Nanotechnology-based reformulation of AUY922 mitigates retinal toxicity and retains potent anti-tumor activity

AUY922, a heat-shock protein 90 inhibitor, shows broad antitumor activity but is limited by dose-limiting ocular toxicity. In this study, we engineered FLIM02, a PLGA/DSPE-PEG2000 (1,2-Distearoyl-sn-glycero-3-phosphoethanolamine-N-[poly(ethylene glycol)-2000])-based nanoparticle via single-emulsion, and evaluated its physicochemical profile, biodistribution, ocular safety, and efficacy. FLIM02 formed ∼100-nm particles with efficient encapsulation and retained stability after lyophilization. In tumor-bearing mice, LC-MS/MS biodistribution showed reduced ocular retention of AUY922 with preserved tumor exposure and comparable hepatic/renal distribution versus prototype. FLIM02 preserved retinal architecture as evidenced by reduced TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling)-positive cells and attenuated GFAP induction, while maintaining antitumor activity in xenograft tumor models. No overt systemic toxicity was observed, supported by stable body weight, normal serum biochemical parameters, and absence of apparent pathological abnormalities in major organs. These findings support that nanoparticle reformulation can decouple antitumor efficacy from tissue-specific toxicity. FLIM02 suggests potential to reduce ocular toxicity while preserving antitumor activity, meriting further mechanistic studies and longitudinal preclinical models.