Mucoadhesive drug conjugates for controlled-release inhalation delivery

SUMMARY Sustained release of drugs delivered onto mucosal surfaces by oraltopical or inhaled routes can be a highly effective means of improving topical bioavailabilityProlongation of epithelial residence time is especially relevant to anti infective therapies in diseases characterized by chronic infection and inflammation where treatment needs to be both locally potent and systemically safeInhaled antibiotics have been used to treat chronic airway infections and have transformed the management of cystic fibrosisCFan inherited disease of thickenedabnormally viscoelastic and poorly transported airway mucus leading to persistent lung infectionwhich affects approximatelypatients in the US andworld wideDespite these benefitsdoselimiting and potentially toxic serum concentrations are an inherent risk of bolus inhalation deliveryespecially for drugs with systemic bioavailabilityIn order to address this we have developed a novel therapeutic solution based on conjugation of inhaled drugs to a natural airway protein modified to have strong mucus binding propertiesCSTrxa monocysteinic active site variant of thioredoxinTrxremains bound covalently to soluble and tethered airway mucus for many hoursand does not induce inflammationirritationor adverse reactionsIn preliminary studies the CSTrx scaffold could be conjugated to over ten individual linkerseach of which can be attached modularly to one drug moleculewithout loss of target binding activityWith typical mucus clearance times ofhours such mucus bound CSTrx drug conjugates are anticipated to persist on the airway surface and allow controlled release of drug payloads over a much longer duration and at lower maximum systemic exposure levels than possible with inhaled delivery of free drug moleculesThis phase I application is focused on proof of concept using the potent antibiotic vancomycin as a payloadSpecificallyin Aimwe will construct CSTrx vancomycin conjugates using modular cleavable linkers and characterize their physical propertiessizecleavability and stabilityin Aimwe will evaluate the conjugates in vitro for valencydrug scaffold ratiomucus protein binding activity and antibacterial activityminimum inhibitory concentrationof cleaved vancomycin conjugates vsfreenon conjugated vancomycinand in Aimwe will determine the lung inflammation statusin vivo pharmacokinetics and airway residence time following intratrachealITdelivery to mice of vancomycin CSTrx conjugates in both the reducedtarget bindingand oxidizedinertforms as compared to free vancomycin lacking the CSTrx scaffoldThe pharmacokinetics of IT delivered vancomycin conjugates will be compared to that of free vancomycin delivered intravenouslyIf the Aims of this project are achieved key validation of the feasibility of sustained mucosal release of active drug payloads conjugated to CSTrx will be establishedThis will enable subsequent Phase II activities to further develop and optimize sustained delivery of vancomycin or other antibiotics leading to human trials of potentially safer and more efficacious inhalation treatment regimens for CF PROJECT NARRATIVE OrPro TherapeuticsIncis developing a novel inhaled mucoadhesive drug delivery system to improve antibiotic treatment in cystic fibrosisCFa chronic life threatening respiratory disease that affects approximatelypeople in the USThe approach is based on sustained mucosal release of antibiotic payloads conjugated to CSTrxa monocysteinic active site variant of the natural human airway enzyme thioredoxinengineered for covalent attachment to airway epithelial mucus disulfide bondsThe proposed Phase I SBIR research program is designed to evaluate feasibility of sustained mucosal surface antibiotic release by evaluating in vitro antibacterial activity and in vivo pharmacokinetics of polyvalent Vancomycin conjugated to CSTrx via a cleavable linker system