P-selectin-Mediated Targeting of PI3K Nanomedicines to the Tumor Microenvironment

P-选择素介导的 PI3K 纳米药物靶向肿瘤微环境

基本信息

批准号：
10310486
负责人：
Daniel Alan Heller
金额：
$ 62.65万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-15 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10310486
关键词：
Acute Address Affect Affinity Antineoplastic Agents Apoptosis Attenuated Biochemical Biodistribution Blood Blood Platelets Blood Vessels Cell Adhesion Molecules Cell membrane Cells Chronic Clinical Research Code Disease Dose-Limiting Drug Carriers Drug Delivery Systems Drug Kinetics Drug Modulation Drug Targeting Encapsulated Endothelial Cells Endothelium Environment Exhibits External Beam Radiation Therapy Genomics Glucose Goals Head and Neck Squamous Cell Carcinoma Histology Human Hyperglycemia Insulin Ionizing radiation Laboratories Malignant Neoplasms Measures Mediating Microscopy Mutation Neoplasm Metastasis Neoplasms in Vascular Tissue Organ Outcome P-Selectin PIK3CA gene Patients Pharmaceutical Preparations Pharmacology Polysaccharides Positron-Emission Tomography Radiation Radioisotopes Research Research Personnel Serum Signal Pathway Site Solid Neoplasm Technology Therapeutic Therapeutic Index Tissues Toxic effect Toxicology Treatment-related toxicity Tumor Tissue Work base cancer cell cell stroma improved individualized medicine inhibitor liquid chromatography mass spectrometry nanomedicine nanomolar nanoparticle nanoparticle delivery nanoparticle drug neoplastic cell novel strategies novel therapeutic intervention pancreatic islet function personalized medicine phase I trial side effect targeted treatment treatment response tumor tumor growth tumor microenvironment

项目摘要

SUMMARY Personalized medicine, based on the genomic context of a patient’s disease, has become a leading strategy to treat cancer. However, despite the promising results from customized treatments, targeted therapies affect the same signaling pathways in non-cancerous cells, often leading to dose-limiting, “on-target” toxicities. One such example involves PI3K inhibitors. In head and neck squamous cell carcinoma (HNSCC), the 6th most common cancer worldwide, 34%-56% of tumors harbor mutations or amplifications in PIK3CA, the gene coding for the p110α subunit of PI3K. PI3Kα inhibitors carry a significant toxicity profile, however, that limits their therapeutic window, specifically in patients who develop intractable hyperglycemia. Using a targeted drug delivery approach, we have identified a strategy to address this need. The PI developed a new class of nanoparticles targeted to P-selectin which allows the incorporation of a wide variety of therapeutic molecules, including targeted therapies (Shamay, Sci Transl Med 2016). We built a collaborative research team that employed this technology to target tumors expressing endothelial P-selectin, either at baseline or radiation-induced (Mizrachi, Nat Commun 2017). The strategy effected a significantly improved therapeutic index and survival, while minimizing the side effects of targeted therapeutics. Notably, we found that PI3K inhibitors, targeted using our nanoparticle vehicle, resulted in prolonged pS6 inhibition and anti-tumor efficacy, while minimizing acute and chronic effects of hyperglycemia. The objective of this project is to investigate, in the context of HNSCC, the nanoparticle-mediated delivery of PI3K therapies via P-selectin, expressed spontaneously or induced by radiation. This proposal’s goals are to understand the modulation of drug pharmacology, efficacy, toxicities, interactions with HNSCC tumor microenvironment, and the impact of ionizing radiation on these parameters. We plan to pursue the following specific aims: 1) Assess P-selectin-mediated targeting to the tumor microenvironment. We will measure the localization of the nanoparticle and encapsulated drug in the tumor microenvironment from the organ to cellular levels. 2) Enhance nanoparticle localization via radiation-induced endothelial activation. Based on our understanding of radiation-induced expression of P-selectin, we hypothesize that external beam radiation can increase localization of a P-selectin-targeted PI3K inhibitor in disseminated tumors due to the increased availability of the target. 3) Assess efficacy of P-selectin-mediated targeting of PI3K inhibitors. We will assess the relationship between drug delivery mechanism and treatment response. We hypothesize: (i) that the P-selectin-based targeting will improve PI3K inhibitor-mediated efficacy and apoptosis in tumors, (ii) that radiation may increase the relative efficacy of the inhibitor, (iii) that nanoparticle-mediated P-selectin targeting will mitigate PI3K-mediated hyperglycemia, and (iv) that nanoparticle-delivered therapeutic combinations will improve synergistic effects while attenuating toxicities that arise from systemic administration of multiple inhibitors. The outcomes will inform IND and clinical studies.

概括基于患者疾病基因组背景的个性化医疗已成为一种领先策略然而，尽管定制治疗取得了有希望的结果，但靶向治疗仍会影响癌症的治疗。在非癌细胞中存在相同的信号通路，通常会导致剂量限制的“靶向”毒性。例如，在头颈鳞状细胞癌 (HNSCC) 中，PI3K 抑制剂是第六常见的癌症。在全世界的癌症中，34%-56% 的肿瘤存在 PIK3CA 突变或扩增，PIK3CA 是编码然而，PI3Kα 抑制剂的 p110α 亚基具有显着的毒性特征，这限制了其治疗。窗口，特别是对于患有顽固性高血糖的患者，使用靶向药物输送。方法，我们已经确定了解决这一需求的策略，开发了一种新型纳米颗粒。靶向 P-选择素，允许掺入多种治疗分子，包括靶向治疗（Shamay，Sci Transl Med 2016）我们建立了一个采用该疗法的合作研究团队。技术靶向表达内皮 P-选择素的肿瘤，无论是在基线还是辐射诱导的（Mizrachi， Nat Commun 2017）该策略显着改善了治疗指数和生存率。值得注意的是，我们发现 PI3K 抑制剂可以使用我们的靶向药物。纳米颗粒载体，导致延长 pS6 抑制和抗肿瘤功效，同时最大限度地减少急性和该项目的目的是在 HNSCC 的背景下调查高血糖的慢性影响。纳米颗粒介导的通过 P-选择素传递 PI3K 疗法，自发表达或诱导表达该提案的目标是了解药物药理学、功效、毒性的调节，与 HNSCC 肿瘤微环境的相互作用，以及电离辐射对这些参数的影响。我们计划实现以下具体目标：1) 评估 P-选择素介导的肿瘤靶向作用我们将测量纳米颗粒和封装药物在肿瘤中的定位。 2) 通过辐射诱导增强纳米粒子定位基于我们对辐射诱导的 P-选择素表达的理解，我们研究发现外部束辐射可以增加 P-选择素靶向 PI3K 抑制剂在 3) 评估 P-选择素介导的功效我们将评估药物递送机制和治疗之间的关系。我们认为：(i) 基于 P-选择素的靶向将提高 PI3K 抑制剂介导的功效。和肿瘤细胞凋亡，(ii) 辐射可能会增加抑制剂的相对功效，(iii) 纳米颗粒介导的 P-选择素靶向将减轻 PI3K 介导的高血糖，并且 (iv) 纳米颗粒递送的治疗组合将提高协同效应，同时减轻毒性多种抑制剂的全身给药产生的结果将为 IND 和临床研究提供信息。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Merging data curation and machine learning to improve nanomedicines.

合并数据管理和机器学习以改进纳米医学。

DOI：
发表时间：
2022-04
期刊：
影响因子：
16.1
作者：
Chen, Chen;Yaari, Zvi;Apfelbaum, Elana;Grodzinski, Piotr;Shamay, Yosi;Heller, Daniel A
通讯作者：
Heller, Daniel A

Selective nanoparticle-mediated targeting of renal tubular Toll-like receptor 9 attenuates ischemic acute kidney injury.

选择性纳米颗粒介导的肾小管 Toll 样受体 9 的靶向可减轻缺血性急性肾损伤。

DOI：
10.1016/j.kint.2020.01.036
发表时间：
2020-07
期刊：
Kidney international
影响因子：
19.6
作者：
Han SJ;Williams RM;D'Agati V;Jaimes EA;Heller DA;Lee HT
通讯作者：
Lee HT

Glutathione-S-transferase Fusion Protein Nanosensor.

谷胱甘肽-S-转移酶融合蛋白纳米传感器。

DOI：
10.1021/acs.nanolett.0c02691
发表时间：
2020-10-14
期刊：
Nano letters
影响因子：
10.8
作者：
Williams RM;Harvey JD;Budhathoki-Uprety J;Heller DA
通讯作者：
Heller DA

En route to single-step, two-phase purification of carbon nanotubes facilitated by high-throughput spectroscopy.

通过高通量光谱法促进碳纳米管的单步、两相纯化。

DOI：
发表时间：
2021-05-19
期刊：
影响因子：
4.6
作者：
Podlesny, Blazej;Olszewska, Barbara;Yaari, Zvi;Jena, Prakrit V;Ghahramani, Gregory;Feiner, Ron;Heller, Daniel A;Janas, Dawid
通讯作者：
Janas, Dawid

Hyperspectral Counting of Multiplexed Nanoparticle Emitters in Single Cells and Organelles.

单细胞和细胞器中多重纳米颗粒发射器的高光谱计数。

DOI：
发表时间：
2022-02-22
期刊：
影响因子：
17.1
作者：
Jena, Prakrit V;Gravely, Mitchell;Cupo, Christian;Safaee, Mohammad Moein;Roxbury, Daniel;Heller, Daniel A
通讯作者：
Heller, Daniel A