A comprehensive platform for low-cost screening and image-guided photodynamic therapy (PDT) of pre-malignant and malignant oral lesions in low resource settings

受到印度口腔癌严峻形势的鼓舞，并受到我们在UH 2/UH 3中取得的成功的鼓舞 诊断和治疗前和早期癌症的机制，一个新的综合“筛选，成像和治疗” 光学系统”（SITOS）在当前的申请中提出，该申请结合了美国3个地点的专业知识， 与2个印度临床团队合作。所有研究中心均作为2名个人参与了之前的NCI奖项 UH 2/UH 3项目侧重于检测或治疗。治疗仍然是光动力疗法 (PDT)是一种基于光化学的FDA批准的模式，而检测是基于荧光和白色 光成像结合基于云的深度学习AI方法进行图像分类。SITOS 能够实现图像引导的PDT，而双重性质的荧光团/光敏剂前体的局部应用 口腔，更适合LMIC，旨在实现更好的肿瘤渗透比以前的局部 交付，也在发展。这些目标将在三个具体目标中实现。目标1建立在以前的基础上 成功开发和临床验证了用于口内成像和口内成像的单独的低成本设备， PDT产生一种新的，手持的，低成本的，易于使用的，SITOS。该集成平台支持使用 用于初始成像的相同硬件，以及用于图像引导PDT和在线监测的单个热疗分子 在治疗期间。结合了人体工程学的口内光传输PDT和初步验证的光学 体模和体外3D肿瘤模型。目的2A建立了局部光敏化的条件， Photonamic GmbH提供的粘附性ALA贴片在离体猪粘膜模型中的应用。根据2A的数据， 目的2B在鼠异种移植模型中建立最佳PDT参数。目标2C验证了其中最好的 参数在致癌物诱导的仓鼠颊囊模型，概括过渡， 恶性病变目的3应用SITOS识别和治疗高危口腔潜在恶性肿瘤 病变（OPML）和早期口腔癌，使用临床前研究的广泛指导。筛选 病人将在营地和偏远的村庄进行，由印度的临床小组领导，就像在UH的努力一样。患者 经组织学证实的HGD/OPML患者（并符合其他入选标准）将有资格入选。患者将 使用ALA局部贴剂治疗，（在一个小队列建立安全性和最佳接触时间后，基于 目标2）。最后，PDT对高危OPML和早期癌症患者采用光传递和同步成像 将使用新的口内探针进行引导。 影响和相关性：该研究首次提供了一种全面的低成本方法， 不仅检测癌前/恶性口腔病变，而且是LMIC的有效监测治疗 设置. SITOS平台是移动的、手持式的，适合床旁应用。它汇集了 合作者（科学家、口腔癌外科医生、肿瘤学家和行业）帮助FDA批准ALA 补丁和SITOS。能力建设：一种新的临床模式和人工智能/工程开发平台。

Motivated by the bleak situation of oral cancer in India and encouraged by our successes in the UH2/UH3 mechanism for diagnosing and treating pre- and early cancers, a new integrated “Screen, Image and Treat Optical System” (SITOS) is proposed in the current application which combines the expertise of 3 US sites in collaboration with 2 clinical Indian teams. All sites were participants in the previous NCI awards as 2 individual UH2/UH3 projects focused on either detection or therapy. The treatment continues to be photodynamic therapy (PDT), a photochemistry-based, FDA approved modality while the detection is based on fluorescence and white light imaging combined with a cloud-based deep-learning AI approach for image classification. The SITOS enables image guided PDT, while a topical application of the dual property flourophore/photosensitizer precursor to the oral cavity, more suitable for LMICs and designed to achieve better tumor penetration than previous topical deliveries, is also developed. The goals will be accomplished in 3 Specific Aims. Aim 1 builds on previous successful development and clinical validation of separate low-cost devices for intraoral imaging, and intraoral PDT to produce a new, handheld, low-cost, easy-to-use, SITOS. The integrated platform enables the use of the same hardware for initial imaging, and a single thernostic molecule for image-guided PDT and online monitoring during therapy. Incorporated is an ergonomic intraoral light delivery for PDT and preliminarily validated in optical phantoms and in vitro 3D tumor models. Aim 2A establishes conditions for topical photosensitization using an adhesive ALA patch provided by Photonamic GmbH in ex vivo porcine mucosa model. Based on data from 2A, Aim 2B establishes optimal PDT parameters in a murine xenograft model. Aim 2C validates the best of these parameters in a carcinogen-induced hamster cheek pouch model which recapitulates transition from pre- malignant to malignant lesions. Aim 3 applies SITOS to identify and treat high-risk oral potentially malignant lesions (OPML), and early-stage oral cancer using broad guidance from the preclinical studies. Screening of patients will take place at camps and remote villages led by the clinical teams in India as in the UH effort. Patients with histologically confirmed HGD/OPML (and meeting other inclusion criteria) will be eligible. Patients will be treated using the ALA topical patch, (after a small cohort establishes safety and optimal contact time, based on Aim 2). Finally, PDT of high-risk OPML and early cancer in patients using light delivery and simultaneous image guidance with the new intraoral probe will be performed. Impact and relevance: The study provides, for the first time, a comprehensive low-cost approach that enables not only detection of pre-malignant/malignant oral lesions, but also an effective, monitored therapy in LMIC settings. The SITOS platform is mobile, handheld and appropriate for point of care applications. It brings together collaborators (scientists, oral cancer surgeons, oncologists and industry) to help with FDA clearance of ALA patch and SITOS. Capacity building: a new clinical modality and a platform for AI/engineering development.