Polyketal nanoparticles: a new biomaterial for protein delivery

描述（由申请人提供）：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治疗急性肝衰竭的巨大前景。不幸的是，由于药物输送问题，SOD在临床试验中表现不佳。这项R21申请的目的是开发一类新的聚合物纳米颗粒，可以在体内递送SOD并治疗急性肝衰竭。这种新的纳米颗粒家族被称为聚缩酮纳米颗粒（PKN）。该提议的中心假设是：PKN具有将SOD递送到体内枯否细胞、抑制ROS产生和治疗急性肝衰竭所需的物理和化学性质。该假设基于PKN的独特化学性质和我们的初步发现，其表明PKN在内体和溶酶体的酸性条件下快速降解（1-2天），体内靶向库普弗细胞，并且水解后不产生酸性降解产物。本提案中的实验将通过确定包封在PKN中的SOD抑制肝脏巨噬细胞中ROS生成并保护小鼠免受泰诺诱导的急性肝衰竭的能力来验证我们的中心假设。这项R21应用的成功完成将证明PKN可以在体内将蛋白质递送到巨噬细胞，并将产生治疗急性肝功能衰竭的潜在方法。此外，PKN具有递送小有机分子、DNA和蛋白质治疗剂的潜力。鉴于巨噬细胞和吞噬细胞参与的疾病范围广泛，我们预计PKN将在药物递送领域中得到广泛应用。

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.