Targeting nanotherapeutics against murine and feline oral cancer

 描述（由申请人提供）：针对小鼠和猫口腔癌的靶向纳米治疗药物摘要：这是我们的R 01 EB 012569赠款的竞争性更新提案。通过R 01的支持，我们最近开发了一个令人兴奋的纳米平台，我们相信这将是这次竞争性R 01更新的一个很好的主题。这种新的多功能卟啉基胶束纳米平台，最近发表在自然通讯（2014年8月），允许（i）疏水化疗药物或hsp 90抑制剂的有效包封，（ii）基于卟啉和/或包封的花青染料的固有荧光的肿瘤的近红外荧光（NIRF）检测，（iii）在分别用于光动力疗法（PDT）和光热疗法（PTT）的光激活时，在肿瘤部位有效的自由基和热生成，（iv）将癌症靶向配体方便地连接到胶束的表面，用于癌症特异性靶向递送，和（v）螯合Gd（III）或64 Cu用于MRI和PET成像，分别我们已经表明，纳米卟啉介导的PDT导致显着的肿瘤抑制相比，最近报道的卟啉制剂，例如脂质体卟啉使用低得多的光和光敏剂的剂量。此外，纳米卟啉介导的联合化疗和PDT（Chemo-PDT）比单独的单一治疗显著更有效。这种新的PDT剂远远优于现有的FDA批准的光敏剂上级。因此，我们希望开发这种用于治疗口腔癌的药物，这种药物很容易接受近红外光（NIRL）的照射。我们将使用异种移植模型和伴侣猫的自发性口腔癌来评估这种新型纳米治疗诊断剂。四个具体目标是：目标1。设计并合成卟啉/菁染料衍生物，并利用它们制备各种杂化末端树枝状大分子，以构建胶束型卟啉纳米粒子，称为纳米卟啉（NP）。目标2.使用光学和MR成像来确定目标1中的靶向交联NP（CNP）的生物分布和OSCC靶向特性，使用原位植入的转移酶转染的OSCC异种移植模型。目标3。确定在目标2中优化的阿霉素/17 AAG负载的靶向-CNP的体内毒性和抗肿瘤功效。目标4。使用患有自发性口腔癌的伴侣猫作为模型系统，（i）使用光学成像和MRI扫描确定靶向CNP的生物分布和肿瘤摄取，（ii）进行CNP的药代动力学和药效学研究，以及（iii）进行载药靶向CNP光疗的I期临床试验。创新和影响我们的交联纳米卟啉（CNP）可以（i）提供多模态成像（近红外荧光，MRI，PET和SPECT）和针对靶向肿瘤的“四重打击”（ii）达到甚至非常小的转移性肿瘤细胞簇（50-100 μm），和（iii）利用我们已经鉴定的肿瘤配体LLS 13增强细胞内摄取。乳头瘤病毒相关口咽癌在美国呈上升趋势3。它是少数几种可以用光照射的癌症之一，使其成为一种理想的肿瘤类型，可以从这种新型光治疗诊断剂中大大受益，用于检测和消除疾病。

 DESCRIPTION (provided by applicant): Targeting nanotherapeutics against murine and feline oral cancer Abstract: This is a competitive renewal proposal of our R01 EB012569 grant. Through the R01 support, we have recently developed an exciting nanoplatform, which we believe will be an excellent subject for this competitive R01 renewal. This novel multifunctional porphyrin-based micellar nanoplatform, recently published in Nature Communication (August 2014), allows (i) efficient encapsulation of hydrophobic chemotherapeutic drugs or hsp90 inhibitor, (ii) near-infra red fluorescent (NIRF) detection of the tumor based on the intrinsic fluorescence of porphyrins and/or encapsulated cyanine dye, (iii) efficient free radical and heat generation at tumor site upon activation with light for photodynamic therapy (PDT) and photothermal therapy (PTT), respectively, (iv) convenient ligation of cancer-targeting ligands to the surface of the micelle for cancer-specific targeted delivery, and (v) chelation of Gd (III) or 64Cu for MRI and PET imaging, respectively. We have shown that nanoporphyrin-mediated PDT led to significant tumor inhibition by using much lower dose of light and photosensitizer compared with the recently reported porphyrin formulations, e.g. liposomal porphyrins. Furthermore, the nanoporphyrin-mediated combination chemotherapy and PDT (Chemo-PDT) was dramatically more efficacious than single treatment alone. This novel PDT agent is far superior than existing FDA approved photosensitizer. We therefore would like to develop this agent for the treatment of oral cancers, which is readily accessible to illumination with near infrared light (NIRL). We will use both xenograft model and spontaneous oral cancer in companion cat to evaluate this novel nanotheranostic agent. The 4 specific aims are: Aim 1. To design and synthesize porphyrin/cyanine dye derivatives and use them to prepare various hybrid telodendrimers suitable for the construction of micelle-based porphyrin nanoparticles called nanoporphyrins (NP). Aim 2. To use optical and MR imaging to determine the biodistribution and OSCC targeting properties of targeting-crosslinked NPs (CNPs) from aim 1, using orthotopically implanted luciferase-transfected OSCC xenograft models. Aim 3. To determine the in vivo toxicity and anti-tumor efficacy of the doxorubicin/17AAG-loaded targeting-CNPs optimized in aim 2. Aim 4. To use companion cat with spontaneous oral cancer as a model system to (i) determine the biodistribution and tumor uptake of targeting-CNP using optical imaging and MRI scan, (ii) perform pharmacokinetic and pharmacodynamics studies of CNP, and (iii) perform a Phase I clinical trial of phototherapy of drug-loaded targeting CNP. Innovation and Impact Our crosslinked nanoporphyrin (CNP) can (i) afford multimodality imaging (near- infra red fluorescent, MRI, PET, and SPECT), and "quadruple whammy" against targeted tumor (PDT, PTT, chemotherapy and Hsp90 inhibitor), (ii) reach even very small metastatic tumor cell cluster (50-100 µm), and (iii) take advantage of the tumor ligand LLS13 that we have already identified for enhancing intracellular uptake. Papilloma virus associated oropharyngeal cancer is on the rise in the United States3. It is one of the few cancers that are accessible to illumination with light, making it an ideal tumor type that can greatly benefit from this novel photo-theranostic agent for both detection and elimination of the disease.