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Detecting Functional and Accessible Folate Receptor Expression in Cancer and Polycystic Kidneys.
- Source :
-
Molecular pharmaceutics [Mol Pharm] 2019 Sep 03; Vol. 16 (9), pp. 3985-3995. Date of Electronic Publication: 2019 Aug 13. - Publication Year :
- 2019
-
Abstract
- Folate-based small molecule drug conjugates (SMDCs) are currently under development and have shown promising preclinical and clinical results against various cancers and polycystic kidney disease. Two requisites for response to a folate-based SMDC are (i) folate receptor alpha (FRα) protein is expressed in the diseased tissues, and (ii) FRα in those tissues is accessible and functionally competent to bind systemically administered SMDCs. Here we report on the development of a small molecule reporter conjugate (SMRC), called EC2220, which is composed of a folate ligand for FRα binding, a multilysine containing linker that can cross-link to FRα in the presence of formaldehyde fixation, and a small hapten (fluorescein) used for immunohistochemical detection. Data show that EC2220 produces a far greater IHC signal in FRα-positive tissues over that produced with EC17, a folate-fluorescein SMRC that is released from the formaldehyde-denatured FRα protein. Furthermore, the extent of the EC2220 IHC signal was proportional to the level of FRα expression. This EC2220-based assay was qualified both in vitro and in vivo using normal tissue, cancer tissue, and polycystic kidneys. Overall, EC2220 is a sensitive and effective reagent for evaluating functional and accessible receptor expression in vitro and in vivo .
- Subjects :
- A549 Cells
Animals
Doxycycline pharmacology
Fluorescein-5-isothiocyanate chemistry
Fluorescein-5-isothiocyanate metabolism
Folate Receptor 1 analysis
Folic Acid analogs & derivatives
Folic Acid chemistry
Folic Acid metabolism
HeLa Cells
Humans
Lysine analogs & derivatives
Lysine chemistry
Lysine metabolism
Mice
Mice, Inbred BALB C
Mice, Nude
Mice, Transgenic
Neoplasms metabolism
Oligopeptides chemistry
Oligopeptides metabolism
Polycystic Kidney Diseases chemically induced
Polycystic Kidney Diseases metabolism
Protein Kinase C genetics
Tissue Distribution
Trityl Compounds chemistry
Trityl Compounds metabolism
Xenograft Model Antitumor Assays
Folate Receptor 1 metabolism
Molecular Targeted Therapy methods
Neoplasms drug therapy
Polycystic Kidney Diseases drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1543-8392
- Volume :
- 16
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Molecular pharmaceutics
- Publication Type :
- Academic Journal
- Accession number :
- 31356752
- Full Text :
- https://doi.org/10.1021/acs.molpharmaceut.9b00624