Smart Packaging: A Novel Technique for Localized Drug Delivery for Ovarian Cancer

智能包装：卵巢癌局部给药的新技术

• 批准号: 8009757
• 负责人: Eva Christabel Williams
• 金额: $ 3.09万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8009757
• 关键词: Adhesions; Adverse effects; Affect; Atomic Force Microscopy; Behavior; Biological Assay; Body cavities; Carboplatin; Cells; Chitosan; Deacetylation; Drug Delivery Systems; Dyes; Encapsulated; Excision; Exposure to; Gel; High Pressure Liquid Chromatography; Hydrogels; Injection of therapeutic agent; Intake; Left; Malignant neoplasm of ovary; Measures; Molecular Weight; Oncologist; Operative Surgical Procedures; Paclitaxel; Patients; Pharmaceutical Preparations; Phase Transition; Polymers; Positioning Attribute; Process; Recovery; Research; Shapes; Site; Solid; Solutions; Surface; System; Techniques; Testing; Therapeutic; Time; Tissues; Toxic effect; Tracer; Trauma; Vesicle; Work; base; biomaterial compatibility; body cavity; cancer cell; chemotherapeutic agent; chemotherapy; crosslink; cytotoxicity; density; design; dosage; experience; fighting; in vivo; mouse model; novel; prevent; public health relevance; surfactant; treatment duration; tumor

DESCRIPTION (provided by applicant): The main challenge of the proposed research is to develop a novel drug delivery system that apart from providing targeted and better control over the drug release and dosage, will also aid in reducing the toxic side effects associated with administration of chemotherapeutic drugs. The design strategy is based on a 'Smart Packaging' system in which the chemotherapeutic drugs are encapsulated in non-ionic surfactant vesicles (niosomes) embedded in a cross-linked hydrogel network. The 'Smart Packaging' is applied directly to the affected site thus enabling the stabilization of the drug and preventing systemic exposure to healthy cells. It also assists in sustained drug delivery over extended periods and eliminates the need for frequent administration. The accomplishment of this work includes four aims. Aim 1 is to immobilize the drug/dye encapsulated niosomes in cross-linked chitosan polymeric networks having different molecular weights, degree of deacetylation, cross-link density, niosome loading and to characterize the behavior of the chitosan- niosome system. Characterization of the system will be done using Surface Forces Apparatus(SFA) and Atomic Force Microscopy (AFM). Aim 2 is to compare the stability, encapsulation efficiency and the release rate of two niosomal systems: i) where a hydrophobic drug (Paclitaxel) and a hydrophilic drug (Carboplatin) are encapsulated in the same niosome and ii) where the drugs are encapsulated in separate niosomes and then mixed together. TEM/ DLS will be used to determine the stability and HPLC/ UV-VIS spectrometer to determine the release rate. Aim 3 is to study the cytotoxicity of the chitosan- niosome system in normal and cancer cells and determine the selectivity, biocompatibility, and adhesion of the system to cancer cells. Cytotoxicity will be determined by the standard MTT dye reduction assay. Selectivity will be determined by exposing normal and cancer cells to the proposed system and measuring the drug intake by the cells. Aim 4 is to determine the release rate of drugs from the chitosan-niosome system in in-vivo mice models, analyze the implementation of our system in real tumor-like conditions, and to test the biodegradability and biocompatibility of our system. Xenogen and Fluorescent Spectrometer will be used to determine the release rate of the drugs tagged with a fluorescent tracer. PUBLIC HEALTH RELEVANCE: The main purpose of the proposed research is to develop a drug delivery system which allows targeting and control over the drug release and dosage process. Such a delivery system is expected to aid in the reduction of the toxic side effects associated with administration of chemotherapeutic drugs. The design strategy is based on a 'Smart Packaging' concept in which the chemotherapeutic drugs are encapsulated in non-ionic surfactant vesicles (niosomes) embedded in a cross-linked hydrogel network. The 'Smart Packaging' is applied directly to the affected site, enabling stabilization of the drug and preventing systemic exposure to healthy cells. It also assists a sustained drug delivery over extended periods and eliminates the need for frequent administration. The novelty of this system is in its high ability to control time release and dosage of chemotherapy drugs to allow judicious manipulation to treat many different types of tumor sites. For instance, if a tumor is removed surgically, it may be desirable to administer a low dosage of chemotherapy drugs for a short period of time (3-7 days) to allow a successful recovery of the cells that have been subjected to the surgical trauma. In that case, an outer layer of the polymer network can be tuned to be more compact and the niosomes to contain small concentrations of the drug cocktails. After this short period, the treatment may require to administer a high dosage and quick release to fight any cancer cells left behind. In that case, a middle layer can be constructed to be loose and the niosomes to contain high concentrations. Then, an inner layer can be constructed tight containing niosomes with systemic concentrations to allow sustained release of chemotherapy drugs for larger periods of time (3-9 months). Many other layers with different capabilities for delivery can also be constructed as needed depending on the oncologist experience and tissue integrity of the patient. A potential application would be in intra-cavitary drug delivery in ovarian cancer tumors and in the administration of labile drugs. Toxicities associated with systemic administration of much larger quantities of the drug are avoided, by the direct administration of chemotherapeutic agents directly to the tumor or to body cavities created after surgical removal of the tumor. The therapeutic system is a clear viscous solution, which, upon injection (at contact with warm tissue, 37:C) undergoes a phase transition to a semi-solid gel. This gel which conforms to the shape of the cavity, quickly blends with the surrounding tissue, and allows setting position for the delivery.

描述(申请人提供)：拟议研究的主要挑战是开发一种新的药物输送系统，该系统除了提供对药物释放和剂量的有针对性的和更好的控制外，还将有助于减少与给予化疗药物相关的毒副作用。该设计策略基于一种“智能包装”系统，在该系统中，化疗药物被包裹在嵌入在交联水凝胶网络中的非离子表面活性剂囊泡(微囊)中。“智能包装”直接应用于受影响的部位，从而使药物稳定并防止全身暴露于健康细胞。它还有助于在较长时间内持续给药，并消除了频繁给药的需要。这项工作的完成包括四个目标。目的一是将药物/染料包埋在不同分子质量、不同脱乙酰度、不同交联度、不同负载量的壳聚糖聚合物网络中，并对壳聚糖-微球系统的行为进行表征。将使用表面力装置(SFA)和原子力显微镜(AFM)对该系统进行表征。目的2比较两种微球系统的稳定性、包封率和释放率：一种是疏水性药物(紫杉醇)和一种亲水性药物(卡铂)被包裹在同一个微球中；另一种是药物被包裹在不同的微球中，然后混合在一起。用透射电子显微镜/差示扫描量热法测定其稳定性，用高效液相/紫外-可见光谱仪测定其释放度。目的3研究壳聚糖-微球系统对正常细胞和癌细胞的细胞毒性，并测定其对癌细胞的选择性、生物相容性和粘附性。细胞毒性将通过标准的四甲基偶氮唑蓝染料还原试验进行测定。选择性将通过将正常细胞和癌细胞暴露在建议的系统中并测量细胞的药物摄入量来确定。目的4测定壳聚糖纳米粒系统在小鼠体内的释药速率，分析该系统在真实肿瘤环境中的应用情况，并测试该系统的生物降解性和生物相容性。Xenogen和荧光光谱仪将用于确定标记有荧光示踪剂的药物的释放速度。 公共卫生相关性：拟议研究的主要目的是开发一种药物输送系统，该系统允许靶向和控制药物释放和剂量过程。这种给药系统预计将有助于减少与给药有关的毒副作用。该设计策略基于“智能包装”的概念，即化疗药物被包裹在嵌入在交联水凝胶网络中的非离子表面活性物质囊泡(微囊)中。“智能包装”直接应用于受影响的部位，使药物稳定并防止全身暴露于健康细胞。它还有助于在较长时间内持续给药，并消除了频繁给药的需要。该系统的创新之处在于它能够控制化疗药物的时间、释放和剂量，从而允许明智的操作来治疗许多不同类型的肿瘤部位。例如，如果通过手术切除肿瘤，可能需要在短时间内(3-7天)使用小剂量的化疗药物，以使遭受手术创伤的细胞成功恢复。在这种情况下，聚合物网络的外层可以调整为更紧密，而微泡可以包含小浓度的药物鸡尾酒。在这一短时间后，治疗可能需要给予高剂量和快速释放，以对抗任何遗留下来的癌细胞。在这种情况下，中间层可以被构造为松散的，而神经小体可以包含高浓度。然后，可以构建一个紧密的内层，其中包含具有全身浓度的微球，以允许化疗药物在更长的时间段(3-9个月)内持续释放。根据肿瘤医生的经验和患者的组织完整性，还可以根据需要构建许多具有不同传输能力的其他层。潜在的应用将是卵巢癌肿瘤的腔内给药和不稳定药物的给药。通过直接向肿瘤或手术切除肿瘤后形成的体腔直接给予化疗药物，可避免与全身大量给药相关的毒性。治疗系统是一种透明的粘性溶液，注射后(与热组织接触，37：C)经历向半固体凝胶的相变。这种凝胶符合空洞的形状，可以快速与周围组织混合，并允许设定输送位置。