Albumin binding revitalizes NQO1 bioactivatable drugs as novel therapeutics for pancreatic cancer

NAD(P)H:quinone oxidoreductase 1 (NQO1) is an enzyme significantly overexpressed in pancreatic ductal adenocarcinoma (PDAC) tumors compared to the associated normal tissues. NQO1 bioactivatable drugs, such as β-lapachone (β-lap), can be catalyzed to generate reactive oxygen species (ROS) for direct tumor killing. However, the extremely narrow therapeutic window caused by methemoglobinemia and hemolytic anemia severely restricts its further clinical translation despite considerable efforts in the past 20 years. Previously, we demonstrated that albumin could be utilized to deliver cytotoxic drugs selectively into KRAS-mutant PDAC with a much expanded therapeutic window due to KRAS-enhanced macropinocytosis and reduced neonatal Fc receptor (FcRn) expression in PDAC. Herein, we analyzed the expression patterns of albumin and FcRn across major organs in LSL-Kras^G12D/+;LSL-Trp53^R172H/+;Pdx-1-Cre (KPC) mice. The tumors were the predominant tissues with both elevated albumin and reduced FcRn expression, thus making them an ideal target for albumin-based drug delivery. Quantitative proteomics analysis of tissue samples from 5 human PDAC patients further confirmed the elevated albumin/FcRn ratio. Given such a compelling biological rationale, we designed a nanoparticle albumin-bound prodrug of β-lap, nab-(pro-β-lap), to achieve PDAC targeted delivery and expand the therapeutic window of β-lap. We found that nab-(pro-β-lap) uptake was profoundly enhanced by KRAS mutation. Compared to the solution formulation of the parent drug β-lap, nab-(pro-β-lap) showed enhanced safety due to much lower rates of methemoglobinemia and hemolytic anemia, which was confirmed both in vitro and in vivo. Furthermore, nab-(pro-β-lap) significantly inhibited tumor growth in subcutaneously implanted KPC xenografts and enhanced the pharmacodynamic endpoints (e.g., PARP1 hyperactivation, γ-H₂AX). Thus, nab-(pro-β-lap), with improved safety and antitumor efficacy, offers a drug delivery strategy with translational viability for β-lap in pancreatic cancer therapy.