PFI:AIR - TT: Novel Nanoprinting for Oral Delivery of Poorly Soluble Drugs

这个PFI: AIR技术翻译项目的重点是翻译纳米级3D打印技术，使口服制备难溶性药物成为可能。由美国国家科学基金会高速率纳米制造中心开发的新型药物3D纳米打印工艺非常重要，因为它将使目前只能静脉注射的各种有前途的候选药物口服给药成为可能。这将增加患者的依从性，减少治疗所涉及的时间和成本，同时提高药物从开发到患者过程的安全性。该项目将为一种全新的药物纳米打印技术提供概念验证，该技术可通过口服给药控制和有效地递送难溶性药物。该技术具有以下独特的特点。这项研究将把载药聚合物胶束打印成100纳米或更小尺寸的纳米棒，形状明确。精确控制纳米棒的大小和形状将在血液中提供足够高和固定的药物剂量，以获得所需的治疗反应。这种3-D载药纳米棒将被嵌入一种独特的聚合物中，这种聚合物只能在特定的碱性pH值下溶解，该pH值可以根据药物在体内释放的理想位置来选择。例如，药物纳米棒可以在通过胃后在肠道中释放，这也消除了由于胃肠道pH值变化而引起的稳定性问题。由于它们的小尺寸，这些纳米棒将具有高渗透性，因此与球体或其他形状相比，能够有效地通过肠壁运输。此外，药物纳米棒有望比球形药物纳米颗粒更有效、更快地穿透肿瘤。这将导致药物的更好的生物利用度，减少毒性和副作用。该打印技术还将使多药纳米棒的制备成为可能，其中纳米棒可以由几种难溶性药物组成，以克服多药耐药性。与目前市场上的胶束紫杉醇和游离紫杉醇等药物相比，这些特性将使低溶性药物能够有效地通过肠道在细胞内渗透，并可控制口服给药。该项目解决了以下技术差距，因为它从研究发现转化为商业应用。各种直径小于100nm的纳米棒将被表征为它们的体外渗透性，以发展对纳米棒尺寸和长径比对细胞渗透的影响的基本理解。拟议的研究将评估和表征打印的载药胶束纳米棒在癌细胞中的体外细胞毒性，以确定血液中这些药物的足够高水平以获得所需的治疗反应。该研究还将调查纳米棒的大小和形状对癌细胞内化的影响。此外，参与该项目的本科生和研究生将通过与制药公司的互动、指导会议和东北大学提供的创业课程，获得创新、教育和创业经验。

This PFI: AIR Technology Translation project focuses on translating nanoscale 3D printing technology to enable oral preparation of poorly soluble drugs. The novel drug 3D nanoprinting process, developed at the NSF Center for High Rate Nanomanufacturing, is important because it will enable oral administration of various promising drug candidates that currently can only be given intravenously. This will increase patient compliance and decrease the time and cost involved in therapy, while enhancing drug safety from the development-to-patient process. The project will result in a proof-of-concept for an entirely new drug nanoprinting technology for controlled and effective delivery of poorly soluble drugs via oral administration. This technology has the following unique features. The research will print drug-loaded polymeric micelles into 100nm or smaller size nanorods with well-defined shapes. The precise control of the size and shape of the nanorods will provide a sufficiently high and fixed drug dosage in the blood to get a desired therapeutic response. The 3-D drug-loaded nanorods will be embedded into a unique polymer that can only dissolve at a specific basic pH that can be chosen based on the desired location for the drug release in the body. For example, the drug nanorods can be released in the intestine after passing through the stomach, and this also eliminates the stability issue due to pH variation in the GI track. Due to their small size, these nanorods will have a high permeability, thus enabling effective transport through the intestinal wall as compared to spheres or other shapes. In addition, the drug nanorods are expected to penetrate tumors more efficiently and much faster than spherical drug nanoparticles. This should lead to a better bioavailability of the drug with reduced toxicity and side effects. The printing technique will also enable the preparation of multi-drug nanorods, where the nanorods can be composed of several poorly soluble drugs to overcome multi-drug resistance. These features will enable effective intracellular penetration through the intestine and controlled oral administration of poorly soluble drugs when compared to drugs such as micellar paclitaxel and free paclitaxel in this market space. This project addresses the following technology gap(s) as it translates from research discovery toward commercial application. Various sub 100nm diameter nanorods will be characterized for their in vitro permeability to develop a fundamental understanding of the effect of nanorod size and aspect ratio on the cell penetration. The proposed research will evaluate and characterize in vitro cytotoxicity of the printed drug-loaded micellar nanorods in cancer cells to determine the sufficiently high level of these drugs in the blood to get a desired therapeutic response. The research will also investigate the effect of size and shape of the nanorods on internalization by the cancer cells. In addition, personnel involved in this project, undergraduates and graduates students, will receive innovation, educational and entrepreneurial experiences through interaction with pharmaceutical companies, mentoring sessions, and entrepreneurship courses provided at Northeastern University.