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（由适用提供）：越来越多的证据表明，影响多个目标的合理设计的组合疗法最有可能改善胶质母细胞瘤（GBM）患者的预后。但是，在正确的时间，在正确的序列中选择性地递送多个方案向正确的位置传递，并考虑机械相互作用仍然是一个重大挑战。与纳米技术相结合的光激活方法为交付针对多种关键分子途径的多种试剂提供了独特的机会。光动力疗法（PDT）是一种基于光基的细胞毒性方式，可以与化学和生物学剂协同作用。 PDT已通过FDA批准了多种癌症，并且正在GBM的III期试验中。潜在的假设是，基于交互式机制，适当定时，纳米技术辅助疗法的组合疗法针对多个非重叠肿瘤生长/生存途径是提高治疗效率的关键，并允许非重叠的毒性和剂量减少。该提案利用图像引导的方法和聚合物工程开发了摄影型偶联 - 纳米载体（PITNC），该载体（PICNC）整合了FDA批准的PDT Agent（Verteporfin），这是一种临床上有望化学剂（SN-38），SN-38）和多人促毒素酪氨酸基因酶Inmibib（RIRTKI）。所有试剂均经过隔离，以进行适当的释放动力学，以确保正确的作用序列，以说明组合处理的机械协同作用。在K99阶段，SN-38负载的纳米载体将用Cetuximab-verteporfin photimmunoconjugates（PICS）装饰，用于肿瘤靶向和图像引导的组合疗法（PDT + SN-38）。假设SN-38改善肿瘤组织氧合以有利于氧依赖性PDT，而PDT会破坏外排泵以提高细胞内SN-38水平，将改善总体结果。为了准备R00过渡，黄博士将利用其化学工程背景来开发各种装有第三个RTKI剂的改良聚合物纳米颗粒，该纳米颗粒设计用于调节RTKI释放动力学，并将其纳入PICNC。假设是自定义的RTKI释放动力学将最大化PDT和SN-38引起的补偿性RTK生存途径的缓解，以改善预后。在R00阶段，Huang博士将建立PICNCS的分子影响和图像引导的治疗计划，然后评估PICNCS和自定义PDT时间表的治疗效果。一个强大的心理委员会已经组建了，以指导黄博士的研究，并促进他向独立的过渡。 Tayyaba Hasan博士（主要导师）将培训黄博士的光生物学，PIC-Nanocarrier和组合机制。 David Boas博士（Co-Incertor）是组织氧代谢的光学和光谱成像专家。其他杰出成员是：荧光成像专家Brian Pogue博士；聚合物纳米颗粒专家Shiladitya Sengupta博士； Robert Martuza博士，Xandra Breakefield和Anat Stemmer-Rachamimov是GBM的临床管理，动物模型和分子生物学专家。