Cellular uptake of folate-olaparib conjugates via folate receptor-mediated endocytosis: Potential for selective delivery of DNA damage response inhibitors into tumour cells
- 1Centre for Cancer Drug Discovery, The Institute of Cancer Research, London, UK & The Royal Marsden NHS Foundation Trust, London, UK
Abstract
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 facilitating combination studies of the DDRi-based FDC with DNA damaging chemotherapy. FR-mediated cellular uptake of the proposed folate drug conjugates is requisite for FDC selective delivery into tumours. In this study, we synthesised a series of olaparib-based folate conjugates that maintained the biochemical PARP1 inhibition associated with olaparib and showed binding affinity for the folate receptor. Significantly, we identified compounds 10b and 11 that selectively enter FR overexpressing tumour cells via folate receptor-mediated endocytosis in their intact form and engage with their target as demonstrated by the potent inhibition of PARylation (KB cells, PARylation IC50 = 5.7 and 3.9 nM; respectively).
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BibTeX
@misc{bavetsias2026cellular,
title = {{Cellular uptake of folate-olaparib conjugates via folate receptor-mediated endocytosis: Potential for selective delivery of DNA damage response inhibitors into tumour cells}},
author = {V. Bavetsias and L. Pickard and S. Diaz-Sanchez and S. Gowan and F. Wood and R. Ruddle and C. Wong and H. Sharif and F. Raynaud and R. Burke and A. Wang and J. Blagg and V. Kirkin and O. Rossanese and U. Banerji},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.23.752340},
url = {https://www.biorxiv.org/content/10.64898/2026.09.23.752340v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Cellular uptake of folate-olaparib conjugates via folate receptor-mediated endocytosis: Potential for selective delivery of DNA damage response inhibitors into tumour cells
AU - V. Bavetsias
AU - L. Pickard
AU - S. Diaz-Sanchez
AU - S. Gowan
AU - F. Wood
AU - R. Ruddle
AU - C. Wong
AU - H. Sharif
AU - F. Raynaud
AU - R. Burke
AU - A. Wang
AU - J. Blagg
AU - V. Kirkin
AU - O. Rossanese
AU - U. Banerji
PY - 2026
DA - 2026/09/23
PB - bioRxiv
DO - 10.64898/2026.09.23.752340
UR - https://www.biorxiv.org/content/10.64898/2026.09.23.752340v1
AB - 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 facilitating combination studies of the DDRi-based FDC with DNA damaging chemotherapy. FR-mediated cellular uptake of the proposed folate drug conjugates is requisite for FDC selective delivery into tumours. In this study, we synthesised a series of olaparib-based folate conjugates that maintained the biochemical PARP1 inhibition associated with olaparib and showed binding affinity for the folate receptor. Significantly, we identified compounds 10b and 11 that selectively enter FR overexpressing tumour cells via folate receptor-mediated endocytosis in their intact form and engage with their target as demonstrated by the potent inhibition of PARylation (KB cells, PARylation IC50 = 5.7 and 3.9 nM; respectively).
ER -