Physiological processes (e.g., hypoxia, acidity and changes in temperature), which are present in 90% of tumor microenvironments, are considered promising environmental markers for tumor targeting. We propose to employ intrinsic tumor acidity for the detection of tumors by non-invasive nuclear imaging. Our method is based on the pH- selective interaction of pHLIP (pH (Low) Insertion Peptide) with cell membranes. The pHLIP peptide contains 37 residues and at neutral pH it interacts weakly with the surface of membranes, but at acidic pH (<7.0) it inserts across the membrane and forms a stable transmembrane 1-helix. pHLIP conjugated to a PET or SPECT radionuclide, offers the possibility of developing a non-invasive imaging method that will be translatable to the clinical for the diagnosis of solid tumors and metastasis. The major objective of this project is to develop a new approach for the imaging of solid tumors based on pHLIP- based radiopharmaceuticals, with the final goal of translating an agent to the clinic. There are four Specific Aims we plan to undertake in the proposed study (1) To develop conjugation and labeling protocols for determining the optimal 64Cu-pHLIP-based radiopharmaceutical and to perform comparative testing in vitro and in vivo in the LnCAP and PC-3 tumor models;(2) To determine which radiometal results in the optimal in vivo tumor delivery of pHLIP;(3) To develop a conjugation protocol for the preparation of pHLIP-S-S-metal-chelate, and, secondly, to evaluate the intracellular delivery of fluorescent Eu-DOTA by pHLIP on liposomes, cell culture and in vivo by whole-body fluorescent imaging, and, (4) The most promising constructs from SA1, SA2 &SA3 will be studied with PET imaging and pharmacokinetics studies with direct correlation to tumor pHe determined by MRS studies. By combining the knowledge and experience of the two centers (URI and MSKCC), we aim to develop an optimized, novel radiometal- pHLIP peptide construct as a PET imaging agent which will be translatable to the clinic for the diagnosis and monitoring of therapy of primary cancers and metastasis in their earliest stages of development.
PET Imaging of Cancer with pH (Low) Insertion Peptide (pHLIP) The pHLIP peptide contains 37 residues and at neutral pH it interacts weakly with the surface of membranes, but at acidic pH (<7.0) it inserts across the membrane and forms a stable transmembrane 1-helix. By combining the knowledge and experience of the two centers (URI and MSKCC), we aim to develop an optimized, novel radiometal-pHLIP peptide construct as a PET imaging agent which will be translatable to the clinic for the diagnosis and monitoring of therapy of primary prostate cancer and metastasis in their earliest stages of development.
|Wyatt, Linden C; Lewis, Jason S; Andreev, Oleg A et al. (2017) Applications of pHLIP Technology for Cancer Imaging and Therapy. Trends Biotechnol 35:653-664|
|Demoin, Dustin Wayne; Wyatt, Linden C; Edwards, Kimberly J et al. (2016) PET Imaging of Extracellular pH in Tumors with (64)Cu- and (18)F-Labeled pHLIP Peptides: A Structure-Activity Optimization Study. Bioconjug Chem 27:2014-23|
|Carlin, Sean; Zhang, Hanwen; Reese, Megan et al. (2014) A comparison of the imaging characteristics and microregional distribution of 4 hypoxia PET tracers. J Nucl Med 55:515-21|
|Viola-Villegas, Nerissa Therese; Carlin, Sean D; Ackerstaff, Ellen et al. (2014) Understanding the pharmacological properties of a metabolic PET tracer in prostate cancer. Proc Natl Acad Sci U S A 111:7254-9|
|Adochite, Ramona-Cosmina; Moshnikova, Anna; Carlin, Sean D et al. (2014) Targeting breast tumors with pH (low) insertion peptides. Mol Pharm 11:2896-905|
|Cruz-Monserrate, Zobeida; Roland, Christina L; Deng, Defeng et al. (2014) Targeting pancreatic ductal adenocarcinoma acidic microenvironment. Sci Rep 4:4410|
|Emmetiere, Fabien; Irwin, Christopher; Viola-Villegas, Nerissa Therese et al. (2013) (18)F-labeled-bioorthogonal liposomes for in vivo targeting. Bioconjug Chem 24:1784-9|
|Weerakkody, Dhammika; Moshnikova, Anna; Thakur, Mak S et al. (2013) Family of pH (low) insertion peptides for tumor targeting. Proc Natl Acad Sci U S A 110:5834-9|
|Daumar, Pierre; Wanger-Baumann, Cindy A; Pillarsetty, NagaVaraKishore et al. (2012) Efficient (18)F-labeling of large 37-amino-acid pHLIP peptide analogues and their biological evaluation. Bioconjug Chem 23:1557-66|
|Karabadzhak, Alexander G; Weerakkody, Dhammika; Wijesinghe, Dayanjali et al. (2012) Modulation of the pHLIP transmembrane helix insertion pathway. Biophys J 102:1846-55|
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