Tri-modal Polymeric Micelles for 'See & Treat' Applications in Surgical Oncology

用于“See”的三峰聚合物胶束

• 批准号: 8175145
• 负责人: Glen S. Kwon
• 金额: $ 14.33万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-07 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8175145
• 关键词: Apoptosis; Apoptotic; Beds; Biocompatible; Blood; Caliber; Clinical Trials; Colon Carcinoma; Coupled; Disease; Drug Delivery Systems; Drug Kinetics; Dyes; Ethylene Glycols; Excision; Fluorescence; Generations; Goals; Gossypol; Human; Image; Imagery; In Vitro; Lasers; Light; Lung; Malignant Neoplasms; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Micelles; Microscopic; Modality; Modeling; Morbidity - disease rate; Mus; Nanotechnology; Neuroblastoma; Operative Surgical Procedures; Optics; Palpable; Palpation; Patients; Penetration; Permeability; Pharmaceutical Preparations; Photochemotherapy; Photosensitizing Agents; Procedures; Proteins; Radiation; Research; Series; Singlet Oxygen; Solid Neoplasm; Surgeon; Surgical Oncology; Surgical margins; Tars; Testing; Therapeutic; Time; Tissues; Translations; Visual; base; cancer cell; caprolactone; cell killing; chemotherapy; cost effective; ethylene glycol; imaging modality; improved; in vivo; inhibitor/antagonist; insight; intravenous injection; killings; light effects; malignant breast neoplasm; mimetics; mouse model; nanocarrier; nanoparticle; neoplastic cell; novel; optical imaging; research study; tumor

DESCRIPTION (provided by applicant): The major goal of surgical oncology is the complete resection of tumors with adequate tumor-free margins and minimal surgical morbidity, noting that surgery cures about 45% of patients, whereas chemotherapy and radiation cure only 5% of patients. In lung, breast, prostate, colon, and pancreatic cancers, a complete resection of tumors has a 3- to 5-fold increase in survival over partial or incomplete surgical resection. However, the intraoperative assessment of tumor margins is merely based on palpation and visual inspection, resulting frequently in incomplete tumor resection (R1 resections). The goal is to develop nanotechnology for "see and treat" modalities in surgical oncology, enabled by polymeric micelles that emit tissue penetrating near-infrared light for delineation of tumor margins and surgical guidance; generate singlet oxygen upon intra- operative photodynamic therapy (PDT); and enhance cancer cell apoptosis by the co-delivery of gossypol, a natural BH3 mimetic that inhibits anti-apoptotic Bcl-2 proteins: Bcl-2, Bcl-xL, and Mcl-1. We have proven that poly(ethylene glycol)-block-poly(e-caprolactone) (PEG-b-PCL) assembles into nanoparticles that entrain a near-infrared dye (DiR), a photosensitizer (mTHPP), and gossypol, forming micelles that are 100 nm in diameter and slowly release all 3 components over 24 hrs. We hypothesize that PEG-b-PCL micelles filled with DiR, mTHPP, and gossypol will accumulate at solid tumors via the enhanced permeability and retention effect and "light up" tumor margins, enabling surgical guidance, more complete surgical resection, and lower tumor reoccurrence. We hypothesize that laser light delivered to the "lit up" region of the tumor bed (intraoperative PDT) will generate singlet oxygen that kills tumor cells, especially in concert with co-delivered gossypol. Specific Aims: (1) To assess the stability, generation of singlet oxygen, and tumor targeting of PEG-b-PCL micelles filled with DiR, mTHPP, and gossypol by in vitro physicochemical and photophysical studies and in vivo experiments: whole body optical imaging of DiR and mTHPP and a pharmacokinetics study on gossypol. (2). To assess tumor reoccurrence after surgical guidance by PEG-b-PCL micelles filled with DiR and surgical resection of tumors and after surgical resection of tumors alone as a positive control. (3). To assess tumor reoccurrence after surgical resection and intraoperative PDT with PEG-b-PCL micelles filled with mTHPP, with or without co-incorporated gossypol. (4). To assess tumor reoccurrence after optical imaging of DiR, surgical resection, and intraoperative PDT with mTHPP and gossypol (tri-modal therapy). Advances in integrated optical imaging and therapeutic capability of biocompatible PEG-b-PCL micelles will enable tenable nano-technology applications in surgical oncology and rapid translation into clinical trials. PUBLIC HEALTH RELEVANCE: The goal is to develop a unique tri-functional nanocarrier for surgical oncology that can deliver near-infrared dye, photosensitizer, and gossypol together into solid tumors for intraoperative optical imaging of solid tumors and light-activated cancer cell killing. In a mouse model of neuroblastoma, we will test whether surgical guidance, surgical resection, and intraoperative light-activated cancer cell killing will maximize tumor killing, minimize collateral damage, and prolong survival.

描述（由申请人提供）：肿瘤外科的主要目标是完全切除肿瘤，并具有足够的无瘤边缘和最小的手术发病率，并指出手术治愈了约 45% 的患者，而化疗和放疗只能治愈 5% 的患者。在肺癌、乳腺癌、前列腺癌、结肠癌和胰腺癌中，与部分或不完全手术切除相比，完全切除肿瘤的生存率可提高 3 至 5 倍。然而，术中对肿瘤边缘的评估仅基于触诊和目视检查，经常导致肿瘤切除不完全（R1切除）。目标是开发用于肿瘤外科“观察和治疗”模式的纳米技术，通过聚合物胶束发射组织穿透近红外光来描绘肿瘤边缘和手术指导；术中光动力治疗 (PDT) 时产生单线态氧；并通过共同递送棉酚来增强癌细胞凋亡，棉酚是一种天然的 BH3 模拟物，可抑制抗凋亡 Bcl-2 蛋白：Bcl-2、Bcl-xL 和 Mcl-1。我们已经证明，聚乙二醇-嵌段聚己内酯 (PEG-b-PCL) 组装成纳米颗粒，夹带近红外染料 (DiR)、光敏剂 (mTHPP) 和棉酚，形成直径 100 nm 的胶束，并在 24 小时内缓慢释放所有 3 种成分。我们假设填充有 DiR、mTHPP 和棉酚的 PEG-b-PCL 胶束将通过增强的渗透性和保留效应在实体瘤中积聚并“照亮”肿瘤边缘，从而实现手术引导、更完整的手术切除和更低的肿瘤复发。我们假设，传递到肿瘤床“照亮”区域（术中 PDT）的激光将产生杀死肿瘤细胞的单线态氧，特别是与共同传递的棉酚配合使用。具体目的：（1）通过体外理化和光物理研究以及体内实验（DiR和mTHPP的全身光学成像以及棉酚的药代动力学研究）评估DiR、mTHPP和棉酚填充的PEG-b-PCL胶束的稳定性、单线态氧的产生和肿瘤靶向性。 （2）。评估用 DiR 填充的 PEG-b-PCL 胶束进行手术引导和手术切除肿瘤后以及仅手术切除肿瘤后作为阳性对照的肿瘤复发情况。 （3）。评估手术切除和术中 PDT 后肿瘤的复发情况，使用填充有 mTHPP 的 PEG-b-PCL 胶束（含或不含共混棉酚）。 （4）。评估 DiR 光学成像、手术切除以及术中使用 mTHPP 和棉酚进行 PDT（三模式疗法）后肿瘤的复发情况。生物相容性 PEG-b-PCL 胶束的集成光学成像和治疗能力的进步将使纳米技术在外科肿瘤学中的应用成为可能，并快速转化为临床试验。 公共健康相关性：目标是开发一种用于肿瘤外科的独特三功能纳米载体，可以将近红外染料、光敏剂和棉酚一起输送到实体瘤中，用于实体瘤的术中光学成像和光激活癌细胞杀伤。在神经母细胞瘤小鼠模型中，我们将测试手术引导、手术切除和术中光激活癌细胞杀灭是否能最大限度地杀灭肿瘤、最大限度地减少附带损害并延长生存期。