Detecting Functional and Accessible Folate Receptor
Expression in Cancer and Polycystic Kidneys
Version 2 2019-08-15, 13:04Version 2 2019-08-15, 13:04
Version 1 2019-08-13, 00:13Version 1 2019-08-13, 00:13
Posted on 2019-08-15 - 13:04
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.
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Chu, Haiyan; Shillingford, Jonathan M.; Reddy, Joseph A.; Westrick, Elaine; Nelson, Melissa; Wang, Emilia Z.; et al. (2019). Detecting Functional and Accessible Folate Receptor
Expression in Cancer and Polycystic Kidneys. ACS Publications. Collection. https://doi.org/10.1021/acs.molpharmaceut.9b00624