Development of a novel tocolytic delivery system to treat preterm labor

Project Summary The following proposal was carefully crafted to foster achievement in both academic and professional development to promote my future goals of becoming a faculty member at a tier-one research institute. The plan is designed to enrich technical, conceptual, and professional realms of my training. I will gain technical training

in: (i) particle formulation and characterization, (ii) antibody conjugation chemistry in biomaterials, and (iii) preclinical in vivo therapeutic testing in mice. While completing technical training, I will master conceptual training in biomaterials, clinical concepts, and pregnancy-associated physiology. Concurrent with the technical and

conceptual benchmarks, my professional training will include: building a network within my field, strengthening my leadership and mentoring abilities, learning how to communicate effectively through manuscripts and grants, and developing my time management and project planning skills. The vast resources available at Vanderbilt

make it the ideal environment for my technical, conceptual, and professional training required to achieve my long-term goal of becoming a leader in the field of obstetrics nanomedicine. The studies proposed in this fellowship address the goal of developing a novel, uterine-specific, drug delivery system to treat preterm labor - the leading cause of neonatal mortality worldwide. The true efficacy of current

tocolytics, used to inhibit premature uterine contractions, is unknown due to their adverse maternal and fetal effects that occur if used greater than 48-72hr. I hypothesize that a uterine-targeted, slow-release drug delivery system (DDS) would allow therapeutic concentrations of tocolytics for longer-term efficacy and reduced off-target

effects. Under the Sponsorship and Co-Sponsorship of Drs. Herington and Giorgio, I have generated unpublished data that shows: (i) reproducible fabrication of poly(lactic-co-glycolic) acid carriers with minimal

polydispersity, (ii) ex vivo tocolytic efficacy of nifedipine-loaded DDS, similar to that of free-drug, and (iii) targeted DDS increased in vivo delivery to the uterus by 10-fold. Building on this promising data, the proposed research strategy will improve the drug encapsulation and antibody targeting efficiencies of our DDS. In Aim I, modification

of the physical-chemical parameters in the formulation (such a polymer concentration, solvent type, surfactant concentration, and initial drug load) will maximize encapsulation efficiency of current tocolytics: nifedipine and indomethacin. Moreover, the specific chemical conditions that maximize antibody conjugation while maintaining

antibody selectivity to the oxytocin receptor will be developed. In Aim II, I will determine the in vivo efficacy and side-effect mitigation of uterine-targeted DDS to delay birth in mouse models of induced preterm labor. The well- known lack of uterine-selectivity and side-effects of nifedipine and indomethacin make them ideal for use in this

Aim, in which I will compare free-drug versus drug-loaded DDSs. The successful completion of the proposed studies will solidify the basis of a much-needed therapeutic alternative to treat preterm labor: a uterine selective, sustained-release drug delivery system.