Polyketal nanoparticles: a new biomaterial for protein delivery

说明(申请人提供)：超氧化物歧化酶(SOD)是一种可以抑制ROS产生的酶，在动物模型中显示出巨大的治疗急性肝功能衰竭的前景。不幸的是，由于药物输送问题，超氧化物歧化酶在临床试验中表现不佳。这项R21应用的目标是开发一种新型的聚合物纳米颗粒，可以在体内传递SOD并治疗急性肝功能衰竭。这一新的纳米粒子家族被称为聚酮纳米粒子(PKNS)。这一建议的中心假设是：PKN具有在体内将SOD运送到Kupffer细胞、抑制ROS产生和治疗急性肝功能衰竭所需的物理和化学性质。这一假说建立在PKN独特的化学基础上，我们的初步发现表明，PKN在内体和溶酶体的酸性条件下迅速降解(1-2天)，在体内以Kupffer细胞为靶标，并且在水解后不产生酸性降解产物。这项提议中的实验将检验我们的中心假设；通过确定包裹在PKN中的SOD抑制肝巨噬细胞中ROS的生成并保护小鼠免受泰诺诱导的急性肝功能衰竭的能力。R21应用的成功完成将证明PKN可以将蛋白质运送到体内的巨噬细胞，并将产生一种潜在的治疗急性肝功能衰竭的方法。此外，PKN还具有输送有机小分子、DNA和蛋白质治疗药物的潜力。鉴于巨噬细胞和吞噬细胞涉及的疾病范围广泛，我们预计PKN将在药物输送领域得到广泛应用。

DESCRIPTION (provided by applicant): Superoxide dismutase (SOD) is an enzyme that can inhibit the production of ROS and has shown tremendous promise for the treatment of acute liver failure in animal models. Unfortunately, SOD has performed poorly in clinical trials because of drug delivery problems. The objective of this R21 application is to develop a new class of polymeric nanoparticles that can deliver SOD in vivo and treat acute liver failure. This new family of nanoparticles are termed the polyketal nanoparticles (PKNs). The central hypothesis of this proposal is that the: The PKNs have the physical and chemical properties needed to deliver SOD to Kupffer cells in vivo, inhibit the production of ROS, and treat acute liver failure. This hypothesis is based upon the unique chemistry of the PKNs and our preliminary findings, which indicate that the PKNs degrade rapidly (1-2 days) under the acidic conditions of the endosomes and lysosomes, target Kupffer cells in vivo, and do not generate acidic degradation products after hydrolysis. The experiments in this proposal will test our central hypothesis; by determining the ability of SOD encapsulated in the PKNs to inhibit ROS generation in liver macrophages and protect mice from Tylenol induced acute liver failure. The successful completion of this R21 application will demonstrate that the PKNs can deliver proteins to macrophages in vivo and will generate a potential treatment for acute liver failure. Furthermore, the PKNs have the potential to deliver small organic molecules, DNA and protein therapeutics. Given the wide range of diseases that macrophages and phagocytic cells are involved in, we anticipate that the PKNs will find widespread use in the field of drug delivery.