Engineered prodrug with tumor-selective delivery for targeted glycolysis inhibition
A conjugate of 2-deoxy-D-glucose and a fatty acid forms albumin-binding nanoparticles that enter cancer cells via glucose and fatty acid transporters, inhibit glycolysis, and induce tumor-selective cell death with enhanced potency and targeting.
Background
The Warburg effect—whereby cancer cells preferentially metabolize glucose via aerobic glycolysis—has spurred interest in therapies that inhibit key metabolic pathways. Glycolysis inhibitors can selectively starve tumor cells of energy, reducing proliferation while sparing healthy tissues that rely more on oxidative phosphorylation. To maximize impact, these agents must achieve adequate tumor accumulation, avoid rapid systemic clearance, and minimize off-target toxicity. Despite their promise, current glycolytic inhibitors exhibit critical shortcomings. Agents like 2-deoxy-D-glucose require high systemic doses to outcompete endogenous glucose, leading to dose-limiting toxicities and narrow therapeutic windows. Their hydrophilic nature results in rapid renal clearance and poor tumor retention, while limited solubility complicates formulation at clinically relevant concentrations. Moreover, reliance on single uptake pathways often leads to the development of resistance through transporter downregulation. These challenges underscore the unmet need for metabolic therapies capable of efficient tumor targeting, sustained circulation, and robust intracellular delivery.
Technology description
2DG-ODDA is a soluble nanoparticle therapeutic developed in the lab of Dr. Cassandra Callman. Dr. Callman’s approach yields <10 nm soluble nanoparticles that bind human serum albumin for extended circulation and exploit both GLUT and CD36 transporters to enter malignant cells. The 2DG moiety inhibits glycolysis, inducing metabolic stress and apoptosis, while the ODDA segment enhances pharmacokinetics and tumor accumulation. In vitro, 2DG-ODDA achieves a 15- to 16-fold reduction in IC50 versus free 2DG, and in mouse models of triple-negative breast cancer, subcutaneous doses of 7.5 mg/kg suppress tumor growth without observable toxicity. Linker or ester modifications can improve aqueous solubility and enable further prodrug designs. This approach addresses the clinical limitations of high-dose 2DG by lowering the effective dose by over an order of magnitude and minimizing systemic toxicity. Dual transporter engagement mitigates resistance from single-pathway downregulation, while albumin binding prolongs circulation half-life and concentrates the compound in tumor microenvironments. These compounds have a modular serine-derived linker that allows tuning of hydrophilicity and release kinetics, and ester deprotection or alternative amino acid linkers can further enhance solubility and targeting. By combining metabolic inhibition with enhanced delivery, 2DG-ODDA represents a differentiated platform for metabolic cancer therapy with potential applicability across glycolysis-dependent malignancies.
Benefits
Publication:
Partnering opportunity:
We have filed a provisional patent application covering this technology and are looking for a partner to license or collaborate on further development.
