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.