title: Targeting breast tumors with pH (low) insertion peptides.
abstract: Extracellular acidity is associated with tumor progression. Elevated glycolysis and acidosis promote the appearance of aggressive malignant cells with enhanced multidrug resistance. Thus, targeting of tumor acidity can open new avenues in diagnosis and treatment of aggressive tumors and targeting metastatic cancers cells within a tumor. pH (low) insertion peptides (pHLIPs) belong to the class of pH-sensitive agents capable of delivering imaging and/or therapeutic agents to cancer cells within tumors. Here, we investigated targeting of highly metastatic 4T1 mammary tumors and spontaneous breast tumors in FVB/N-Tg (MMTV-PyMT)634Mul transgenic mice with three fluorescently labeled pHLIP variants including well-characterized WT-pHLIP and, recently introduced, Var3- and Var7-pHLIPs. The Var3- and Var7-pHLIPs constructs have faster blood clearance than the parent WT-pHLIP. All pHLIPs demonstrated excellent targeting of the above breast tumor models with tumor accumulation increasing over 4 h postinjection. Staining of nonmalignant stromal tissues in transgenic mice was minimal. The pHLIPs distribution in tumors showed colocalization with 2-deoxyglucose and the hypoxia marker, Pimonidazole. The highest degree of colocalization of fluorescent pHLIPs was shown to be with lactate dehydrogenase A, which is related to lactate production and acidification of tumors. In sum, the pHLIP-based targeting of breast cancer presents an opportunity to monitor metabolic changes, and to selectively deliver imaging and therapeutic agents to tumors.
authors.affiliation: Physics Department, University of Rhode Island , 2 Lippitt Road, Kingston, Rhode Island 02881, United States.
authors.forename: Ramona-Cosmina
authors.initials: RC
authors.lastname: Adochite
authors.forename: Anna
authors.initials: A
authors.lastname: Moshnikova
authors.forename: Sean D
authors.initials: SD
authors.lastname: Carlin
authors.forename: Renato A
authors.initials: RA
authors.lastname: Guerrieri
authors.forename: Oleg A
authors.initials: OA
authors.lastname: Andreev
authors.forename: Jason S
authors.initials: JS
authors.lastname: Lewis
authors.forename: Yana K
authors.initials: YK
authors.lastname: Reshetnyak
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000737:chemistry; D045744:Cell Line, Tumor; D003847:Deoxyglucose / Q000737:chemistry; D016503:Drug Delivery Systems; D005260:Female; D006863:Hydrogen-Ion Concentration; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000737:chemistry; D007770:L-Lactate Dehydrogenase / Q000737:chemistry; D000080864:Lactate Dehydrogenase 5; D007773:Lactates / Q000737:chemistry; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009368:Neoplasm Transplantation; D009593:Nitroimidazoles / Q000737:chemistry; D010455:Peptides / Q000737:chemistry*; D013997:Time Factors
chemical_list: D001786:Blood Glucose; D007527:Isoenzymes; D007773:Lactates; D009593:Nitroimidazoles; D010455:Peptides; C033815:pimonidazole; D003847:Deoxyglucose; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5