Controlled Self-Immolative Release of β-Lapachone via an Optimized <i>para</i> -Hydroxybenzyl Linker for Targeted Pancreatic Cancer Therapy

Methodologies to target cancer cells without affecting healthy surrounding cells have the potential to vastly improve both patient outcomes and quality of life. <i>ortho</i>-Quinone natural products such as β-lapachone have exhibited great therapeutic potential, but their clinical use has been limited thus far due to systemic toxicity, making them ideal candidates for targeted prodrug development. Previously developed β-lapachone prodrugs suffered from suboptimal release rates, low solubility, and poor tumor specificity, which have hindered their advancement into the clinic. This work explores the development of an optimized β-lapachone small molecule prodrug platform that utilizes a β-glucuronide-protected <i>para</i>-hydroxybenzyl (PHB) moiety alkylated to one of β-lapachone's carbonyls via an indium-mediated Barbier-type reaction. The β-glucuronide moiety detoxifies and solubilizes the <i>ortho</i>-quinone systemically and triggers specific release in the tumor microenvironment (TME). Additionally, the drug release rate is largely controlled by pH and can be fine-tuned via the addition of electron-donating/withdrawing groups to the PHB self-immolative linker. The prodrug is rationally designed to have numerous layers of pancreatic cancer targeting via the tumor-selective overexpression of the key β-lapachone activating enzymes NQO1 and 5-LO, the TME expression pattern of the release-triggering enzyme β-glucuronidase, and the opportunity for modular attachment to carrier systems targeting pancreatic cancer membrane proteins. Various derivatives of this prodrug have shown promising stability, release, and efficacy against pancreatic cancer cell lines. This unique prodrug platform allows us to mask the toxicity of an <i>ortho</i>-quinone payload and utilize several layers of tumor specificity in the hope of effectively treating pancreatic cancer patients while minimizing toxic side effects.