Cellular uptake of folate-olaparib conjugates via folate receptor-mediated endocytosis: Potential for selective delivery of DNA damage response inhibitors into tumour cells
The folate receptor (FR) is overexpressed in a range of human tumours including ovarian cancer cells. We propose that the overexpression of the FR on the surface of ovarian tumour cells could be exploited for the selective delivery of a DNA damage response inhibitor (DDRi) in the form of an intact folate drug conjugate (FDC). This approach would improve the therapeutic index of the parent DDRi…
Ovarian cancer cells exhibit an overexpression of the folate receptor (FR), a protein that could be harnessed for the selective delivery of a DNA damage response inhibitor (DDRi) in the form of a folate drug conjugate (FDC). The utilization of FR-mediated cellular uptake for FDC selective delivery into tumours is crucial. In this study, researchers synthesized a series of olaparib-based folate conjugates, which retained the PARP1 inhibition exhibited by olaparib and demonstrated binding affinity for the folate receptor.
Compounds 10b and 11 were identified as particularly promising, as they selectively entered FR-overexpressing tumour cells while remaining in their intact form and demonstrating potent inhibition of PARylation in KB cells (with PARylation IC50 values of 5.7 and 3.9 nM, respectively).
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