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

手术是所有类型实体瘤最常见的治疗方法。一个成功的癌症手术 彻底清除癌细胞，最大限度地保留正常结构。来改善癌症手术 结果，荧光分子探针已被开发并越来越多地用于引导肿瘤 在手术中取出。从这些术中分子探针发出的荧光使得 外科医生可以真实的实时观察肿瘤组织并进行荧光引导的肿瘤切除。它有 已经很好地证明，荧光引导的肿瘤切除术能够实现更完整的肿瘤切除， 并提高治疗效果。氨基乙酰丙酸（ALA）是FDA批准的少数几种术中 荧光探针。虽然ALA本身不发荧光，但它在血红素生物合成中代谢 荧光和光敏代谢物原卟啉IX（PpIX）的途径，使荧光 检测和光动力疗法（PDT）。ALA-PpIX已在临床上用于指导切除 各种类型的肿瘤然而，ALA的临床应用受到诸如低PpIX肿瘤等问题的限制 产生、PpIX荧光异质性和低肿瘤/正常荧光对比度。我们的目标是 通过解决肿瘤表型和基因型特征，优化基于ALA的模式， 肿瘤PpIX荧光。本研究提出两种最佳化策略。具体目标1是 通过抑制PpIX流出来优化ALA-PpIX荧光引导的肿瘤切除和治疗。我们 已经发现三阴性乳腺癌（TNBC）细胞系显示降低的ALA-PpIX荧光， 由于ABCG 2转运蛋白活性升高，对ALA-PDT具有抗性。我们搜索了临床ABCG 2 转运蛋白抑制剂，并将使用它们来改善ALA-PpIX荧光引导切除和治疗 ABCG 2转运蛋白活性增加的TNBC肿瘤。具体目标2是优化ALA的剂量 用于PpIX荧光引导切除和治疗具有血红素遗传改变的肿瘤 生物合成酶我们发现胰腺癌表现出血红素的遗传改变， 生物合成酶，其改变ALA-PpIX生产概况。我们将优化ALA剂量， 肿瘤和正常组织之间的PpIX荧光对比，以改善荧光引导切除肿瘤的效果。 胰腺癌通过这项研究，我们希望证明ALA协议优化，以适应 肿瘤表型和基因型提供了更好的手术结果比应用它的基础上一刀切 approach.

Surgery is the most common treatment for all types of solid tumors. A successful cancer surgery is to completely remove cancer cells and maximally preserve normal structures. To improve cancer surgery outcomes, fluorescent molecular probes have been developed and increasingly used for guiding tumor removal during surgery. Fluorescence emitted from these intraoperative molecular probes enables surgeons to visualize tumor tissues in real time and perform fluorescence-guided tumor resection. It has been well demonstrated that fluorescence-guided tumor resection enables more complete tumor resection and enhances treatment outcomes. Aminolevulinic acid (ALA) is one of a few FDA-approved intraoperative fluorescent probes. Although ALA itself is not fluorescent, it is metabolized in the heme biosynthesis pathway to a fluorescent and photosensitizing metabolite protoporphyrin IX (PpIX), enabling fluorescence detection and photodynamic therapy (PDT). ALA-PpIX has been clinically used for guiding the resection of various types of tumors. However, clinical applications of ALA are limited by issues such as low PpIX tumor production, PpIX fluorescence heterogeneity, and low tumor/normal fluorescence contrast. Our goal is to optimize ALA-based modalities by addressing tumor phenotypic and genotypic characteristics that affect tumor PpIX fluorescence. Two optimization strategies are proposed in this research. Specific Aim 1 is to optimize ALA-PpIX fluorescence-guided tumor resection and treatment by suppressing PpIX efflux. We have found that triple negative breast cancer (TNBC) cell lines show reduced ALA-PpIX fluorescence and are resistant to ALA-PDT due to elevated ABCG2 transporter activity. We have searched for clinical ABCG2 transporter inhibitors and will use them to improve ALA-PpIX fluorescence-guided resection and treatment of TNBC tumors with increased ABCG2 transporter activity. Specific Aim 2 is to optimize the dose of ALA for PpIX fluorescence-guided resection and treatment of tumors with genetic alterations in heme biosynthesis enzymes. We have found that pancreatic cancers exhibit genetic alterations in heme biosynthesis enzymes, which change ALA-PpIX production profile. We will optimize ALA dose to increase PpIX fluorescence contrast between tumor and normal tissues to improve fluorescence-guided resection of pancreatic cancers. Through this research, we hope to demonstrate that ALA protocols optimized to fit tumor phenotype and genotype offer better surgical outcomes than applying it based on one-size-fits-all approach.