Repurposing Approved Chemotherapeutics as Intrinsic Photosensitizers for Single-Molecule Chemophototherapy
Abstract Chemophototherapy (CPT), combining chemotherapy and photodynamic therapy (PDT), is a promising strategy to enhance anticancer efficacy while reducing systemic toxicity. Many approved drugs contain chromophoric moieties that absorb visible light, suggesting their potential as intrinsic photosensitizers. Herein, we introduce a single-molecule chemophototherapy (SM-CPT) approach based on computational screening of approved anticancer drugs for repurposing as photosensitizers. A curated library of 238 small-molecule drugs was screened using time-dependent density functional theory to identify compounds with favourable photophysical properties. Fifteen candidates were identified, and mitoxantrone, pixantrone, daunorubicin, and epirubicin were selected for experimental validation. All compounds generated reactive oxygen species upon irradiation and showed enhanced cytotoxicity in breast cancer cell models, with up to an order-of-magnitude reduction in half-maximal inhibitory concentration values. The approach was further validated in ovarian cancer models, including platinum-resistant cells and patient-derived ascites, highlighting SM-CPT as a translationally attractive light-activated cancer therapy.
Authors
- Francesca Maffei (ORCID: https://orcid.org/0000-0003-4144-230X)
- Michele Trivini
- Giulia Greco (ORCID: https://orcid.org/0000-0001-8174-9977)
- Paolo Emidio Costantini (ORCID: https://orcid.org/0000-0003-1597-6404)
- Giuseppe Gasparre (ORCID: https://orcid.org/0000-0003-1229-9006)
- Manuela Sollazzo (ORCID: https://orcid.org/0000-0001-5451-0063)
- Alessia Marconi (ORCID: https://orcid.org/0000-0002-0738-2211)
- Alberto Danielli (ORCID: https://orcid.org/0000-0002-9414-9898)
- Matteo Calvaresi (ORCID: https://orcid.org/0000-0002-9583-2146)
- Eleonora Turrini (ORCID: https://orcid.org/0000-0003-4743-1126)
- Anna Maria Porcelli (ORCID: https://orcid.org/0000-0002-6209-0692)
- Julia Westermayr (ORCID: https://orcid.org/0000-0002-6531-0742)
- Edoardo Jun Mattioli (ORCID: https://orcid.org/0000-0002-2598-497X)
- Matteo Di Giosia (ORCID: https://orcid.org/0000-0003-3494-298X)
- Tainah Dorina Marforio (ORCID: https://orcid.org/0000-0003-0690-306X)
- Carmela Fimognari (ORCID: https://orcid.org/0000-0002-2461-8214)
- Alessandro Calza
- Giulia Giugliano (ORCID: https://orcid.org/0009-0000-9927-7154)
- Francesco Zerbetto (ORCID: https://orcid.org/0000-0002-2419-057X)
- Manuele Di Sante (ORCID: https://orcid.org/0009-0005-5523-4132)
- Giulia Neggiani (ORCID: https://orcid.org/0009-0007-8836-8713)
Institutions
- Leipzig University of Applied Sciences (DE)
- Azienda USL di Bologna (IT)
- Leipzig University (DE)
- University of Bologna (IT)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-10-12
- DOI
- https://doi.org/10.1021/acs.jmedchem.6c02353
- Primary Topic
- Photodynamic Therapy Research Studies
- Type
- article
- Field-Weighted Citation Impact
- 0.00