2. Academic Validation
  3. Co-Packaged PARP inhibitor and photosensitizer for targeted photo-chemotherapy of 3D ovarian cancer spheroids

Co-Packaged PARP inhibitor and photosensitizer for targeted photo-chemotherapy of 3D ovarian cancer spheroids

  • Cell Biosci. 2024 Feb 6;14(1):20. doi: 10.1186/s13578-024-01197-6.
Aaron Sorrin 1,  Anika Dasgupta # 1,  Kathryn McNaughton # 1,  Carla Arnau Del Valle 1,  Keri Zhou 1,  Cindy Liu 1,  Dana M Roque 2 3,  Huang Chiao Huang 4 5
Affiliations

Affiliations

  • 1 Fischell Department of Bioengineering, University of Maryland, College Park, MD, 20742, USA.
  • 2 Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
  • 3 Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD, 21201, USA.
  • 4 Fischell Department of Bioengineering, University of Maryland, College Park, MD, 20742, USA. hchuang@umd.edu.
  • 5 Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD, 21201, USA. hchuang@umd.edu.
  • # Contributed equally.
PMID: 38321470 DOI: 10.1186/s13578-024-01197-6
Abstract

Background: Within the last decade, poly(ADP-ribose) polymerase inhibitors (PARPi) have emerged in the clinic as an effective treatment for numerous malignancies. Preclinical data have demonstrated powerful combination effects of PARPi paired with photodynamic therapy (PDT), which involves light-activation of specialized dyes (photosensitizers) to stimulate Cancer cell death through Reactive Oxygen Species generation.

Results: In this report, the most potent clinical PARP Inhibitor, talazoparib, is loaded into the core of a polymeric nanoparticle (NP-Tal), which is interfaced with antibody-photosensitizer conjugates (photoimmunoconjugates, PICs) to form PIC-NP-Tal. In parallel, a new 3D fluorescent coculture model is developed using the parental OVCAR-8-DsRed2 and the chemo-resistant subline, NCI/ADR-RES-EGFP. This model enables quantification of trends in the evolutionary dynamics of acquired chemoresistance in response to various treatment regimes. Results reveal that at a low dosage (0.01 μM), NP-Tal kills the parental cells while sparing the chemo-resistant subline, thereby driving chemoresistance. Next, PIC-NP-Tal and relevant controls are evaluated in the 3D coculture model at multiple irradiation doses to characterize effects on total spheroid ablation and relative changes in parental and subline cell population dynamics. Total spheroid ablation data shows potent combination effects when PIC and NP-Tal are co-administered, but decreased efficacy with the conjugated formulation (PIC-NP-Tal). Analysis of cell population dynamics reveals that PIC, BPD + NP-Tal, PIC + NP-Tal, and PIC-NP-Tal demonstrate selection pressures towards chemoresistance.

Conclusions: This study provides key insights into manufacturing parameters for PARPi-loaded nanoparticles, as well as the potential role of PDT-based combination therapies in the context of acquired drug resistance.

Keywords

3D spheroid; Cancer organoid; Ovarian cancer; PARP inhibitor; Photodynamic therapy; Photoimmunotherapy; Polymeric nanoparticles.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-16106
    99.89%, PARP抑制剂
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