A key challenge in the oral administration of biologics such as hormones, antibodies, growth factors, enzymes, and vaccines is overcoming the physiological barriers presented by the gastrointestinal tract. These include extreme pH environments, enzymatic degradation, and poor permeability across the intestinal epithelium. Encapsulation of biologics inside polymeric nanoparticles allows the therapeutic agent to be shielded from the low pH environment and enzymes of the GI tract. However, there are currently no strategies that efficiently and safely overcome the intestinal epithelium transport barrier. We propose to overcome this barrier by targeting biologic-encapsulated nanoparticles to the neonatal Fc receptor (FcRn) present in the intestines. The FcRn is responsible for active transport of IgG antibodies across the intestinal epithelium through the process of transcytosis. We hypothesize that using the Fc portion of IgG to target biologic-encapsulated nanoparticles to the FcRn will allow Fc-targeted nanoparticles to be actively transported across the intestinal epithelium and enter systemic circulation after oral administration. In this proposal, using insuli as a model biologic and diabetes as a model disease, we aim to develop insulin-encapsulated and FcRn-targeted nanoparticles for efficient oral delivery of insulin. Biodegradable and biocompatible polymers will be used to develop nanoparticles with sizes less than 100 nm that are able to encapsulate insulin with a load greater than 5%, release insulin with bioactivity greater than 90%, and are surface functionalized with IgG Fc fragments. The nanoparticles will be tested in an in vitro human epithelium cell model to demonstrate enhanced transcytosis due specifically to the FcRn and in vivo to evaluate the efficacy of insulin-encapsulated and FcRn-targeted nanoparticles after oral administration with a target bioavailability of 20% for insulin. Successful completion of this study will have a significant impact on the treatment of many diseases by overcoming a critical barrier and enabling efficient oral delivery of biologics.
Oral administration is considered a more favorable route of administration than injection because of improved convenience and compliance by patients, resulting in improved treatment efficacy. In this project, we will develop a novel nanoparticle delivery system designed to overcome all of the barriers of the gastrointestinal tract and provide efficient oral delivery of biologics such as insulin. This technology may have a significant impact on diseases that are currently limited to injection-based therapies, such as diabetes.
|Lim, Jong-Min; Cai, Truong; Mandaric, Stefan et al. (2018) Drug loading augmentation in polymeric nanoparticles using a coaxial turbulent jet mixer: Yong investigator perspective. J Colloid Interface Sci 538:45-50|
|Chopra, Sunandini; Bertrand, Nicolas; Lim, Jong-Min et al. (2017) Design of Insulin-Loaded Nanoparticles Enabled by Multistep Control of Nanoprecipitation and Zinc Chelation. ACS Appl Mater Interfaces 9:11440-11450|
|Corbo, Claudia; Molinaro, Roberto; Tabatabaei, Mateen et al. (2017) Personalized protein corona on nanoparticles and its clinical implications. Biomater Sci 5:378-387|
|Xu, Xiaoding; Saw, Phei Er; Tao, Wei et al. (2017) Tumor Microenvironment-Responsive Multistaged Nanoplatform for Systemic RNAi and Cancer Therapy. Nano Lett 17:4427-4435|
|Shi, Jinjun; Kantoff, Philip W; Wooster, Richard et al. (2017) Cancer nanomedicine: progress, challenges and opportunities. Nat Rev Cancer 17:20-37|
|Behzadi, Shahed; Luther, Gaurav A; Harris, Mitchel B et al. (2017) Nanomedicine for safe healing of bone trauma: Opportunities and challenges. Biomaterials 146:168-182|
|Mahmoudi, Morteza; Yu, Mikyung; Serpooshan, Vahid et al. (2017) Multiscale technologies for treatment of ischemic cardiomyopathy. Nat Nanotechnol 12:845-855|
|Xu, Xiaoding; Wu, Jun; Liu, Yanlan et al. (2017) Multifunctional Envelope-Type siRNA Delivery Nanoparticle Platform for Prostate Cancer Therapy. ACS Nano 11:2618-2627|
|Bertrand, Nicolas; Grenier, Philippe; Mahmoudi, Morteza et al. (2017) Mechanistic understanding of in vivo protein corona formation on polymeric nanoparticles and impact on pharmacokinetics. Nat Commun 8:777|
|Behzadi, Shahed; Serpooshan, Vahid; Tao, Wei et al. (2017) Cellular uptake of nanoparticles: journey inside the cell. Chem Soc Rev 46:4218-4244|
Showing the most recent 10 out of 37 publications