Material-guided delivery and local activation of bioorthogonal prodrugs

ABSTRACT Systemic administration of small molecule therapeutics to treat disease can be ineffectiveand even hazardousbecause the drugs distribute widely in the bodyThis lack of site specificity means large systemic doses are needed to achieve effective concentrations in the diseased tissuesbut these high doses often result in nonspecific toxicityRoughlyinhospitalized patients experience adverse drug eventsADEsandthroughout the U Shealthcare systemover a million ADEs are reported every yearThese unintended consequences of drug therapy double the risk of mortality and increase the length of hospital stayswith an economic toll that greatly exceeds $annuallyIn additionADEs have a crippling indirect effect on our therapeutic arsenalRoughlyof drug development programs fail before completion of Phase II studies due to problems with clinical safetyResearch groups have responded by developing drug delivery systems to optimize the localized and timely delivery of therapeuticshoweverthe approaches used have major limitationsFor exampledrugs that are conjugated to antibodies to achieve their target specificity can cause immune responsesand their therapeutic efficacy can be compromised by limited drug releaseOther researchers are embedding drugs in biocompatible polymerswhich allows them to be implanted where neededbut the technologies lack the capacity for repeatedoptimal dosing without an invasive cycle of implant removal and replacementShasqi is developing a platform technology for efficient and modular drug delivery that enables precise spatiotemporal localization of therapeuticsone that can combat localized diseases without causing systemic side effectsand that allows for the modulation of drug releaseBuilt around a biocompatible gel that remains at the target site for andgtmonthsit relies on bio orthogonal chemistry to concentrate systemic prodrugsdrugs modified to be quiescentwhere they are needed and convert them to their therapeutic formOur biodegradable gel can be implanted at the time of biopsy or surgery and would not require an additional invasive procedure for additional treatments or removalIn the futureour gel can be designed to have dual attachment chemistries forcatchingprodrugsthus allowing for the controlled releasespatially and temporallyof combination therapiesWhile there is a market need for our technology in many therapeutic areasShasqi is initially focusing on developing chemotherapeutics for patients with neoplasms that are candidates for surgical interventionTo achieve these goalswe will pursue seven specific aims through the proposed Fast Track projectIn Phase Iwe will optimize gel dosage in combination with a prodrug for cancer treatment using tumor bearing miceWe will also develop validated methods suitable for anticipated IND studies and expand our prodrug arsenalIn Phase IIwe will conduct medium termdaystoxicity studies in canines guided by data from maximum tolerated doseMTDexperiments and pharmacokinetics work in ratsWe will also optimize prodrug formulation for stability and packaging of the drug product then manufacture GMP grade gel for I eventual Phaseclinical trials NARRATIVE Systemic administration of drugs to treat disease can be medically ineffectiveand even hazardousbecause the drugs fail to concentratespecificallyat the location in the body where intervention is neededShasqi is developing a modular platform technology for drug delivery that enables precise spatiotemporal localization of therapeutics and that allows for the modulation of drug releaseRelying on proprietarycatch and releaseinteractions between an implantable gel and initiallysilentprodrugsthe extensible technology is applicable to diverse medical areas and has the potential to accelerate drug discovery