Multifunctional, GBM-activatable nanocarriers for image-guided photochemotherapy

 描述(由申请人提供)：越来越明显的是，合理设计的联合疗法影响到多个靶点，最有可能改善胶质母细胞瘤(GBM)患者的预后。然而，在考虑到机械性相互作用的情况下，在正确的地点、正确的时间和正确的顺序有选择地提供多种方案仍然是一个重大挑战。光激活方法与纳米技术相结合，提供了一种独特的机会，可以针对几个关键的分子途径提供多种药物。光动力疗法(PDT)是一种可以与化疗和生物制剂协同作用的光基细胞毒疗法。PDT已被FDA批准用于几种癌症，目前正处于GBM的第三阶段试验。潜在的假设是，基于针对多个非重叠的肿瘤生长/生存途径的互动机制的适当时机的纳米技术辅助的联合治疗是提高治疗效果的关键，并允许非重叠的毒性和减少剂量。这项建议利用图像引导方法和聚合物工程来开发一种光免疫偶联纳米载体(PICNC)，它集成了FDA批准的PDT试剂(维替普芬)、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，头孢拉尼)。所有的药剂都被划分为适当的释放动力学，以确保正确的作用顺序，这说明了联合治疗的机制协同作用。在K99阶段，装载SN-38的纳米载体将被西妥昔单抗-维替普芬光免疫结合物(PICS)修饰，用于肿瘤靶向和图像引导联合治疗(PDT+SN-38)。据推测，SN-38改善肿瘤组织的氧合，有利于氧依赖的光动力疗法，而光动力疗法破坏外排泵，增加细胞内SN-38水平，将改善整体预后。为了准备R00过渡，黄博士将利用他的化学工程背景开发各种加载了第三种RTKI试剂的改性聚合物纳米粒子，这些纳米粒子旨在调节RTKI的释放动力学，并将被纳入PICNC。假设定制的RTKI释放动力学将最大限度地缓解PDT和SN-38引发的代偿RTK生存途径，以改善预后。在R00阶段，黄博士将建立PICNCs的分子影响和图像引导的治疗计划，然后评估PICNCs的治疗效果和定制的PDT方案。一个强大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。塔亚巴·哈桑博士(主要导师)将对黄博士进行光生物学、PIC纳米载体和结合机制方面的培训。David Boas博士(共同导师)是组织氧代谢的光学和光谱成像方面的专家。其他杰出成员还包括：荧光成像专家Brian Pogue博士；聚合物纳米颗粒专家Shiladitya Sengupta博士；GBM临床管理、动物模型和分子生物学方面的专家Robert Martuza博士、Xandra Breakefield博士和Anat Stemmer-rachamimov博士。

 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.