Targeting breast tumors with pH (Low) insertion peptides Journal Article
| Authors: | Adochite, R. C.; Moshnikova, A.; Carlin, S. D.; Guerrieri, R. A.; Andreev, O. A.; Lewis, J. S.; Reshetnyak, Y. K. |
| Article 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. © 2014 American Chemical Society. |
| Keywords: | controlled study; unclassified drug; nonhuman; protein localization; animal cell; mouse; metastasis; breast cancer; fluorescence; tumor xenograft; peptide; transgenic mouse; hypoxia; breast tumor; staining; imaging; glucose; lactate dehydrogenase; pimonidazole; tumor growth; ph low insertion peptide; acidification; deoxyglucose; lactate dehydrogenase isoenzyme 5; plasma clearance; female; priority journal; article; transgenic mice model; tumor acidity |
| Journal Title: | Molecular Pharmaceutics |
| Volume: | 11 |
| Issue: | 8 |
| ISSN: | 1543-8384 |
| Publisher: | American Chemical Society |
| Date Published: | 2014-08-04 |
| Start Page: | 2896 |
| End Page: | 2905 |
| Language: | English |
| DOI: | 10.1021/mp5002526 |
| PROVIDER: | scopus |
| PMCID: | PMC4123937 |
| PUBMED: | 25004202 |
| DOI/URL: | |
| Notes: | Export Date: 2 September 2014 -- CODEN: MPOHB -- Source: Scopus |
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