PLK1 and EGFR targeted nanoconstruct as a monotherapy and a radiation sensitizer for lung cancer

肺癌是癌症死亡的主要原因，超过了结肠癌、乳腺癌和前列腺癌。 癌症加在一起。对化疗和靶向治疗的耐药性是非常常见的。放射治疗(RT) 对于大约60%的肺癌患者来说，这仍然是一个关键的治疗方法。 我们寻求开发一种新的纳米疗法(称为PETTRA)，它可以治疗EGFR+的肺癌和 提供针对Polo-like kinase1(SiPLK1)的siRNA。EGFR是一个理想的寻的目标，因为它经常被剖析； 并且在50%的肺癌患者中过表达。PLK1是最强大的癌症靶点之一，因为它 在细胞分裂和DNA修复中起关键作用，抑制PLK1导致G2/M细胞周期停滞和凋亡 死亡。处于G2/M期停滞的细胞对辐射也最敏感。因此，假设PETTRA是有效的 作为肺癌的单一疗法和辐射增敏剂。或原型PETTRA已证明良好 这种双重建议在细胞和小鼠中的安全性和有效性。在此，我们建议进一步优化 增强药效和安全性的材料。而基于脂质的颗粒已经有效地传递了 在过去的几年里，siRNAs随着FDA批准的4种药物进入肝脏，还没有一个平台在固体上取得成功 肿瘤还没有。我们已经解决了纳米颗粒输送的限制并实现了长的循环半衰期(例如， 猴子25小时)，肿瘤中siRNA积累增加10倍，特异性递送到靶细胞(增加5到8- 比正常细胞折叠)，出色的PLK1基因敲除(例如，84%)，以及肿瘤抑制(例如，90%) 老鼠模型。我们的纳米颗粒的GMP制造的技术转让已经完成。 第一阶段：在目标1中，我们将优化(通过评估各种EGFR抗体药物(Ab)并增加 将EGFR抗体和siPLK1负载至少3倍)，并筛选产生 流体力学尺寸120 nm，75%的基因敲除，对EGFR+的摄取是EGFR-细胞的7倍，&gt；70% EGFR+肺癌细胞死亡，对正常细胞安全(&lt；15%死亡)。概念验证功效和 铅纳米结构的安全性将在转移性肺肿瘤小鼠身上进行。 第二阶段：在目标2中，将单独和结合RT评估最佳PETTRA的疗效。 将利用临床相关的原位非小细胞肺癌小鼠模型，并将在人源化中验证研究结果 携带患者来源肿瘤的小鼠。自由药物对应物，纳米粒递送单剂，以及第一 LINE化疗将被用作基准。在目标3中，阿司匹林的药代动力学、生物分布和安全性 PETTRA将在荷瘤小鼠和非人类灵长类动物身上进行评估。 研究结果将为FDA的研究新药申请提供重要数据。成功 SiRNA的传递有可能创造出数百种新的靶向疗法，用于难以在低浓度下对基因进行药物治疗 成本，精准药物和个性化药物都受益。该项目是PDX之间的合作 药剂学、生物医学工程系和俄亥俄州立大学奈特癌症研究所。

Lung cancer is the leading cause of cancer mortality, exceeding deaths from colon, breast, and prostate cancers combined. Resistance to chemo and targeted therapy is very common. Radiation therapy (RT) remains a key treatment in about 60% of lung cancer patients. We seek to develop a novel nanotherapeutic (termed PETTRA) that homes to EGFR+ lung tumors and delivers siRNA against Polo-like kinase 1 (siPLK1). EGFR is an ideal homing target since it is routinely profiled; and is overexpressed in 50% of lung cancer patients. PLK1 is among the strongest cancer targets due to its crucial roles in cell division and DNA repair, and inhibiting PLK1 leads to G2/M cell cycle arrest and apoptotic death. Cells in G2/M arrest are also most sensitive to radiation. Thus, PETTRA is hypothesized to be effective as a monotherapy and as a radiation sensitizer for lung cancer. Or prototype PETTRA has demonstrated good safety and efficacy for such dual proposes in cells and in mice. Herein, we propose to further optimize the material to enhance the efficacy and safety. While lipid-based particles have been effective at delivering siRNAs to the liver with 4 FDA approved drugs in the past few years, no platform has been successful in solid tumors yet. We have solved the limitations of nanoparticle delivery and achieved long circulation half-life (e.g., 25 hrs in monkeys), 10-fold increased siRNA accumulation in tumors, specific delivery to target cells (by 5 to 8- fold over normal cells), excellent PLK1 gene knock-down (e.g., by 84%), and tumor inhibition (e.g., by 90%) in mouse models. Tech-transfer for GMP manufacturing of our nanoparticles has been accomplished. Phase I: In Aim 1, we will optimize (by evaluating various EGFR antibody drugs (Ab) and increasing the loading of EGFR antibody and siPLK1 by at least 3-fold) and screen for the lead constructs that yield hydrodynamic size <120 nm, 75% gene knockdown, 7-fold greater uptake to EGFR+ over EGFR- cells, >70% cell death in EGFR+ lung cancer cells, and safety to normal cells (<15% death). Proof of concept efficacy and safety of the lead nanoconstruct will be performed in metastatic lung tumor mice. Phase II: In Aim 2, efficacy of the optimal PETTRA will be assessed, both alone and in combination with RT. Clinically relevant orthotopic NSCLC mouse models will be utilized, and findings will be validated in humanized mice bearing patient-derived tumors. Free drug counterparts, nanoparticle delivering single agents, and first- line chemo will be used as benchmarks. In Aim 3, the pharmacokinetics, biodistribution, and safety profile of PETTRA will be evaluated in tumor-bearing mice and in non-human primates. Results will provide important data towards an investigational new drug application to the FDA. Successful siRNA delivery has the potential to create hundreds of new targeted therapies for difficult to drug genes at low costs, benefiting both precision and personalized medicines. This project is a collaboration among PDX Pharmaceuticals, Biomedical Engineering Department, and the Knight Cancer Institute of OHSU.