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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.

总结

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）

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

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

Fragment-based drug nanoaggregation reveals drivers of self-assembly.

DOI：
10.1038/s41467-023-43560-0
发表时间：
2023-12-14
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Chen, Chen;Wu, You;Wang, Shih-Ting;Berisha, Naxhije;Manzari, Mandana T.;Vogt, Kristen;Gang, Oleg;Heller, Daniel A.
通讯作者：
Heller, Daniel A.

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

DOI：
10.1038/s41598-021-89839-4
发表时间：
2021-05-19
期刊：
Scientific reports
影响因子：
4.6
作者：
Podlesny B;Olszewska B;Yaari Z;Jena PV;Ghahramani G;Feiner R;Heller DA;Janas D
通讯作者：
Janas D

Glutathione-S-transferase Fusion Protein Nanosensor.