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

描述（由申请人提供）：拟议研究的主要挑战是开发一种新的药物输送系统，除了提供靶向和更好地控制药物释放和剂量外，还将有助于减少与化疗药物管理相关的毒副作用。该设计策略基于“智能包装”系统，其中化疗药物被封装在嵌入交联水凝胶网络的非离子表面活性剂囊泡（niosomes）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。它还有助于长期持续给药，并消除频繁给药的需要。这项工作的完成包括四个目标。目的1将药物/染料包封的乳质体固定在不同分子量、去乙酰化程度、交联密度、乳质体负载的壳聚糖聚合物网络中，并表征壳聚糖-乳质体体系的行为。系统的表征将使用表面力仪（SFA）和原子力显微镜（AFM）来完成。目的2是比较两种膜体系统的稳定性、包封效率和释放速度：1)疏水药物（紫杉醇）和亲水药物（卡铂）被包封在同一个膜体中；2)药物被包封在单独的膜体中，然后混合在一起。用TEM/ DLS测定其稳定性，用HPLC/ UV-VIS光谱仪测定其释放速度。目的3是研究壳聚糖-膜小体系统在正常细胞和癌细胞中的细胞毒性，并确定该系统对癌细胞的选择性、生物相容性和粘附性。细胞毒性将通过标准MTT染料还原试验确定。选择性将通过将正常细胞和癌细胞暴露在拟议的系统中并测量细胞的药物摄入量来确定。目的4是在体内小鼠模型中确定壳聚糖-膜小体系统的药物释放率，分析我们的系统在真实肿瘤样条件下的实施情况，并测试我们系统的生物可降解性和生物相容性。氙气和荧光光谱仪将用于确定用荧光示踪剂标记的药物的释放速度。

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.