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，影响多个靶点的合理设计的联合治疗最有可能改善胶质母细胞瘤（GBM）患者的结局。然而，考虑到机械相互作用，在正确的时间以正确的顺序将多种方案选择性地递送到正确的地点仍然是一个重大挑战。光激活方法与纳米技术相结合，提供了一个独特的机会，提供多种药物靶向几个关键的分子途径。光动力疗法（PDT）是一种基于光的细胞毒性方式，可以与化学和生物制剂协同作用。PDT已被FDA批准用于多种癌症，并正在进行GBM的III期试验。潜在的假设是，基于靶向多种非重叠肿瘤生长/存活途径的相互作用机制的适当定时的纳米技术辅助的联合疗法是提高治疗疗效的关键，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），其整合了FDA批准的PDT剂（维替泊芬）、临床上有前途的化疗药物（SN-38）和多受体酪氨酸激酶抑制剂（RTKi，西地尼布）。将所有药剂分区以获得适当的释放动力学，以确保正确的作用顺序，从而解释组合治疗的机械协同作用。在K99阶段，装载SN-38的纳米载体将用西妥昔单抗-维替泊芬光免疫缀合物（PIC）修饰，用于肿瘤靶向和图像引导的联合治疗（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破坏外排泵以增加细胞内SN-38水平，将改善总体结果。为了准备R 00过渡，黄博士将利用他的化学工程背景来开发各种装载有第三种RTKi试剂的改性聚合物纳米颗粒，该试剂被设计用于调节RTKi释放动力学，该试剂将被纳入PICNC中。假设是定制的RTKi释放动力学将最大化由PDT和SN-38引起的代偿性RTK存活途径的缓解以改善结果。在R 00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PICNC和定制PDT方案的治疗效果。一个强有力的指导委员会已经成立，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）将在光生物学，PIC纳米载体和组合机制方面培训Huang博士。大卫博阿斯博士（共同导师）是组织氧代谢的光学和光谱成像专家。其他杰出成员包括：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博士和Anat Stemmer-Rachamimov博士是GBM临床管理、动物模型和分子生物学方面的专家。