Inhibition of P‐glycoprotein using photoimmunotherapy in peritoneal metastasis mouse model

Up to 80%-90% of recurrent peritoneal metastasis cases exhibit resistance to multiple chemotherapy agents. A major contributor to this multidrug resistance is the active efflux of chemotherapeutics by P-glycoprotein (P-gp), also known as ATP-binding cassette subfamily B member 1 (ABCB1) transporter and multidrug resistance protein 1 (MDR1). Clinical attempts to inhibit P-gp using small molecule inhibitors have been limited by systemic toxicity or poor tumor selectivity, underscoring the need for safer, targeted strategies. To address this challenge, we demonstrated, for the first time, that intraperitoneal photoimmunotherapy (PIT) using a photoimmunoconjugate (PIC) can inhibit the function of P-gp in a mouse model of peritoneal carcinomatosis. PIC was synthesized and characterized, and a sterile filtration protocol was implemented for its in vivo administration and intraperitoneal PIT application. To assess P-gp function following low-dose PIT, in vivo tumor cells were isolated and evaluated for intracellular accumulation of a well-established P-gp substrate (Rhodamine 123). PIC-PIT significantly increased intracellular Rhodamine 123 retention, indicating effective reduction of P-gp activity. This study provides the first in vivo evidence that PIT can inhibit P-gp function, offering a promising, targeted approach to overcoming chemoresistance while avoiding the systemic toxicity associated with conventional P-gp inhibitors.