TOTAL SYNTHESIS OF TOPOISOMERASE INHIBITING PYRROLOIMINOQUINONES

抑制拓扑异构酶的吡咯亚氨基醌的全合成

• 批准号: 6246932
• 负责人: SAMUEL E WATSON
• 金额: $ 10.16万
• 依托单位: LONG ISLAND UNIVERSITY BROOKLYN CAMPUS
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-30 至 2003-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6246932
• 关键词: DNA topoisomerases; biomaterial development /preparation; biomaterial evaluation; biotransformation; dosage forms; drug vehicle; enzyme inhibitors; gel; microcapsule; nanotechnology; polymers; pyrroles; quinones; slow release drug; statistics /biometry; technology /technique development

Protein drug delivery is challenging the conventional dosage forms such as tablets; gelatin capsules, and intramuscular and subcutaneous injections. Many new approaches to deliver protein drugs have been tried. These approaches are using either hydrophobic polymers or hydrophilic polymers. Since both the hydrophobic and the hydrophilic polymers have their own intrinsic problems, little or no progress has been made in protein drug delivery. in this study, a hydrophobic polymer and a hydrophilic polymer are combined by using a novel method to promote their advantages and overcome their problems. This combination will be conducted in a nontraditional way to create a novel protein drug delivery system. The traditional combination of hydrophobic polymers and hydrophilic polyniers uses either physical mixing/blending of the two types of polymers or chemical copolymerization of a hydrophobic monomer with a hydrophilic monorner. Both of these two traditional approaches give a homogeneously structured matrix. A kind of heterogeneous (or domain) structure is to be produced through the nontraditional combination of a hydrophobic polymer and a hydrophilic polymer in this proposal. Namely, two polymers will be combined in a manner that the hydrophobic polymer will be formulated as microspheres and the hydrophilic polymer will be formulated as hydrogel nanoparticles. Then, the hydrogel nanoparticles will be combined with the hydrophobic polymeric microspheres. The protein drugs will first be encapsulated in the hydrogel nanoparticles. Then, the protein-containing hydrogel nanoparticles will be further loaded in the hydrophobic polymer microspheres. The hydrogel provides a non- denaturing microenvironment for protein drugs while the hydrophobic polymer provides an inert carrier for prolonged release of protein drugs. Therefore, proposed is a new protein drug delivery system having advantage of (1) prolonged protein release and (2) prevention of protein drugs from biological activity loss. The hydrophobic polymer to be used is biodegradable poly(lactic-co-glycolic acid). The hydrophilic polymer to be tried will be chosen from natural or synthetic biodegradable polymers including gelatin, starch, and polyesteramides. The final dosage form of this composite is injectable microparticles. Therefore, this novel delivery system has the characteristics of ease of administration to patient as well as biodegradability.

蛋白质药物递送正在挑战常规剂型，如片剂、明胶胶囊、肌内和皮下注射剂。已经尝试了许多递送蛋白质药物的新方法。这些方法使用疏水性聚合物或亲水性聚合物。由于疏水性和亲水性聚合物都有其自身的固有问题，因此在蛋白质药物递送方面几乎没有取得进展。本研究将疏水性聚合物和亲水性聚合物通过一种新的方法结合在一起，以发挥它们的优点并克服它们的问题。这种组合将以非传统的方式进行，以创造一种新的蛋白质药物递送系统。疏水性聚合物和亲水性聚合物的传统组合使用两种类型的聚合物的物理混合/共混或疏水性单体与亲水性单体的化学共聚。这两种传统方法都给出了均匀结构的矩阵。该方案通过疏水聚合物和亲水聚合物的非传统组合，产生一种非均相（或畴）结构。即，两种聚合物将以疏水性聚合物将被配制为微球并且亲水性聚合物将被配制为水凝胶纳米颗粒的方式组合。然后，将水凝胶纳米颗粒与疏水性聚合物微球组合。蛋白质药物将首先被封装在水凝胶纳米颗粒中。然后，含蛋白质的水凝胶纳米颗粒将进一步负载在疏水性聚合物微球中。水凝胶为蛋白质药物提供非变性微环境，而疏水性聚合物为蛋白质药物的延长释放提供惰性载体。因此，提出了一种新的蛋白质药物递送系统，其具有（1）延长蛋白质释放和（2）防止蛋白质药物生物活性损失的优点。待使用的疏水性聚合物是可生物降解的聚（乳酸-共-乙醇酸）。待试验的亲水性聚合物将选自天然或合成的可生物降解的聚合物，包括明胶、淀粉和聚酯酰胺。该复合物的最终剂型是可注射微粒。因此，这种新型给药系统具有易于患者给药以及生物降解性的特点。