Polyketal nanoparticles: a new biomaterial for protein delivery

描述（由申请人提供）：超氧化物歧化酶（SOD）是一种可以抑制活性氧产生的酶，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，由于给药问题，SOD在临床试验中表现不佳。这项R21应用的目的是开发一种新的聚合纳米颗粒，可以在体内传递SOD并治疗急性肝衰竭。这种新的纳米颗粒家族被称为聚酮纳米颗粒（PKNs）。该建议的中心假设是：pkn具有将SOD传递到体内库普弗细胞所需的物理和化学性质，抑制ROS的产生，并治疗急性肝衰竭。这一假设是基于pkn独特的化学性质和我们的初步发现，这些发现表明pkn在内体和溶酶体的酸性条件下降解迅速（1-2天），在体内靶向Kupffer细胞，并且在水解后不产生酸性降解产物。本提案中的实验将检验我们的中心假设；通过检测包封在pkn内的SOD抑制肝巨噬细胞ROS生成和保护泰诺诱发小鼠急性肝衰竭的能力。这项R21应用的成功完成将证明pkn可以在体内将蛋白质传递给巨噬细胞，并将产生急性肝衰竭的潜在治疗方法。此外，pkn具有传递小有机分子、DNA和蛋白质治疗的潜力。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将在药物传递领域得到广泛应用。

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.