Our long-term goal is the development of systems providing controlled drug delivery of a broad set of therapeutics including those that are limited to parenteral routes. In this proposal, we build on our prior work to focus on the gastrointestinal (GI) barrier and specifically propose a platform enabling the high-throughput GI transport evaluation of novel formulations rapidly. Developing therapies which are compatible with oral administration, requires significant formulation and in vitro and in vivo evaluation for maximal oral bioavailability in humans. Current in vitro models of GI absorption are limited by their throughput and approximation of the physiologic state. Consequently, we propose: 1) the development of systems enabling prolonged culturing of intact mammalian GI tissue coupled to 2) high-throughput robotics to transform formulation development and study of the GI tract. These investigations are supported by strong preliminary data demonstrating: 1) culture conditions which maintain the presence of a broad set of cellular markers and drug transporters ex vivo in porcine GI tissue, 2) fabrication of prototype systems enabling high-throughput interrogation, 3) demonstration of predictive capacity of drug absorption for a large panel of drugs, 4) demonstration of near order of magnitude enhancement of uptake of a model molecule following a large-scale excipient screen. Currently, promising therapeutics which are poorly absorbed through the oral route can manifest in drug development delays on the order of years and many times no formulation solution is identified. The proposed work will target a critical unmet clinical need by providing tools to rapidly identify formulations that enable: maximal drug solubility and absorption and minimal local toxicity. Moreover, the proposed system will enable interrogation and study of the GI tract entero-endocrine system enabling the discovery of new therapies for metabolic disorders. Through this proposal we will develop a novel set of formulations and novel material-drug combinations enabling the oral delivery of drugs previously restricted to parenteral routes. Moreover, we will develop novel modulators of the enteroendocrine system providing novel solutions to the metabolic disease epidemic. In sum, this proposal aims to provide a platform akin to an ?intestine-on-a-chip? with the capacity to transform formulation science and the study of the GI tract with the potential to transform treatments for metabolic disease and other diseases of the GI tract.

Public Health Relevance

This proposal aims to develop an in vitro model of the gastrointestinal tract with all of the native cellular components found in a large mammal and interface with high-throughput robotics for the development of novel treatments. Specifically, it will contribute to the improvement in management of multiple diseases by providing drug formulations which can be readily absorbed orally including the absorption macromolecules.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB000244-41
Application #
9926852
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Rampulla, David
Project Start
1979-07-01
Project End
2022-04-30
Budget Start
2020-05-01
Budget End
2021-04-30
Support Year
41
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Miscellaneous
Type
Organized Research Units
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02142
Lo, Justin H; Hao, Liangliang; Muzumdar, Mandar D et al. (2018) iRGD-guided Tumor-penetrating Nanocomplexes for Therapeutic siRNA Delivery to Pancreatic Cancer. Mol Cancer Ther 17:2377-2388
Bartelt, Alexander; Widenmaier, Scott B; Schlein, Christian et al. (2018) Brown adipose tissue thermogenic adaptation requires Nrf1-mediated proteasomal activity. Nat Med 24:292-303
Kirtane, Ameya R; Abouzid, Omar; Minahan, Daniel et al. (2018) Development of an oral once-weekly drug delivery system for HIV antiretroviral therapy. Nat Commun 9:2
Mimee, Mark; Nadeau, Phillip; Hayward, Alison et al. (2018) An ingestible bacterial-electronic system to monitor gastrointestinal health. Science 360:915-918
Tong, Zhixiang; Martyn, Keir; Yang, Andy et al. (2018) Towards a defined ECM and small molecule based monolayer culture system for the expansion of mouse and human intestinal stem cells. Biomaterials 154:60-73
DiCiccio, Angela M; Lee, Young-Ah Lucy; Glettig, Dean L et al. (2018) Caffeine-catalyzed gels. Biomaterials 170:127-135
Liu, Jinyao; Pang, Yan; Zhang, Shiyi et al. (2017) Triggerable tough hydrogels for gastric resident dosage forms. Nat Commun 8:124
Abid, Abubakar; O'Brien, Jonathan M; Bensel, Taylor et al. (2017) Wireless Power Transfer to Millimeter-Sized Gastrointestinal Electronics Validated in a Swine Model. Sci Rep 7:46745
Schoellhammer, Carl M; Lauwers, Gregory Y; Goettel, Jeremy A et al. (2017) Ultrasound-Mediated Delivery of RNA to Colonic Mucosa of Live Mice. Gastroenterology 152:1151-1160
Caffarel-Salvador, Ester; Abramson, Alex; Langer, Robert et al. (2017) Oral delivery of biologics using drug-device combinations. Curr Opin Pharmacol 36:8-13

Showing the most recent 10 out of 125 publications