Cross-linked Polymer Micelles in Cancer Therapy

交联聚合物胶束在癌症治疗中的应用

• 批准号: 7624215
• 负责人: TATIANA K BRONICH
• 金额: $ 25.34万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7624215
• 关键词: Acids; Address; Adverse effects; Animals; Antineoplastic Agents; Ants; Biological Availability; Blood Circulation; Carboxylic Acids; Cations; Cells; Characteristics; Charge; Chemotherapy-Oncologic Procedure; Cisplatin; Cleaved cell; Clinical; DNA Adduction; Development; Diagnostic; Dialysis procedure; Dissociation; Dose; Drug Containers; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Drug or chemical Tissue Distribution; Drug resistance; Encapsulated; Environment; Ethylene Oxide; Excretory function; Extravasation; Figs - dietary; Hand; Human; Induction of Apoptosis; Injection of therapeutic agent; Intravenous; Investigation; Ions; Kidney; Lead; Malignant neoplasm of ovary; Metals; Micelles; Modality; Modeling; Molecular; Morphology; Nanosphere; Nanotechnology; Pathology; Permeability; Pharmaceutical Preparations; Pharmacology; Physical condensation; Physiological; Plasma; Platinum; Polyethylene Glycols; Polymers; Process; Renal clearance function; Research Personnel; Research Proposals; Resistance; Site; Solubility; Structure; System; Therapeutic; Therapeutic Effect; Therapeutic Studies; Toxic effect; Toxicology; Treatment Efficacy; Vascular Permeabilities; anticancer activity; aqueous; base; cancer cell; cancer therapy; clinically relevant; comparative; controlled release; copolymer; crosslink; cytotoxic; cytotoxicity; design; di-block copolymer; disulfide bond; divalent metal; drug efficacy; improved; in vivo; meetings; metal complex; nanocarrier; nanofabrication; nanoscale; nanostructured; nanosystems; novel; novel therapeutics; premature; prevent; programs; research study; tumor; uptake

DESCRIPTION (provided by applicant): The objective of this project is to develop an optimal anti-tumor delivery system for cisplatin. This will be realized by utilizing cross-linked nanoscale size polymer micelles. The nanofabrication of these micelles involves condensation of diblock copolymers of poly(ethylene oxide) (PEO) and poly(carboxylic acid) by divalent metal cations into spherical micelles of core-shell morphology. The core of the micelles is then chemically cross-linked and cations removed by dialysis. The ionic character of the core allows for the encapsulation of cisplatin while the cross-linking of the core will suppress dissociation of the micelle upon dilution. As a result, cisplatin will be protected from premature release. Such a formation would maximize clinical benefit while limiting untoward side effects. Indeed, the cisplatin-loaded polymer micelles will be long circulating in the body and provide for on-site delivery of cisplatin with accumulation of the micelles at the tumor site due to enhanced permeability and retention effect. After delivery of cisplatin into the cells the micelles will disintegrate, which will be achieved using cross-linked agents with disulfide bonds that are known to cleave in the reducing intracellular environment. The induced degradation of the polymer micelle will result in the release of the copolymer chains that will be removed through renal clearance. We hypothesize that these micelles can be used as carriers for systemic delivery of cisplatin to improve drug efficacy in cancer treatment. Taken together, the proposal addresses the following specific aims: (1) development and characterization of polymer micelles with cross-linked ionic cores that can efficiently encapsulate and release cisplatin; (2) the determination of whether the incorporation of cisplatin into the polymer micelles potentiates cytotoxic effects of the drug; and (3) the utilization in vivo tumor models to determine whether incorporation of cisplatin into cross-linked polymer micelles enhances tumor regression. It is anticipated that these studies will lead to the design of new formulation of cisplatin for improved cancer treatment.

描述（由申请人提供）：该项目的目的是为顺铂开发最佳的抗肿瘤输送系统。这将通过利用交联的纳米尺寸聚合物胶束来实现。这些胶束的纳米化作用涉及将二价金属阳离子聚集到核心壳形态的球形胶束的聚（乙烷氧化物）（PEO）（PEO）（PEO）（PEO）和聚（羧酸）的二嵌段共聚物的凝结。然后，胶束的核心进行化学交联，并通过透析去除阳离子。核心的离子特征允许将顺铂包裹起来，而核心的交联将在稀释后抑制胶束的解离。结果，顺铂将受到保护免受过早释放。这样的形成将最大程度地提高临床益处，同时限制不良的副作用。实际上，顺铂负载的聚合物胶束将长期循环在体内，并在肿瘤部位积聚和胶束在肿瘤部位的积聚，由于渗透率增强和保留效果，胶束会积聚。将顺铂递送到细胞中后，胶束将分解，使用具有二硫键的交联药物可以实现，这些硫化物键已知在还原细胞内环境中裂解。聚合物胶束的诱导降解将导致共聚物链的释放，这些链将通过肾脏清除去除。我们假设这些胶束可以用作载体，以全身递送顺铂，以提高癌症治疗中的药物疗效。综上所述，该提案解决了以下特定目的：（1）具有交联的离子核的聚合物胶束的开发和表征，可以有效地封装和释放顺铂； （2）确定将顺铂掺入聚合物胶束中是否会增强该药物的细胞毒性作用； （3）在体内肿瘤模型中的利用来确定将顺铂掺入交联聚合物胶束中是否会增强肿瘤的消退。可以预料，这些研究将导致为改进癌症治疗的新型顺铂制定设计。