Optimization of aminolevulinic acid-protoporphyrin IX for fluorescence-guided tumor resection and treatment

我们研究的长期目标是确定肿瘤表型和基因型特征， 肿瘤原卟啉IX荧光和设计机制为基础的方法，以克服这些限制 因素-第一次延长是在我们最初供资期间取得的进展的基础上进行的。手术是最常见的 治疗所有类型的实体瘤。成功的癌症手术是完全切除肿瘤组织， 最大限度地保持正常结构。为了提高癌症手术的准确性和精确性，荧光分子 探针已经被开发出来并且越来越多地用于肿瘤外科手术中。的荧光 术中分子探针使外科医生能够真实的实时观察肿瘤组织， 荧光引导切除术（FGR）。已经充分证明FGR导致更完整的肿瘤 在白色光下手术效果优于传统手术。氨基乙酰丙酸（ALA）是 是FDA批准的少数几种术中荧光探针之一，也是唯一一种基于 肿瘤细胞的代谢改变。ALA本身没有荧光，需要在体内代谢。 肿瘤细胞中血红素生物合成途径以产生荧光和光敏代谢物 原卟啉IX（PpIX），其能够实现肿瘤荧光成像和光动力疗法（PDT）。虽然 ALA-PpIX已在临床上用于肿瘤FGR，但其应用受到肿瘤PpIX荧光较低的限制， 高肿瘤荧光异质性和低肿瘤与正常组织荧光对比度。的研究 该奖项的最初资助期导致ABCG 2转运蛋白活性被确定为关键因素 减少肿瘤PpIX荧光。重要的是，我们已经确定了临床上使用的药物，以抑制ABCG 2 增强肿瘤PpIX荧光的活性。在这次更新中，我们将使用FDA批准的药物拉帕替尼（Lap）， 我们已经鉴定出最有效的一种，用于增强肿瘤PpIX荧光，并假设 拉帕替尼改善了ALA在神经胶质瘤FGR和PDT中的应用。我们选择研究这种增强策略 因为ALA现在主要用于指导胶质瘤的切除，更重要的是，ABCG 2 表达升高是人类神经胶质瘤的共同特征。为此，我们将结合 用ALA增强不同浓度的人胶质瘤细胞系中的PpIX荧光和PDT反应， 基因型和表型（Aim 1）和胶质瘤肿瘤模型（Aim 2）。通过这项研究，我们希望 证明Lap与ALA组合增强肿瘤PpIX荧光和PDT响应。的 这项研究的成功完成将导致ALA在FGR和PDT治疗中的优化使用 神经胶质瘤

The long-term goal of our research is to determine tumor phenotypic and genotypic characteristics that reduce tumor protoporphyrin IX fluorescence and design mechanism-based approaches to overcome these limiting factors – this first renewal builds on progress made in our initial funding period. Surgery is the most common treatment for all types of solid tumors. A successful cancer surgery is to completely remove tumor tissues and maximally preserve normal structures. To improve cancer surgery accuracy and precision, fluorescent molecular probes have been developed and are being increasingly used in the oncological surgery. Fluorescence from intraoperative molecular probes enables surgeons to visualize tumor tissues in real time and perform fluorescence-guided resection (FGR). It has been well demonstrated that FGR leads to more complete tumor resection and better surgical outcomes than conventional surgery under white light. Aminolevulinic acid (ALA) is one of a few FDA-approved intraoperative fluorescent probes and the only molecular probe based on the metabolic alterations in tumor cells. ALA has no fluorescence on its own and needs to be metabolized in the heme biosynthesis pathway in tumor cells to produce a fluorescent and photosensitizing metabolite protoporphyrin IX (PpIX), which enables tumor fluorescence imaging and photodynamic therapy (PDT). Although ALA-PpIX has been clinically used for tumor FGR, its applications are limited by low tumor PpIX fluorescence, high tumor fluorescence heterogeneity, and low tumor-to-normal tissue fluorescence contrast. Studies in the initial funding period of this award have led to the identification of ABCG2 transporter activity as a critical factor in reducing tumor PpIX fluorescence. Importantly, we have identified clinically used agents to suppress ABCG2 activity to enhance tumor PpIX fluorescence. In this renewal, we will use an FDA-approved drug lapatinib (Lap), the most potent one we have identified for the enhancement of tumor PpIX fluorescence, and hypothesize that lapatinib improves the use of ALA for FGR and PDT of gliomas. We chose to study this enhancement strategy in gliomas because ALA is now primarily used for guiding the resection of gliomas and, more importantly, ABCG2 expression elevation is a common feature in human gliomas. To this end, we will evaluate Lap in combination with ALA for the enhancement of PpIX fluorescence and PDT response in human glioma cell lines with different genotype and phenotype (Aim 1) and glioma tumor models (Aim 2). Through this research, we hope to demonstrate that Lap in combination with ALA enhances tumor PpIX fluorescence and PDT response. The successful completion of this research will lead to an optimized use of ALA for FGR and PDT treatment of gliomas.