Material-guided delivery and local activation of bioorthogonal prodrugs

ABSTRACT Systemic administration of small molecule therapeutics to treat disease can be ineffective, and even hazardous, because the drugs distribute widely in the body. This lack of site-specificity means large systemic doses are needed to achieve effective concentrations in the diseased tissues, but these high doses often result in non- specific toxicity. Roughly 1 in 20 hospitalized patients experience adverse drug events (ADEs) and, throughout the U.S. healthcare system, over a million ADEs are reported every year. These unintended consequences of drug therapy double the risk of mortality and increase the length of hospital stays, with an economic toll that greatly exceeds $100 annually. In addition, ADEs have a crippling indirect effect on our therapeutic arsenal. Roughly 25% of drug development programs fail before completion of Phase II studies due to problems with clinical safety. Research groups have responded by developing drug delivery systems to optimize the localized and timely delivery of therapeutics, however, the approaches used have major limitations. For example, drugs that are conjugated to antibodies to achieve their target specificity can cause immune responses, and their therapeutic efficacy can be compromised by limited drug release. Other researchers are embedding drugs in biocompatible polymers, which allows them to be implanted where needed, but the technologies lack the capacity for repeated, optimal dosing without an invasive cycle of implant removal and replacement. Shasqi is developing a platform technology for efficient and modular drug-delivery that enables precise spatiotemporal localization of therapeutics, one that can combat localized diseases without causing systemic side effects, and that allows for the modulation of drug release. Built around a biocompatible gel that remains at the target site for andgt;3 months, it relies on bio-orthogonal chemistry to concentrate systemic prodrugs (drugs modified to be quiescent) where they are needed and convert them to their therapeutic form. Our biodegradable gel can be implanted at the time of biopsy or surgery and would not require an additional invasive procedure for additional treatments or removal. In the future, our gel can be designed to have dual attachment chemistries for “catching” prodrugs, thus allowing for the controlled release (spatially and temporally) of combination therapies. While there is a market need for our technology in many therapeutic areas, Shasqi is initially focusing on developing chemotherapeutics for patients with neoplasms that are candidates for surgical intervention. To achieve these goals, we will pursue seven specific aims through the proposed Fast Track project. In Phase I, we will optimize gel dosage in combination with a prodrug for cancer treatment using tumor-bearing mice. We will also develop validated methods suitable for anticipated IND studies and expand our prodrug arsenal. In Phase II, we will conduct medium term (28 days) toxicity studies in canines guided by data from maximum tolerated dose (MTD) experiments and pharmacokinetics work in rats. We will also optimize prodrug formulation for stability and packaging of the drug product then manufacture GMP-grade gel for I eventual Phase 1 clinical trials.NARRATIVE Systemic administration of drugs to treat disease can be medically ineffective, and even hazardous, because the drugs fail to concentrate, specifically, at the location in the body where intervention is needed. Shasqi is developing a modular platform technology for drug-delivery that enables precise spatiotemporal localization of therapeutics and that allows for the modulation of drug release. Relying on proprietary “catch and release” interactions between an implantable gel and initially “silent” prodrugs, the extensible technology is applicable to diverse medical areas and has the potential to accelerate drug discovery.