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 >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.
