Secretory Phospholipases sPLA2 and their Receptors for Delivering Nanoparticles

分泌型磷脂酶 sPLA2 及其用于递送纳米颗粒的受体

• 批准号: 8777093
• 负责人: Robert D Arnold
• 金额: $ 32.68万
• 依托单位: AUBURN UNIVERSITY AT AUBURN
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8777093
• 关键词: Binding; Cells; Clinical; Data; Development; Disease; Drug Carriers; Drug Controls; Drug Delivery Systems; Drug Formulations; Encapsulated; Engineering; Enzymes; Esters; Functional disorder; Goals; Grant; Health; Human; Inflammation; Inflammatory; Intracellular Transport; Kinetics; Knowledge; Lead; Lipids; Liposomes; Literature; MAP Kinase Gene; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Mole the mammal; Mus; National Institute of Biomedical Imaging and Bioengineering; Pathology; Peptides; Performance; Pharmaceutical Preparations; Phospholipase; Phospholipase A2; Phospholipids; Positioning Attribute; Prostate; Protein Isoforms; Proteins; Regulation; Reporting; Role; Signal Transduction; Specificity; Sterically Stabilized Liposome; Surface; Testing; Therapeutic Index; Tissues; Toxic effect; Work; Xenograft Model; base; design; differential expression; drug efficacy; extracellular; improved; lipid metabolism; mouse model; nanocarrier; nanodrug; nanoparticle; nanoparticulate; novel; prostate cancer cell; receptor; receptor expression; small hairpin RNA; targeted delivery; targeted sequencing; tumor; uptake

DESCRIPTION (provided by applicant): Nanoparticle formulations, such as pegylated long-circulating liposomes, can stably entrap drug, alter drug disposition, improve antitumor activity and minimize toxicity. However, control of their drug-release kinetics has limited their clinical potential. Secretory phospholipases A2 (sPLA2) are excreted and over expressed in a variety of tumors, e.g., up to 22-fold in prostate. These enzymes degrade phospholipids preferentially at the sn-2 ester position and have been hypothesized as targets to control drug release from lipid-based nanoparticles, such as liposomes. We developed a platform to quantify sPLA2-meidated degradation and release kinetics of sPLA2 responsive liposomes (SPRL). Unfortunately, the clinical performance of similar formulations has been limited. Recently we identified the presence of PLA2 receptors (PLA2R), in prostate cancer. Binding of sPLA2 to PLA2R typically results in internalization of both proteins and inactivation of sPLA2. It is not known if this negative regulation occurs with all sPLA2. In addition to sPLA2 inactivation, sPLA2 binding to PLA2R is reported to alter cell invasion, proliferation and MAPK activation. Studies also suggest alterations in lipid metabolism and increases in lipid signaling. Little data exists identifying ho interactions between sPLA2 and PLA2R mediate the delivery of lipid-based nanoparticles. This grant tests the hypothesis that sPLA2 and PLA2R control degradation, cell uptake, efficacy, and non-targeted toxicity of liposomes. This hypothesis will be tested by pursuing four aims: Aim 1. Identify the role of PLA2R in the targeted delivery and efficacy of SPRL in prostate cancer cells; Aim 2. Delineate the role of sPLA2 isoforms on the targeted delivery and efficacy of SPRL in prostate cancer cells; Aim 3. Identify novel sPLA2-based peptides to target uptake of liposomes by PLA2R; and Aim 4. Determine the specificity and antitumor activity of SPRL for PLA2R in a mouse xenograft model of human prostate cancer.

描述（由申请人提供）：纳米颗粒制剂，例如斑型长循环脂质体，可以稳定地捕获药物，改变药物处置，改善抗肿瘤活性并最大程度地减少毒性。但是，对其药物释放动力学的控制限制了其临床潜力。分泌性磷酸酶A2（SPLA2）被排泄，并在多种肿瘤中表达过多，例如前列腺中的22倍。这些酶优先在SN-2酯位置降解磷脂，并被认为是控制药物从脂质纳米颗粒（例如脂质体）中释放的靶标。我们开发了一个平台来量化SPLA2杀析的降解并释放SPLA2响应脂质体（SPRL）的动力学。不幸的是，类似配方的临床性能受到限制。最近，我们确定了前列腺癌中PLA2受体（PLA2R）的存在。 SPLA2与PLA2R的结合通常会导致蛋白质的内在化和SPLA2的失活。尚不清楚这种负调节是否发生在所有SPLA2中。除SPLA2灭活外，据报道SPLA2与PLA2R结合会改变细胞浸润，增殖和MAPK激活。研究还表明，脂质代谢的改变和脂质信号的增加。很少有数据识别SPLA2和PLA2R之间的HO相互作用介导基于脂质的纳米颗粒的递送。该赠款检验了以下假设：SplA2和PLA2R控制降解，细胞摄取，功效和非靶向脂质体毒性。该假设将通过追求四个目标来检验：目标1。确定PLA2R在SPRL在前列腺癌细胞中的靶向递送和功效中的作用； AIM 2。描述SPLA2同工型在SPRL在前列腺癌细胞中的靶向递送和功效中的作用；目标3。确定新型的基于SPLA2的肽，以靶向PLA2R摄取脂质体的摄取；和目标4。确定人类前列腺癌小鼠异种移植模型中SPRL对PLA2R的特异性和抗肿瘤活性。