18636715" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18636715</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>22.</dt><dd><div class="bk_ref" id="PHLIP-Cy5.REF.22">Reshetnyak Y.K., Andreev O.A., Segala M., Markin V.S., Engelman D.M.
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<em>Energetics of peptide (pHLIP) binding to and folding across a lipid bilayer membrane.</em>
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<span><span class="ref-journal">Proc Natl Acad Sci U S A. </span>2008;<span class="ref-vol">105</span>(40):15340–5.</span> [<a href="/pmc/articles/PMC2556629/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2556629</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18829441" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18829441</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>23.</dt><dd><div class="bk_ref" id="PHLIP-Cy5.REF.23">Zoonens M., Reshetnyak Y.K., Engelman D.M.
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<em>Bilayer interactions of pHLIP, a peptide that can deliver drugs and target tumors.</em>
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<span><span class="ref-journal">Biophys J. </span>2008;<span class="ref-vol">95</span>(1):225–35.</span> [<a href="/pmc/articles/PMC2426637/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2426637</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18359793" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18359793</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>24.</dt><dd><div class="bk_ref" id="PHLIP-Cy5.REF.24">Achilefu S.
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<em>Lighting up tumors with receptor-specific optical molecular probes.</em>
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<span><span class="ref-journal">Technol Cancer Res Treat. </span>2004;<span class="ref-vol">3</span>(4):393–409.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15270591" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15270591</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>25.</dt><dd><div class="bk_ref" id="PHLIP-Cy5.REF.25">Ntziachristos V., Bremer C., Weissleder R.
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<em>Fluorescence imaging with near-infrared light: new technological advances that enable in vivo molecular imaging.</em>
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<span><span class="ref-journal">Eur Radiol. </span>2003;<span class="ref-vol">13</span>(1):195–208.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12541130" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12541130</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>26.</dt><dd><div class="bk_ref" id="PHLIP-Cy5.REF.26">Becker A., Hessenius C., Licha K., Ebert B., Sukowski U., Semmler W., Wiedenmann B., Grotzinger C.
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<em>Receptor-targeted optical imaging of tumors with near-infrared fluorescent ligands.</em>
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<span><span class="ref-journal">Nat Biotechnol. </span>2001;<span class="ref-vol">19</span>(4):327–31.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11283589" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11283589</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>27.</dt><dd><div class="bk_ref" id="PHLIP-Cy5.REF.27">Robeson W., Dhawan V., Belakhlef A., Ma Y., Pillai V., Chaly T., Margouleff C., Bjelke D., Eidelberg D.
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<em>Dosimetry of the dopamine transporter radioligand 18F-FPCIT in human subjects.</em>
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<span><span class="ref-journal">J Nucl Med. </span>2003;<span class="ref-vol">44</span>(6):961–6.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12791826" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12791826</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>28.</dt><dd><div class="bk_ref" id="PHLIP-Cy5.REF.28">Tung C.H.
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<em>Fluorescent peptide probes for in vivo diagnostic imaging.</em>
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<span><span class="ref-journal">Biopolymers. </span>2004;<span class="ref-vol">76</span>(5):391–403.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15389488" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15389488</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>29.</dt><dd><div class="bk_ref" id="PHLIP-Cy5.REF.29">Hunt J.F., Rath P., Rothschild K.J., Engelman D.M.
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<em>Spontaneous, pH-dependent membrane insertion of a transbilayer alpha-helix.</em>
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<span><span class="ref-journal">Biochemistry. </span>1997;<span class="ref-vol">36</span>(49):15177–92.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9398245" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9398245</span></a>]</div></dd></dl></dl></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK23623_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><div class="contrib half_rhythm"><span itemprop="author">Liang Shan</span>, PhD<div class="affiliation small">National Center for Biotechnology Information, NLM, NIH<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="vog.hin.mln.ibcn@dacim" class="oemail">vog.hin.mln.ibcn@dacim</a></div></div><div class="small">Corresponding author.</div></div><h3>Publication History</h3><p class="small">Created: <span itemprop="datePublished">August 8, 2009</span>; Last Update: <span itemprop="dateModified">November 12, 2009</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright Notice</a></div></div><h3>Publisher</h3><p><a href="http://www.ncbi.nlm.nih.gov/" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">National Center for Biotechnology Information (US)</a>, Bethesda (MD)</p><h3>NLM Citation</h3><p>Shan L. Cy5.5-labeled pH low insertion peptide (pHLIP) 2009 Aug 8 [Updated 2009 Nov 12]. In: Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013. <span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"><a href="/books/n/micad/Knottin25FCy55/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a></div><div class="small-screen-next"><a href="/books/n/micad/AF489-Cy55/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div></article><article data-type="table-wrap" id="figobPHLIPCy5T1"><div id="PHLIP-Cy5.T1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK23623/table/PHLIP-Cy5.T1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__PHLIP-Cy5.T1_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">
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<b>Chemical name:</b>
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</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">ACEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTG-Cy5.5</td><td rowspan="9" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">
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<b>Abbreviated name:</b>
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</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">pHLIP-Cy5.5</td></tr><tr><td rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">
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<b>Synonym:</b>
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</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">
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<b>Agent Category:</b>
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</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Peptide</td></tr><tr><td rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">
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<b>Target:</b>
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</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Low pH</td></tr><tr><td rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">
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<b>Target Category:</b>
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</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Others</td></tr><tr><td rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">
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<b>Method of detection:</b>
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</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Near-infrared fluorescence optical imaging</td></tr><tr><td rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">
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<b>Source of signal / contrast:</b>
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</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Cy5.5</td></tr><tr><td rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">
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<b>Activation:</b>
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</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">No</td></tr><tr><td rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">
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<b>Studies:</b>
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</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<ul class="simple-list"><li class="half_rhythm"><div>
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<img alt="Checkbox" src="/corehtml/pmc/css/bookshelf/2.26/img/studies.checkbox.png" />
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<i>In vitro</i>
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</div></li><li class="half_rhythm"><div>
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<img alt="Checkbox" src="/corehtml/pmc/css/bookshelf/2.26/img/studies.checkbox.png" /> Rodents
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</div></li></ul>
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</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">No structure available.</td></tr></tbody></table></div></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.min.js"> </script></div></div>
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