Autoregulated insulin delivery particles for the treatment of diabetes will be de

用于治疗糖尿病的自动调节胰岛素输送颗粒将被开发

• 批准号: 7670575
• 负责人: Mostafa Analoui
• 金额: $ 11.07万
• 依托单位: CENSE BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2010-10-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7670575
• 关键词: Aerosols; Affinity; Area; Behavior; Binding; Biological Assay; Blood; Breathing; Calibration; Catheters; Characteristics; Chemistry; Cleaved cell; Competitive Binding; Concanavalin A; Development; Devices; Diabetes Mellitus; Dose; Drug Delivery Systems; Drug Formulations; Drug Industry; Drug Kinetics; Encapsulated; Epidemiology; Event; Excipients; Family; Feedback; Frequencies; Glucose; Gold; Human; Hyperglycemia; Hypertension; Image; Implant; In Vitro; Incidence; Infection; Inflammation; Inflammatory; Injection of therapeutic agent; Insulin; Insulin Infusion Systems; Intervention; Investigation; Kidney Diseases; Lead; Lectin; Legal patent; Ligand Binding; Ligands; Liposomes; Liquid substance; Lung; Malignant neoplasm of lung; Measures; Methods; Neuropathy; Nuclear Translocation; Nucleosome Core Particle; Patients; Performance; Pharmaceutical Preparations; Pharmacodynamics; Phase; Preparation; Property; Publications; Pump; Rattus; Retinal Diseases; Risk; Scientist; Screening procedure; Site; Small Business Innovation Research Grant; Solutions; Spinal Cord; Subcutaneous Injections; System; Technology; Testing; Time; Tissue Engineering; Toxic effect; Treatment Protocols; Ursidae Family; Variant; Vesicle; base; cancer risk; controlled release; crosslink; cytotoxicity; design; diabetic rat; drug use screening; falls; glucose sensor; glycemic control; high throughput screening; implantation; improved; in vivo; meter; milligram; minimally invasive; nanoparticle; non-compliance; particle; performance tests; public health relevance; sensor; sugar; type I and type II diabetes

DESCRIPTION (provided by applicant): Cense Biosciences was formed specifically to create a minimally invasive, self-regulating delivery technology for insulin, and to extend this technology to other active drugs. The core technology of CenseI, AVT, or Agglomerated Vesicle TechnologyII, developed by the Chief Scientist of Cense, is a chemically cross linked agglomerate of drug encapsulating nanoparticles (such as liposomes) that modulates release by cleavage of the cross links. Insulin is contained within the nanoparticles, while the cross links are capable of cleavage as required. Thus, hyperglycemic events trigger insulin release from the particles, causing an automatic return to normoglycemia. In addition the obvious advantages of autoregulated delivery, the key additional advantage of this technology are the active drug is not chemically modified, thus avoiding the issues surrounding an NCE. The major shortcoming of the current AVT however, is that the glucose-sensitive linkage is based on competitive binding of concanavalin-A (Con-A) to a sugar. Con-A is a lectin, with high glucose affinity, but is highly inflammatory. In this Phase 1 proposal therefore, we propose to identify a suitable glucose binding replacement for Con-A and then test the performance of AVT particles made using this new molecule. i A. Annapragada, R. Bhavane, Agglomerated particles for aerosol drug delivery, US patent application 20030190284, October 9, 2003. ii E. Karathanasis, R. Bhavane, A. V. Annapragada, Triggered release of inhaled insulin from the agglomerated vesicles: Pharmacodynamic studies in rats. Accepted for publication in Jour. Of Controlled release April 2006. PUBLIC HEALTH RELEVANCE: Cense Biosciences was formed specifically to create a minimally invasive, self-regulating delivery technology for insulin, and to extend this technology to other active drugs. The core technology of CenseI, AVT, or Agglomerated Vesicle TechnologyII, developed by the Chief Scientist of Cense, is a chemically cross linked agglomerate of drug encapsulating nanoparticles (such as liposomes) that modulates release by cleavage of the cross links. Insulin is contained within the nanoparticles, while the cross links are capable of cleavage as required. Thus, hyperglycemic events trigger insulin release from the particles, causing an automatic return to normoglycemia. In addition the obvious advantages of autoregulated delivery, the key additional advantage of this technology are the active drug is not chemically modified, thus avoiding the issues surrounding an NCE. The major shortcoming of the current AVT however, is that the glucose-sensitive linkage is based on competitive binding of concanavalin-A (Con-A) to a sugar. Con-A is a lectin, with high glucose affinity, but is highly inflammatory. In this Phase 1 proposal therefore, we propose to identify a suitable glucose binding replacement for Con-A and then test the performance of AVT particles made using this new molecule. We will begin by screening a family of boronates, known glucose-binding molecules, some of which are already used in vivo. Within this Phase 1 project, we will identify new glucose-binding molecules for AVT, using high-content and high-throughput assay methods. Glucose binding will be measured by a competitive sugar binding assay. Inflammation will be measured by an imaging assay for NF: B nuclear translocation. After identification of lead candidates, we will produce AVT particles with them, and test them in vitro, and compare their behavior with the gold-standard ConA particles. In vitro cytotoxicity will also be assessed. The key milestone for Phase 1 will be the identification of 1-10 boronate compounds that have lower inflammatory characteristics than ConA, and equivalent in vitro AVT performance. Upon moving into Phase 2, AVT particles will be tested in normal and diabetic rat models. Pharmacodynamic, pharmacokinetic and inflammation properties of the preparations will be tested, and lead candidates selected for further development. The novelty of this project lies in 2 key areas: (1) the development of a truly "smart" insulin delivery system (2)the use of drug screening methods (HTS, HCS) for the screening of recipients. Both of these are landmarks in the pharmaceutical industry. I A. Annapragada, R. Bhavane, Agglomerated particles for aerosol drug delivery, US patent application 20030190284, October 9, 2003. ii E. Karathanasis, R. Bhavane, A. V. Annapragada, Triggered release of inhaled insulin from the agglomerated vesicles: Pharmacodynamic studies in rats. Accepted for publication in Jour. Of Controlled release April 2006.

描述（由申请人提供）：成立Cense Biosciences是为了创建一种微创，自我调节的胰岛素递送技术，并将这项技术扩展到其他活性药物。由Cense的首席科学家开发的Censei，Avt或团聚囊泡技术的核心技术是一种化学交叉连接的封装纳米颗粒（例如脂质体）的聚集体，可通过切割交叉链路的切割来调节释放。胰岛素包含在纳米颗粒中，而交叉链路则能够根据需要进行分裂。因此，高血糖事件会触发胰岛素从颗粒中释放出来，从而自动回到正常血糖。此外，自动调节性传递的明显优势，该技术的主要附加优势是活性药物没有化学修饰，从而避免了围绕NCE的问题。然而，当前AVT的主要缺点是，对葡萄糖敏感的连锁是基于浓甘那藻蛋白A（CON-A）与糖与糖的竞争结合。 CON-A是一种凝集素，具有高葡萄糖亲和力，但具有高度炎症。因此，在此阶段1建议中，我们建议确定适合CON-A的葡萄糖结合替代品，然后测试使用该新分子制成的AVT颗粒的性能。 I A. Annapragada，R。Bhavane，用于气雾剂药物输送的聚集的颗粒，美国专利申请20030190284，2003年10月9日。 II E. Karathanasis，R。Bhavane，A。V。Annapragada，触发了从聚集的囊泡中释放吸入的胰岛素：大鼠的药效学研究。被接受在JOR中出版。 2006年4月的受控释放。 公共卫生相关性：专门成立了Cense Biosciences，目的是为胰岛素创建一种微创，自我调节的递送技术，并将这种技术扩展到其他活跃药物。由Cense的首席科学家开发的Censei，Avt或团聚囊泡技术的核心技术是一种化学交叉连接的封装纳米颗粒（例如脂质体）的聚集体，可通过切割交叉链路的切割来调节释放。胰岛素包含在纳米颗粒中，而交叉链路则能够根据需要进行分裂。因此，高血糖事件会触发胰岛素从颗粒中释放出来，从而自动回到正常血糖。此外，自动调节性传递的明显优势，该技术的主要附加优势是活性药物没有化学修饰，从而避免了围绕NCE的问题。然而，当前AVT的主要缺点是，对葡萄糖敏感的连锁是基于浓甘那藻蛋白A（CON-A）与糖与糖的竞争结合。 CON-A是一种凝集素，具有高葡萄糖亲和力，但具有高度炎症。因此，在此阶段1建议中，我们建议确定适合CON-A的葡萄糖结合替代品，然后测试使用该新分子制成的AVT颗粒的性能。我们将首先筛选一个硼酸盐家族，即已知的葡萄糖结合分子，其中一些已经在体内使用。在此阶段1项目中，我们将使用高含量和高通量测定方法来确定AVT的新葡萄糖结合分子。葡萄糖结合将通过竞争性糖结合测定法测量。炎症将通过对NF：B核易位的成像测定法测量。鉴定出铅候选物后，我们将与它们产生AVT颗粒，并在体外测试它们，并将其行为与金标准的CONA颗粒进行比较。还将评估体外细胞毒性。第1阶段的关键里程碑将是鉴定1-10个硼酸盐化合物，其炎症特性低于CONA，并且同等的体外AVT性能。进入第2阶段后，将在正常和糖尿病大鼠模型中测试AVT颗粒。将测试制剂的药效，药代动力学和炎症特性，并选择铅候选者进行进一步发展。该项目的新颖性在于2个关键领域：（1）开发真正的“智能”胰岛素输送系统（2）使用药物筛查方法（HTS，HCS）用于筛查受体。这两个都是制药行业的地标。 I A. Annapragada，R。Bhavane，用于气雾剂药物输送的聚集的颗粒，美国专利申请20030190284，2003年10月9日。 II E. Karathanasis，R。Bhavane，A。V。Annapragada，触发了从聚集的囊泡中释放吸入的胰岛素：大鼠的药效学研究。被接受在JOR中出版。 2006年4月的受控释放。

项目成果

Non inflammatory boronate based glucose-responsive insulin delivery systems.

• DOI: 10.1371/journal.pone.0029585
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Dasgupta I;Tanifum EA;Srivastava M;Phatak SS;Cavasotto CN;Analoui M;Annapragada A
• 通讯作者: Annapragada A