This is a renewal application for an interdisciplinary project to understand the biological barriers to protein and DNA transport at mucosal surfaces and to produce new polymeric delivery systems to enhance immune protection within the female reproductive tract. In the past periods of support, we demonstrated that: antibodies (Abs), other proteins, and DNA can be slowly released from biocompatible polymer matrices and microspheres; these agents are active at the mucosal surface; human Abs, plasmid DNA, and other macromolecules can diffuse as fast through human cervical mucus as they do through water; a polymer vaginal ring can continuously release active Abs or DNA that becomes well-distributed throughout the vaginal secretions of a mouse for 30 d; vaginal rings releasing anti-herpes Abs can prevent genital infections in mice and vaginal rings releasing antigens can stimulate a long-lasting, mucosal immune response to sperm antigens in the mouse; orally-administered polymer microparticles loaded with Vg can stimulate mucosal immunity in the vagina; surface modification of particles can influence local transport and antigen processing in dendritic cells; DNA delivered at the mucosal surface can transfect local cells, which leads to local immunity; and mucosal delivery systems that deliver DNA vaccines encoding SIV proteins can protect rhesus macaques from mucosal challenges of SIV. We now propose a novel modular approach to the design and synthesis of biodegradable nanoparticles using modular design to add multiple functions. Our experiments are designed to quantify the barriers to nanoparticle transport at these tissue sites, and to develop polymeric drug delivery systems that overcome the barriers. We propose the following interrelated specific aims: 1) Development and characterization of multifunctional nanoparticle delivery systems for peptides, DNA, and siRNA; 2) Design of new and use of existing delivery systems to examine DNA delivery and siRNA delivery in the intestinal, respiratory, and reproductive tracts of the mouse; and 3) Development of new delivery systems to examine approaches for prevention of unwanted pregnancy and treatment of HIV infection.
| Martin, Darryl T; Shen, Hongliang; Steinbach-Rankins, Jill M et al. (2018) Glycoprotein-130 expression is associated with aggressive bladder cancer and is a potential therapeutic target. Mol Cancer Ther : |
| Kudalkar, Shalley N; Beloor, Jagadish; Quijano, Elias et al. (2018) From in silico hit to long-acting late-stage preclinical candidate to combat HIV-1 infection. Proc Natl Acad Sci U S A 115:E802-E811 |
| Mohideen, Muneeb; Quijano, Elias; Song, Eric et al. (2017) Degradable bioadhesive nanoparticles for prolonged intravaginal delivery and retention of elvitegravir. Biomaterials 144:144-154 |
| Gupta, Anisha; Bahal, Raman; Gupta, Meera et al. (2016) Nanotechnology for delivery of peptide nucleic acids (PNAs). J Control Release 240:302-311 |
| Gavrilov, Kseniya; Seo, Young-Eun; Tietjen, Gregory T et al. (2015) Enhancing potency of siRNA targeting fusion genes by optimization outside of target sequence. Proc Natl Acad Sci U S A 112:E6597-605 |
| Fields, Rachel J; Quijano, Elias; McNeer, Nicole Ali et al. (2015) Modified poly(lactic-co-glycolic acid) nanoparticles for enhanced cellular uptake and gene editing in the lung. Adv Healthc Mater 4:361-6 |
| Cheng, Christopher J; Tietjen, Gregory T; Saucier-Sawyer, Jennifer K et al. (2015) A holistic approach to targeting disease with polymeric nanoparticles. Nat Rev Drug Discov 14:239-47 |
| Deng, Yang; Ediriwickrema, Asiri; Yang, Fan et al. (2015) A sunblock based on bioadhesive nanoparticles. Nat Mater 14:1278-85 |
| Martin, Darryl T; Steinbach, Jill M; Liu, Jingchun et al. (2014) Surface-modified nanoparticles enhance transurothelial penetration and delivery of survivin siRNA in treating bladder cancer. Mol Cancer Ther 13:71-81 |
| Deng, Yang; Saucier-Sawyer, Jennifer K; Hoimes, Christopher J et al. (2014) The effect of hyperbranched polyglycerol coatings on drug delivery using degradable polymer nanoparticles. Biomaterials 35:6595-602 |
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