Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Jul 10:383:113812.
doi: 10.1016/j.jconrel.2025.113812. Epub 2025 May 2.

Radiation-guided nanoparticles enhance the efficacy of PARP inhibitors in primary and metastatic BRCA1-deficient tumors via immunotherapy

Rami Khoury  1 , Giuseppe Longobardi  1 , Tania T Barnatan  1 , Dana Venkert  2 , América García Alvarado  1 , Adi Yona  1 , Marina Green Buzhor  1 , Shir Shahar  1 , Qiwei Wang  3 , Rita C Acúrcio  4 , Rita C Guedes  4 , Helena F Florindo  4 , Jean J Zhao  5 , Ronit Satchi-Fainaro  6
Affiliations

Radiation-guided nanoparticles enhance the efficacy of PARP inhibitors in primary and metastatic BRCA1-deficient tumors via immunotherapy

Rami Khoury et al. J Control Release. .

Abstract

Poly (ADP-ribose) polymerase inhibitors (PARPi) have revolutionized the treatment landscape for patients suffering from BRCA1-mutated breast and ovarian cancers. However, responses are not durable. We demonstrate that treatment with PARPi, niraparib, increases programmed death-ligand 1 (PD-L1) expression in BRCA1-deficient cancer cells, contributing to immune evasion. To circumvent this, we developed P-selectin-targeted poly (lactic-co-glycolic) acid (PLGA)-poly (ethylene glycol) (PEG)-based nanoparticles (NPs) encapsulating PARP and PD-L1 inhibitors at a synergistic ratio. To further enhance tumor targeting, we leveraged radiation-induced P-selectin upregulation in BRCA1-deficient cancer cells and their associated angiogenic endothelial cells, improving NP accumulation in the primary tumors and hard-to-target metastatic sites, including brain metastasis. Using a combination of traditional 2-dimensional (2D) cell cultures, advanced 3-dimensional (3D) spheroids, tumor-on-a-chip platforms, and in vivo models, we demonstrate the enhanced accumulation and efficacy of the radiation-guided P-selectin-targeted NPs in primary and brain-metastatic BRCA1-deficient tumors.

Keywords: 3D models; BRCA1; Brain metastasis; Breast cancer; Combination therapy; Immunotherapy; Nanoparticles; Ovarian cancer; PARPi; PD-L1; Radiotherapy.

PubMed Disclaimer

Conflict of interest statement

Declaration of competing interest R.S.-F. is a board director at Teva Pharmaceutical Industries Ltd. and receives unrelated research funding from Merck KGaA. R.S.-F. is a cofounder and officer with an equity interest in Selectin Therapeutics Inc. R.S.-F. is an inventor of a related patent, “P-selectin targeted nanoparticles and uses thereof” PCT patent application no. PCT/IL2024/050131 filed on 2 February 2024, by Ramot at TAU. All other authors declare that they have no competing interests.

References

    1. O’Donovan PJ, Livingston DM, BRCA1 and BRCA2: breast/ovarian cancer susceptibility gene products and participants in DNA double-strand break repair, Carcinogenesis 31(6) (2010) 961–967. - PubMed
    1. Tung N, Lin NU, Kidd J, Allen BA, Singh N, Wenstrup RJ, Hartman A-R, Winer EP, Garber JE, Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer, Journal of Clinical Oncology 34(13) (2016) 1460–1468. - PMC - PubMed
    1. Friebel TM, Domchek SM, Rebbeck TR, Modifiers of Cancer Risk in BRCA1 and BRCA2 Mutation Carriers: A Systematic Review and Meta-Analysis, JNCI: Journal of the National Cancer Institute 106(6) (2014). - PMC - PubMed
    1. Mavaddat N, Peock S, Frost D, Ellis S, Platte R, Fineberg E, Evans DG, Izatt L, Eeles RA, Adlard J, Davidson R, Eccles D, Cole T, Cook J, Brewer C, Tischkowitz M, Douglas F, Hodgson S, Walker L, Porteous ME, Morrison PJ, Side LE, Kennedy MJ, Houghton C, Donaldson A, Rogers MT, Dorkins H, Miedzybrodzka Z, Gregory H, Eason J, Barwell J, McCann E, Murray A, Antoniou AC, Easton DF, o.b.o. EMBRACE, Cancer Risks for BRCA1 and BRCA2 Mutation Carriers: Results From Prospective Analysis of EMBRACE, JNCI: Journal of the National Cancer Institute 105(11) (2013) 812–822. - PubMed
    1. Girolimetti G, Perrone AM, Santini D, Barbieri E, Guerra F, Ferrari S, Zamagni C, De Iaco P, Gasparre G, Turchetti D, BRCA-Associated Ovarian Cancer: From Molecular Genetics to Risk Management, BioMed Research International 2014(1) (2014) 787143. - PMC - PubMed

MeSH terms

LinkOut - more resources