Light-Triggered Antibody-Photosensitizer Conjugates Disrupt P-Glycoprotein Function to Reverse Multidrug Resistance

Abstract

Ovarian cancer is the deadliest gynecologic disease with a 5-year survival rate of ∼30% for advanced stages. A major cause of poor prognosis is the development of chemoresistance, which accounts for 90% of ovarian cancer deaths. A key mediator of this resistance is the expression of ATP-binding cassette (ABC) drug efflux transporters, particularly P-glycoprotein (P-gp, also known as ABCB1), which is upregulated in response to treatment and confers the development of multidrug resistance (MDR). Existing small molecule inhibitors of P-gp often lack cancer selectivity and are thus associated with normal tissue toxicity. Our team has previously demonstrated that photodynamic therapy (PDT), employing the FDA-approved benzoporphyrin derivative (BPD) photosensitizer, can effectively inhibit ABC transporters in cancer cells. PDT is a localized treatment that utilizes a photosensitizer, a light-activated drug, and light of a specific wavelength to generate cytotoxic reactive oxygen species. However, BPD alone lacks cancer selectivity, making it less suitable for addressing disseminated tumors, such as those found in advanced-stage ovarian cancer. To improve cancer selectivity, we conjugated BPD to an anti-epidermal growth factor receptor (EGFR)-targeting monoclonal antibody (cetuximab) to form a photoimmunoconjugate (PIC). We demonstrate that PIC evades and inhibits P-gp-mediated efflux in chemoresistant ovarian cancer cells. These findings highlight the role of PICs and the importance of understanding their interactions with ABC transporters in combating multidrug resistance in advanced-stage cancer.