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

描述（由申请人提供）：外科肿瘤学的主要目标是完全切除肿瘤，具有足够的无肿瘤边缘和最小的手术发病率，注意到手术治愈约45%的患者，而化疗和放疗仅治愈5%的患者。在肺癌、乳腺癌、前列腺癌、结肠癌和胰腺癌中，肿瘤的完全切除比部分或不完全手术切除的存活率增加3至5倍。然而，术中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）。目标是开发用于外科肿瘤学中的“看和治疗”模式的纳米技术，其通过聚合物胶束实现，所述聚合物胶束发射穿透组织的近红外光用于描绘肿瘤边缘和外科手术引导;在术中光动力疗法（PDT）时产生单线态氧;以及通过共同递送棉酚（一种抑制抗凋亡Bcl-2蛋白的天然BH 3模拟物）来增强癌细胞凋亡：Bcl-2、Bcl-xL和Mcl-1。我们已经证明，聚（乙二醇）-嵌段-聚（e-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，形成直径为100 nm的胶束，并在24小时内缓慢释放所有3种组分。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处积聚并“照亮”肿瘤边缘，从而实现手术指导、更完整的手术切除和更低的肿瘤复发。我们假设，激光输送到肿瘤床的“照亮”区域（术中PDT）将产生单线态氧，杀死肿瘤细胞，特别是在音乐会与共同交付棉酚。具体目标：（1）通过体外理化和生物物理研究以及体内实验：DiR和mTHPP的全身光学成像和棉酚的药代动力学研究，评价填充DiR、mTHPP和棉酚的PEG-b-PCL胶束的稳定性、单线态氧的产生和肿瘤靶向性。（二）、评估通过填充有DiR的PEG-b-PCL胶束手术引导和手术切除肿瘤后以及单独手术切除肿瘤后作为阳性对照的肿瘤复发率。（三）、评估手术切除和术中PDT后的肿瘤复发率，其中PEG-b-PCL胶束填充有mTHPP，有或没有共同掺入棉酚。（四）、评估DiR光学成像、手术切除和术中mTHPP和棉酚PDT（三模式治疗）后的肿瘤复发率。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能够得到支持，并迅速转化为临床试验。 公共卫生相关性：目标是开发一种独特的三功能纳米载体，用于外科肿瘤学，可以将近红外染料，光敏剂和棉酚一起递送到实体肿瘤中，用于实体肿瘤的术中光学成像和光激活癌细胞杀伤。在神经母细胞瘤的小鼠模型中，我们将测试手术指导、手术切除和术中光激活癌细胞杀伤是否会最大限度地杀死肿瘤，最大限度地减少附带损害并延长生存期。

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.