TOTAL SYNTHESIS OF TOPOISOMERASE INHIBITING PYRROLOIMINOQUINONES

蛋白质药物的输送正在挑战传统的剂型，如片剂、明胶胶囊以及肌肉和皮下注射。人们已经尝试了许多传递蛋白质药物的新方法。这些方法要么使用疏水聚合物，要么使用亲水聚合物。由于疏水性和亲水性聚合物都有其固有的问题，在蛋白质药物传递方面取得的进展很少或没有进展。在本研究中，通过一种新的方法将疏水聚合物和亲水聚合物结合在一起，以发挥它们的优势，克服它们的问题。这种结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输送系统。疏水聚合物和亲水聚合物的传统组合使用两种聚合物的物理混合/共混，或者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一个结构均匀的矩阵。在该方案中，通过疏水聚合物和亲水聚合物的非传统组合来产生一种非均相(或结构域)结构。也就是说，两种聚合物将以这样的方式组合，即疏水聚合物将被配方为微球，而亲水性聚合物将被配方为水凝胶纳米颗粒。然后，将水凝胶纳米颗粒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，将含有蛋白质的水凝胶纳米颗粒进一步负载到疏水聚合物微球中。水凝胶为蛋白质药物提供了非变性的微环境，而疏水聚合物为蛋白质药物的长期释放提供了惰性载体。因此，提出了一种新的蛋白质给药系统，它具有(1)延长蛋白质释放时间和(2)防止蛋白质药物生物活性丧失的优点。所使用的疏水聚合物是可生物降解的聚(乳酸-羟基乙酸)。将要尝试的亲水聚合物将从天然或合成的生物可降解聚合物中选择，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患者易于给药和生物可降解性的特点。

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.