Multifunctional, GBM-activatable nanocarriers for image-guided photochemotherapy

用于图像引导光化疗的多功能、GBM 可激活纳米载体

• 批准号: 9260692
• 负责人: Huang Chiao Huang
• 金额: $ 17.9万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-15 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9260692
• 关键词: ABCG2 gene; Acute; Animal Model; Binding; Biodegradation; Biodistribution; Biological; Biological Markers; Biological Products; Boa; Cell Survival; Cells; Cessation of life; Cetuximab; Chemical Engineering; Clinical; Clinical Management; Clinical Trials; Combined Modality Therapy; Custom; Disease; Dose; Drug Delivery Systems; Drug Kinetics; Encapsulated; Engineering; Ensure; Epidermal Growth Factor Receptor; Evaluation; FDA approved; Glioblastoma; Goals; In Vitro; Injectable; KDR gene; Kinetics; Light; Lipid A; Lipid Bilayers; Malignant Neoplasms; Mentors; Metabolism; Modality; Modeling; Molecular; Molecular Biology; Nanotechnology; Outcome; Oxygen; PDGFRB gene; PECAM1 gene; PUVA Photochemotherapy; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Photobiology; Polymers; Proto-Oncogene Protein c-kit; Rattus; Receptor Protein-Tyrosine Kinases; Regimen; Research; SN-38; Schedule; Solid; Surface; Therapeutic; Therapeutic Effect; Time; Tissue imaging; Toxic effect; Training; Treatment Efficacy; Tumor Tissue; Tumor Volume; Verteporfin; Western Blotting; base; brain health; clinically relevant; cytotoxic; density; design; efflux pump; fluorescence imaging; image guided; improved; improved outcome; individualized medicine; kinase inhibitor; member; nanocarrier; nanoparticle; optical imaging; outcome forecast; phase III trial; public health relevance; quantitative imaging; spectrograph; synergism; targeted agent; targeted imaging; therapy outcome; tissue oxygenation; treatment planning; treatment response; tumor; tumor growth; uptake

 DESCRIPTION (provided by applicant): It is increasingly evident that rationally designed combination therapies impacting multiple targets will most likely to improve outcomes in patients with glioblastoma (GBM). However, the selective delivery of multiple regimens to the right place, at the right time, and in the correct sequence with consideration of mechanistic interactions remains a major challenge. Light-activated approaches combined with nanotechnology provide a unique opportunity to deliver multiple agents targeted at several key molecular pathways. Photodynamic therapy (PDT) is a light-based cytotoxic modality that can synergize with chemo and biological agents. PDT is FDA-approved for several cancers and it is in phase III trial for GBM. The underlying hypothesis is that properly timed, nanotechnology-assisted combination therapies based on interactive mechanisms that target multiple non-overlapping tumor growth/survival pathways is key to improving treatment efficacy, and allows for non-overlapping toxicities and reduced dose. This proposal leverages image-guided approaches and polymer engineering to develop a photoimmunoconjugate-nanocarrier (PICNC) that integrates an FDA-approved PDT agent (verteporfin), a clinically promising chemodrug (SN-38), and a multi-receptor tyrosine kinase inhibitor (RTKi, cediranib). All the agents are compartmentalized for appropriate release kinetics to ensure the correct sequence of action that accounts for the mechanistic synergism of the combination treatment. During the K99 phase, SN-38-loaded nanocarriers will be decorated with cetuximab-verteporfin photoimmunoconjugates (PICs) for tumor targeting and image-guided combination therapy (PDT + SN-38). It is hypothesized that SN- 38 improves tumor tissue oxygenation to favor oxygen-dependent PDT, while PDT destroys efflux pumps to increase intracellular SN-38 levels, will improve the overall outcome. To prepare for R00 transition, Dr. Huang will leverage his chemical engineering background to develop a variety of modified polymer nanoparticles loaded with a third RTKi agent, engineered to modulate the RTKi release kinetics, which will be incorporated into the PICNC. The hypothesis is that the customized RTKi release kinetics will maximize the mitigation of the compensatory RTK survival pathways elicited by PDT and SN-38 to improve outcome. During the R00 phase, Dr. Huang will establish the molecular impact and the image-guided treatment planning of PICNCs, and then evaluate the therapeutic effects of PICNCs and customized PDT schedule. A strong mentoring committee has been assembled to guide Dr. Huang's research and facilitate his transition to independence. Dr. Tayyaba Hasan (primary mentor) will train Dr. Huang in photobiology, PIC-nanocarriers, and combination mechanism. Dr. David Boas (co-mentor) is an expert in optical and spectral imaging of tissue oxygen metabolism. Additional distinguished members are: Dr. Brian Pogue, a fluorescence imaging expert; Dr. Shiladitya Sengupta, an polymer nanoparticle expert; Drs. Robert Martuza, Xandra Breakefield, and Anat Stemmer-Rachamimov are experts in clinical management, animal models and molecular biology of GBM.

 描述（由申请人提供）：越来越明显的是，合理设计的影响多个靶点的联合疗法最有可能改善胶质母细胞瘤（GBM）患者的预后，然而，在正确的时间将多种治疗方案选择性地递送到正确的地点。 ，并考虑机械相互作用的正确顺序仍然是一个主要挑战，光激活方法与纳米技术相结合提供了一个独特的机会来提供针对几个关键分子途径的多种药物光动力疗法（PDT）是一种基于光的疗法。 PDT 已获得 FDA 批准，可与化疗和生物制剂协同作用，用于治疗多种癌症，目前正处于针对 GBM 的 III 期试验中。 -重叠的肿瘤生长/生存途径是提高治疗效果的关键，并且允许非重叠毒性和减少剂量。该提案利用图像引导方法和聚合物工程来开发光免疫缀合物纳米载体。 (PICNC)，整合了 FDA 批准的 PDT 药物（维替泊芬）、临床上有前景的化疗药物 (SN-38) 和多受体酪氨酸激酶抑制剂（RTKi、西地尼布​​）。所有药物均按适当的释放动力学进行划分，以确保适当的释放动力学。在 K99 阶段，负载 SN-38 的纳米载体将被解释为联合治疗的机械协同作用的正确顺序。用西妥昔单抗-维替泊芬光免疫缀合物 (PIC) 装饰，用于肿瘤靶向和图像引导联合治疗 (PDT + SN-38) 人们再次认识到，SN-38 改善肿瘤组织氧合作用，有利于氧依赖性 PDT，而 PDT 会破坏外排泵，从而促进氧依赖性 PDT。增加细胞内SN-38水平，将改善整体结果 为了为R00过渡做好准备，黄博士将利用他的化学工程背景来开发多种修饰。聚合物纳米颗粒装载有第三种 RTKi 药物，旨在调节 RTKi 释放动力学，该药物将被纳入 PICNC 中。假设定制的 RTKi 释放动力学将最大限度地缓解 PDT 和 SN- 引起的补偿性 RTK 生存途径。 38 在R00阶段，黄博士将建立PICNC的分子影响和图像引导治疗计划，然后评估治疗效果。 PICNC 和定制的 PDT 时间表已经成立，以指导黄博士的研究并促进他向独立过渡。Tayyaba Hasan 博士将在光生物学、PIC 纳米载体和组合机制方面对黄博士进行培训。 David Boas 博士（共同导师）是组织氧代谢光学和光谱成像方面的专家，其他杰出成员包括：Brian Pogue 博士，荧光成像专家；Shiladitya 博士； Sengupta 博士是聚合物纳米颗粒专家；Robert Martuza 博士、Xandra Breakefield 博士和 Anat Stemmer-Rachamimov 博士是 GBM 的临床管理、动物模型和分子生物学专家。