Molecular and Cellular Transport in Mucus

This is a renewal application for an interdisciplinary project to understand the biologicalbarriers to protein and DNA transport at mucosal surfaces and to produce new polymericdelivery systems to enhance immune protection within the female reproductive tract. Inthe past periods of support, we demonstrated that: antibodies (Abs), other proteins, andDNA can be slowly released from biocompatible polymer matrices and microspheres;these agents are active at the mucosal surface; human Abs, plasmid DNA, and othermacromolecules can diffuse as fast through human cervical mucus as they do throughwater; a polymer vaginal ring can continuously release active Abs or DNA that becomeswell-distributed throughout the vaginal secretions of a mouse for 30 d; vaginal ringsreleasing anti-herpes Abs can prevent genital infections in mice and vaginal ringsreleasing antigens can stimulate a long-lasting, mucosal immune response to spermantigens in the mouse; orally-administered polymer microparticles loaded with Vg canstimulate mucosal immunity in the vagina; surface modification of particles can influencelocal transport and antigen processing in dendritic cells; DNA delivered at the mucosalsurface can transfect local cells, which leads to local immunity; and mucosal deliverysystems that deliver DNA vaccines encoding SIV proteins can protect rhesus macaquesfrom mucosal challenges of SIV. We now propose a novel modular approach to thedesign and synthesis of biodegradable nanoparticles using modular design to addmultiple functions. Our experiments are designed to quantify the barriers to nanoparticletransport at these tissue sites, and to develop polymeric drug delivery systems thatovercome the barriers. We propose the following interrelated specific aims: 1)Development and characterization of multifunctional nanoparticle delivery systems forpeptides, DNA, and siRNA; 2) Design of new and use of existing delivery systems toexamine DNA delivery and siRNA delivery in the intestinal, respiratory, and reproductivetracts of the mouse; and 3) Development of new delivery systems to examineapproaches for prevention of unwanted pregnancy and treatment of HIV infection.