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

手术是所有类型实体肿瘤最常见的治疗方法。一个成功的癌症手术是 彻底清除癌细胞，最大限度地保护正常结构。为了改善癌症手术 结果，荧光分子探针已经被开发出来，并越来越多地用于指导肿瘤 在手术过程中被移除。这些术中分子探针发出的荧光使 外科医生实时显示肿瘤组织，并在荧光引导下进行肿瘤切除。它有 已经很好地证明了在荧光引导下肿瘤切除可以使肿瘤切除更彻底 并提高治疗效果。氨基酮丙酸(ALA)是FDA批准的少数术中药物之一 荧光探头。虽然ALA本身不是荧光的，但它在血红素的生物合成中被代谢。 获得荧光和光敏代谢物原卟啉IX(PpIX)的途径，使能荧光 检测和光动力疗法(PDT)。ALA-PPIX已在临床上用于指导肿瘤切除 各种类型的肿瘤。然而，ALA的临床应用受到低PPIX肿瘤等问题的限制 产生，PpIX荧光不均一，低肿瘤/正常荧光对比度。我们的目标是 通过解决影响ALA的肿瘤表型和基因特征来优化基于ALA的治疗方案 肿瘤PPIX荧光。本研究提出了两种优化策略。具体目标1是 通过抑制PpIX外流优化ALA-PpIX荧光引导肿瘤切除和治疗。我们 发现三重阴性乳腺癌(TNBC)细胞系表现出ALA-PpIX荧光减弱和 由于ABCG2转运蛋白活性升高，对ALA-PDT具有抗性。我们已检索到临床ABCG2 转运蛋白抑制剂，并将使用它们来改进ALA-PPIX荧光引导的切除和治疗 在ABCG2转运蛋白活性增强的TNBC肿瘤中。具体目标2是优化丙氨酸的剂量 在PPIX荧光引导下切除和治疗有血红素基因改变的肿瘤 生物合成酶。我们发现胰腺癌在血红素中表现出基因改变。 生物合成酶，它改变了ALA-PPIX的生产概况。我们将优化ALA剂量以增加 PPIX荧光对比剂在肿瘤和正常组织间的对比研究 胰腺癌。通过这项研究，我们希望证明ALA协议经过优化后能够适应 肿瘤表型和基因分型提供了比一刀切的手术结果更好的结果 接近。

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.