TOTAL SYNTHESIS OF TOPOISOMERASE INHIBITING PYRROLOIMINOQUINONES

蛋白质药物递送正在挑战片剂等传统剂型；明胶胶囊，肌肉注射和皮下注射。人们已经尝试了许多递送蛋白质药物的新方法。这些方法要么使用疏水聚合物，要么使用亲水性聚合物。由于疏水和亲水性聚合物都有其固有的问题，因此在蛋白质药物传递方面几乎没有进展。本研究通过一种新颖的方法将疏水聚合物和亲水聚合物结合在一起，促进了它们的优势，克服了它们的问题。这种组合将以一种非传统的方式进行，以创造一种新的蛋白质药物传递系统。疏水聚合物和亲水聚合物的传统组合使用两种类型的聚合物的物理混合/共混或疏水单体与亲水单体的化学共聚。这两种传统方法都给出了齐次结构矩阵。本方案拟通过疏水聚合物和亲水聚合物的非传统结合产生一种异质（或域）结构。也就是说，两种聚合物将以一种方式组合，疏水聚合物将被配制成微球，亲水聚合物将被配制成水凝胶纳米颗粒。然后，水凝胶纳米颗粒将与疏水聚合物微球结合。蛋白质药物将首先被包裹在水凝胶纳米颗粒中。然后，将含蛋白质的水凝胶纳米颗粒进一步装入疏水聚合物微球中。水凝胶为蛋白质药物提供非变性微环境，疏水聚合物为蛋白质药物的缓释提供惰性载体。因此，提出了一种新的蛋白质药物递送系统，具有(1)延长蛋白质释放和(2)防止蛋白质药物生物活性丧失的优点。所述疏水聚合物为可生物降解聚乳酸-羟基乙酸。要尝试的亲水性聚合物将从天然或合成的可生物降解聚合物中选择，包括明胶，淀粉和聚酯酰胺。该组合物的最终剂型为可注射微粒。因此，这种新型给药系统具有易于给药和可生物降解的特点。

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.