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

描述(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低的手术并发症，并指出手术可治愈约45%的患者，而化疗和放射治疗仅能治愈5%的患者。在肺癌、乳腺癌、前列腺癌、结肠癌和胰腺癌中，完全切除肿瘤的存活率是部分或不完全手术切除的3-5倍。然而，术中对肿瘤边缘的评估仅仅基于触诊和肉眼检查，经常导致肿瘤不完全切除(R1切除)。其目标是开发纳米技术，用于外科肿瘤学中的“看到并治疗”模式，通过聚合物胶束发射组织穿透近红外线来描绘肿瘤边缘和手术指导；在术中光动力疗法(PDT)中产生单线态氧；并通过共传递棉酚来促进癌细胞凋亡，棉酚是一种天然的BH3模拟物，可抑制抗凋亡的Bcl-2蛋白：bcl2、bclxl和mcl1。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，携带近红外染料(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这三种成分。我们假设，填充了DIR、mTHPP和棉酚的聚乙二醇b-PCL胶束将通过增强的渗透性和滞留效应积聚在实体肿瘤处，并“照亮”肿瘤边缘，使手术指导、更彻底的手术切除和更低的肿瘤复发率成为可能。我们假设，传输到肿瘤床“亮”区域的激光(术中PDT)将产生杀死肿瘤细胞的单线态氧，特别是与联合传递的棉酚协同作用。具体目的：(1)通过体外物理化学和光物理研究以及体内实验：对dir、mTHPP和棉酚的全身光学成像和棉酚的药代动力学研究，评价填充dir、mTHPP和棉酚的聚乙二醇b-PCL胶束的稳定性、单线态氧的产生和肿瘤靶向性。(2)。评价用填充DIR的聚乙二醇b-PCL胶束引导手术和手术切除肿瘤后的肿瘤复发情况，以及作为阳性对照的肿瘤单纯手术切除后的肿瘤复发情况。(3)。目的：评估手术切除和术中PDT后使用填充mTHPP的聚乙二醇b-PCL胶束的肿瘤复发情况，以及是否有共掺棉酚。(4)。评估直肠癌光学成像、手术切除、术中光动力疗法联合mTHPP和棉酚(三联疗法)后肿瘤复发情况。生物相容的聚乙二醇b-PCL胶束的集成光学成像和治疗能力的进展将使纳米技术在外科肿瘤学中的应用和快速转化为临床试验成为可能。

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.