A new high-throughput gastrointestinal tract explant platform for drug formulation discovery and metabolic disease modulation

用于药物配方发现和代谢疾病调节的新型高通量胃肠道外植体平台

• 批准号: 10152644
• 负责人: ROBERT Samuel LANGER
• 金额: $ 106.87万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 1979
• 资助国家: 美国
• 起止时间: 1979-07-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10152644
• 关键词: Abattoirs; Adherence; Animal Model; Benchmarking; Biological Availability; Biological Products; Biology; Cells; Chemicals; Classification; Clinical; Complex; Coupled; Data; Developed Countries; Development; Digestive System Disorders; Disease; Drug Combinations; Drug Delivery Systems; Drug Formulations; Drug Modelings; Enteroendocrine Cell; Epidemic; Equilibrium; Evaluation; Excipients; Extravasation; Family suidae; Formulation; Gastrointestinal tract structure; Goals; Histologic; Human; In Vitro; Industry Standard; Intestinal Absorption; Intestines; Investigation; Libraries; Mammals; Metabolic; Metabolic Diseases; Modeling; Non-Insulin-Dependent Diabetes Mellitus; Oral; Oral Administration; Patients; Performance; Permeability; Pharmaceutical Preparations; Physicians; Physiological; Population; Process; Progress Reports; Protocols documentation; Robotics; Route; Science; Solubility; Sum; Surgeon; System; Systems Development; Therapeutic; Time; Tissue Harvesting; Tissues; Toxic effect; Work; absorption; base; cell type; cost; design; drug development; experimental study; gastrointestinal; glucagon-like peptide 1; high throughput screening; high-throughput drug screening; improved; in vitro Model; in vivo; in vivo evaluation; indexing; macromolecule; necrotic tissue; novel; novel therapeutics; parenteral administration; pressure; prototype; standard of care; therapy development; tool; uptake

Project Summary/Abstract 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.

项目总结/摘要 我们的长期目标是开发一种系统，提供广泛的药物控制递送。 治疗剂，包括限于肠胃外途径的那些。在本提案中，我们在先前工作的基础上， 专注于胃肠道（GI）屏障，并特别提出了一个平台，使高通量GI 新制剂的运输评估迅速。开发与口服药物相容的治疗方法 给药，需要大量的制剂和体外和体内评价，以获得最大的口服生物利用度 在人类身上。目前的胃肠道吸收体外模型受到其通量和胃肠道吸收的近似值的限制。 生理状态因此，我们建议：1）开发能够延长培养的系统， 完整的哺乳动物胃肠道组织与2）高通量机器人技术相结合，以改变制剂开发， 研究胃肠道。这些调查得到了强有力的初步数据的支持，表明：1）文化 在体外维持一组广泛的细胞标记物和药物转运蛋白存在的条件下， 猪胃肠道组织，2）制造原型系统，实现高通量询问，3）演示 的预测能力的药物吸收的一个大的面板的药物，4）演示的近顺序， 在大规模赋形剂筛选后模型分子摄取的幅度增强。目前， 通过口服途径吸收差的有希望的治疗剂可以在药物开发中显现 数年的延迟和许多时候没有确定配方解决方案。拟议的工作将针对 通过提供快速鉴定制剂的工具来满足关键的未满足的临床需求， 溶解性和吸收性以及最小的局部毒性。此外，拟议的系统将使审讯 研究胃肠道肠道内分泌系统，发现代谢性疾病的新疗法。 紊乱通过这一建议，我们将开发一套新的配方和新的材料-药物 能够口服递送以前限于肠胃外途径的药物的组合。而且还要 开发新的肠内分泌系统调节剂，为代谢疾病提供新的解决方案 疫情总而言之，这项建议旨在提供一个类似于“芯片上的计算机”的平台， 改变配方科学和胃肠道研究，有可能改变治疗方法， 代谢疾病和其他胃肠道疾病。

项目成果

Polymeric Materials for Gene Delivery and DNA Vaccination.

• DOI: 10.1002/adma.200801478
• 发表时间: 2009-02-23
• 期刊: Advanced materials (Deerfield Beach, Fla.)
• 作者: Nguyen DN;Green JJ;Chan JM;Longer R;Anderson DG
• 通讯作者: Anderson DG

Caffeine-catalyzed gels.

• DOI: 10.1016/j.biomaterials.2018.04.010
• 发表时间: 2018-07
• 期刊: Biomaterials
• 影响因子: 14
• 作者: DiCiccio AM;Lee YL;Glettig DL;Walton ESE;de la Serna EL;Montgomery VA;Grant TM;Langer R;Traverso G
• 通讯作者: Traverso G

A Vibrating Ingestible BioElectronic Stimulator Modulates Gastric Stretch Receptors for Illusory Satiety.

振动可摄入生物电子刺激器调节胃拉伸感受器以获得虚幻的饱腹感。

• DOI: 10.1101/2023.07.17.549257
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Srinivasan,ShriyaS;Alshareef,Amro;Hwang,Alexandria;Bryne,Ceara;Kuosmann,Johannes;Ishida,Keiko;Jenkins,Joshua;Liu,Sabrina;Madani,WiamAbdallaMohammed;Hayward,AlisonM;Fabian,Niora;Traverso,Giovanni
• 通讯作者: Traverso,Giovanni

Gold, poly(beta-amino ester) nanoparticles for small interfering RNA delivery.

• DOI: 10.1021/nl9009793
• 发表时间: 2009-06
• 期刊: Nano letters
• 影响因子: 10.8
• 作者: Lee JS;Green JJ;Love KT;Sunshine J;Langer R;Anderson DG
• 通讯作者: Anderson DG

The biocompatibility of mesoporous silicates.

介孔硅酸盐的生物相容性。

• DOI: 10.1016/j.biomaterials.2008.07.007
• 发表时间: 2008-10
• 期刊: BIOMATERIALS
• 影响因子: 14
• 作者: Hudson, Sarah P.;Padera, Robert F.;Langer, Robert;Kohane, Daniel S.
• 通讯作者: Kohane, Daniel S.