Towards the clinical translation of a novel autophagy inhibitor: Bisaminoquinoline derivative nanoparticles.

Abstract

Targeting autophagy is a promising strategy to sensitize tumors and overcome drug resistance. BAQ13, a novel autophagy inhibitor that self-assembles into nanoparticles, has demonstrated potent antitumor activity in preclinical models; however, effective clinical translation requires establishing safety and tolerability using a stable and clinical-grade formulation. Here, we report the development and manufacturing of BAQ13-loaded lipid nanoparticles (BAQ13-LNP) using a scalable fluidic approach. BAQ13 was efficiently incorporated with helper lipids (SPC, DSPE-PEG2K, cholesterol), producing uniform nanoparticles (<75 nm, PDI ∼0.2) with complete encapsulation. Long-term shelf stability was achieved through lyophilization with 9% w/v sucrose, preserving the formulation for at least two years at 2-8 °C, while multi-gram production under current Good Manufacturing Practice (cGMP) ensured compliance with USP standards for injectable formulations, establishing readiness for clinical use. BAQ13 retained activity in a broad panel of human cancer cell lines, including those resistant to standard therapies. In pancreatic mouse tumor model, BAQ13-LNP efficiently accumulated in and penetrated deeply into tumor tissue, effectively inhibited tumor growth, and prolonged survival. Together with its favorable safety profile, these data supported the initiation of a Phase 1 clinical trial evaluating BAQ13-LNP (TR-002) as an autophagy inhibitor in patients with solid tumors (NCT07189195).