Molecularly Targeted Probes for Photodynamic Therapy and Imaging of Breast Cancer

用于乳腺癌光动力治疗和成像的分子靶向探针

• 批准号: 10738388
• 负责人: Hans F. Schmitthenner
• 金额: $ 3万
• 依托单位: ROCHESTER INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10738388
• 关键词: Administrative Supplement; Affinity; Apoptosis; Area; Binding; Biological Assay; Biological Markers; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer Treatment; Breast Cancer cell line; Breast Cancer therapy; Cell Death; Cell Line; Cells; Cellular biology; Collaborations; Communities; Confocal Microscopy; Dimensions; Disease; Dyes; Epidemic; Fluorescence; Fluorescence Microscopy; Funding; Goals; Grant; Health; Hormones; In Vitro; Injections; Keratin; Laboratories; Lasers; MCF10A cells; MDA MB 231; Methods; Molecular Target; Monitor; Mus; Near-infrared optical imaging; Operative Surgical Procedures; PUVA Photochemotherapy; Patients; Peptide Synthesis; Peptides; Phase; Photosensitizing Agents; Qualifying; Repeat Surgery; Reporting; Research; Research Project Grants; Residual state; Science; Solid; Students; Testing; Tissues; Work; anticancer research; breast imaging; breast lumpectomy; cancer imaging; cancer therapy; deaf; design; educational atmosphere; efficacy testing; experimental study; fluorescence imaging; hard of hearing; imaging agent; in vivo; in vivo evaluation; malignant breast neoplasm; member; minimally invasive; near infrared dye; neoplastic cell; next generation; novel; operation; receptor; side effect; targeted agent; triple-negative invasive breast carcinoma; tumor; undergraduate student

Summary Page: Administrative Supplement Request to Promote Diversity in Health‐Related Research (R15CA260420) Request: We are seeking an administrative supplement to promote diversity in health‐related research for grant number R15CA260420. This funding would support Mr. Cameron Keene, a 3rd year Biomedical Sciences major at RIT. Qualifications: Cameron qualifies for this supplement as a member of the deaf/hard of hearing community. Overview of Cameron's goals: This is a collaborative R15 grant and Cameron is working in Dr. Ferran's laboratory at RIT. This research group is responsible for the research proposed in the second aim of the grant; therefore Cameron's efforts will focus on the in vitro work underlined in the grant abstract below. As Cameron gains expertise he will help the next generation of students working on this project in the lab, therefore his trainees will also contribute to this work. Grant Abstract: The goal of this proposal is to test the hypothesis that small, peptide‐based molecularly targeted probes containing a near infrared (NIR) dye and a photosensitizer (PS) dye will be effective for fluorescence imaging and photodynamic therapy (PDT) of breast cancer (BrCa). This novel treatment method will give patients access to an unprecedented therapy option, without the burden of side effects from traditional BrCa therapy. In particular, the application to fluorescence‐guided lumpectomy combined with PDT in the same operation is envisioned as a remedy for the current epidemic of re‐ operation as it will provide a means of effectively treating residual BrCa cells in the margins. The strategy relies on a targeting deca‐peptide, 18‐4, reported to be an effective targeting agent for the keratin receptor, KRT1, a biomarker that is independent of hormone expression in BrCa cells. Students in our labs have developed a synthesis of 18‐4 by a solid phase peptide synthesis (SPPS) and have merged that with a modular method we developed for the synthesis of BrCa‐targeted molecular imaging agents (TMIAs). This method will provide analogous molecularly targeted photosensitizer (MTPS) probes for PDT and dual TMIA‐MTPS probes for guiding surgery and PDT. Students at RIT will use confocal fluorescence microscopy (CFM) to evaluate the affinity of the 18‐4‐based TMIAs and dual TMIA‐MTPS probes to two triple negative BrCa cell lines, MDA‐MB‐231 and EMT6, utilizing non‐cancerous MCF10A as a control. The in vitro efficacy of PDT in the same cell lines will next be investigated using a single MTPS probe. To ensure that single MTPS and dual TMIA‐MTPS probes are equally effective, PDT will be investigated in vitro in the MDA‐MB‐231 and EMT6 cells lines, using a laser supplied by our collaborator at the U of R. The mechanism of cell death will be studied using CFM and apoptosis assays. The strategy includes testing the binding affinity of the single and dual probes to EMT6 tumors in mice by in vivo NIR imaging, then testing efficacy in PDT experiments after systemic injection of the targeted dual TMIA‐MTPS probe. Therapy will be monitored by tumor dimensions and stereo‐fluorescence microscopy to verify efficacy of targeted and untargeted probes, with and without PDT. The combined in vitro and in vivo experiments will provide an effective strategy to develop single and dual probes for the PDT of BrCa. A key aspect of this proposal is the participation of three undergraduates from RIT in each year, one of whom will participate in the in vivo testing at the U of R, one in synthesis and one in the in vitro analysis at RIT. The collaboration highlights expertise in synthesis, cell biology, and confocal microscopy at RIT, and in cancer imaging and photodynamic therapy at the U of R. These combine to provide a vibrant learning environment in cancer research for undergraduates, with the achievable goal of revolutionizing treatment of BrCa by developing small, peptide‐based TMIA, MTPS, and dual TMIA‐MTPS probes to transform BrCa therapy by the use of molecularly targeted fluorescence‐ guided PDT and provide a breakthrough in the treatment and cure for BrCa patients.

摘要页：行政补充请求，以促进多样性， 健康相关研究（R15 CA 260420） 请求：我们正在寻求一项行政补充，以促进健康相关研究的多样性， 授权号R15 CA 260420。这笔资金将支持先生卡梅隆基恩，3年生物医学 RIT的科学专业。 资格：卡梅隆有资格作为聋人/重听人的一员获得这一补充 社区 卡梅隆的目标概述：这是一个合作R15赠款和卡梅隆是在费兰博士的工作。 实验室在RIT。该研究小组负责第二个目标中提出的研究， 因此，卡梅隆的努力将集中在体外工作中强调的赠款摘要如下。 随着卡梅隆获得专业知识，他将帮助下一代学生在实验室里从事这个项目， 因此，他的学员也将为这项工作作出贡献。 格兰特摘要：这项提案的目标是测试小的，基于肽的分子 含有近红外（NIR）染料和光敏剂（PS）染料的靶向探针将有效用于 荧光成像和光动力疗法（PDT）的乳腺癌（BrCa）。这种新颖的治疗方法 该方法将为患者提供前所未有的治疗选择，而不会产生副作用 传统的溴钙疗法特别是，荧光引导肿块切除术的应用 在同一个操作中结合PDT被设想为当前流行的再感染的补救措施。 这是因为它将提供一种有效治疗边缘残留BrCa细胞的方法。战略 依赖于靶向十肽，18 - 4，据报道是角蛋白的有效靶向剂 受体，KRT 1，一种生物标志物，是独立的激素表达在BrCa细胞。我们实验室的学生 已经开发了通过固相肽合成（SPPS）合成18 - 4，并将其与 我们开发了一种用于合成BrCa靶向分子成像剂（TMIA）的模块化方法。 这种方法将提供类似的分子靶向光敏剂（MTPS）探针的PDT和双 用于引导手术和PDT的TMIA‐MTPS探头。RIT的学生将使用共焦荧光 在显微镜下（CFM）评价18 - 4-基TMIA和双TMIA-MTPS探针对两种 三阴性BrCa细胞系MDA-MB-231和EMT 6，使用非癌性MCF 10A作为对照。的 接下来将使用单一MTPS探针研究PDT在相同细胞系中的体外功效。到 为了确保单MTPS和双TMIA‐MTPS探头同样有效，将在以下研究中研究PDT： 体外MDA-MB-231和EMT 6细胞系，使用我们的合作者在R的U提供的激光。 将使用CFM和凋亡测定来研究细胞死亡的机制。该战略包括 通过体内NIR成像测试单探针和双探针对小鼠中EMT 6肿瘤的结合亲和力， 然后在全身注射靶向双TMIA-MTPS探针后在PDT实验中测试功效。 将通过肿瘤尺寸和立体荧光显微镜监测治疗，以验证 靶向和非靶向探针，有和没有PDT。体内外联合实验 将提供一个有效的策略，开发单探针和双探针的PDT的BrCa。的一个关键方面 该提案是每年由RIT的三名本科生参与，其中一人将 在R的U参与体内测试，一个在合成，一个在RIT的体外分析。的 合作突出了RIT在合成、细胞生物学和共聚焦显微镜以及癌症方面的专业知识 影像学和光动力学疗法这些联合收割机提供了一个充满活力的学习 环境在癌症研究的本科生，与革命性的可实现的目标， 通过开发小的基于肽的TMIA、MTPS和双TMIA-MTPS探针来治疗BrCa， 通过使用分子靶向荧光引导的PDT来改变BrCa治疗，并提供 在治疗和治愈BrCa患者方面取得了突破。

项目成果

Modular Synthesis of Peptide-Based Single- and Multimodal Targeted Molecular Imaging Agents.

• DOI: 10.1021/acsabm.1c00157
• 发表时间: 2021-07-19
• 期刊: ACS APPLIED BIO MATERIALS
• 影响因子: 4.7
• 作者: Schmitthenner, Hans F;Barrett, Taylor M;Beach, Stephanie A;Heese, Lauren E;Weidman, Chelsea;Dobson, Damien E;Mahoney, Emily R;Schug, Nicholas C;Jones, Kelsea G;Durmaz, Ceyda;Otasowie, Osarhuwense;Aronow, Sean;Lee, Yin Peng;Ophardt, Henry D;Becker, Amy E;Hornak, Joseph P;Evans, Irene M;Ferran, Maureen C
• 通讯作者: Ferran, Maureen C