Enabling NIR-PIT therapy to treat deep-tissue cancer

摘要 目前的癌症治疗方法，如手术、放射和化学免疫治疗 努力平衡癌症治疗和不良反应。几种旨在杀死 癌细胞仍在发育中，而正常细胞则未受影响。然而，没有这样的疗法 是为局部晚期深部内脏癌而开发的。光免疫疗法是一种 基于抗体的高选择性细胞杀伤的癌症靶向治疗- 光吸收剂(IR700DX)结合物(APC)和靶向低能量光疗法。由开发人员 在美国国家癌症研究所，这种疗法被称为近红外坑(NIR-PIT)。抗体 可以根据其细胞表面的表达选择与特定癌症的最佳结合。 只有当APC结合到细胞膜上时，IR700DX才对细胞有毒性。当暴露在 近红外光(~690 nm)导致肿瘤细胞迅速坏死 膜通透性，但在没有或几乎没有损伤的正常细胞中没有观察到损伤 目的抗原的表达。NIR-PIT正在对不能手术的复发性头颈部进行临床试验 使用结合物西妥昔单抗-IR700治疗癌症。一项第一阶段的研究表明， 对肿瘤有实质性影响的不良事件，包括几个完全反应。 我们的战略依赖于碳化硅(碳化硅)纳米结构来实现深层组织治疗 通过近红外坑致癌。而APC的单次曝光和单次剂量的近红外光是 有效地击倒癌细胞，但不足以完全杀死肿瘤，这可能是由于 导致APC在肿瘤内未完全穿透。然而，光的多次曝光 用几小时到几天的间隔是有效的，并且经常在模型中导致治愈。APC 表现出相对较长的循环时间，因此，在第一次曝光后，额外的循环 APC进入肿瘤并与剩余的肿瘤细胞结合。由于近红外坑可以杀死肿瘤细胞，但不能 血管内皮细胞，血管保持完好，通透性增加24倍 肿瘤血管长达200 nm的大分子，这种效应被称为超级增强 渗透性和保留率(SUPR)。该项目在初始近红外之后利用SUPR- 用于将x射线激活的纳米颗粒输送到肿瘤的凹坑治疗。

Summary Current methods of cancer treatment such as surgery, radiation, and chemo-immuno-therapy strive to balance cancer treatment against adverse effects. Several treatments that aim to kill cancer cells while sparing normal cells are in development. However, no such therapies have been developed for locally advanced, deep visceral cancers. Photoimmunotherapy (PIT) is a targeted therapy for cancer with highly selective cell killing based on the use of an antibody- photoabsorber (IR700DX) conjugate (APC) and targeted low energy light therapy. Developed by the National Cancer Institute, this therapy is termed near infrared PIT (NIR-PIT). The antibody can be chosen for optimal binding to a particular cancer based on its cell surface expression. IR700DX is only toxic to cells when the APC is bound to the cell membrane. When exposed to near-infrared light (~690nm) rapid cell necrosis occurs in tumor cells due to changes in cell membrane permeability, but no damage is observed in normal cells that have no or minimal expression of the target antigen. NIR-PIT is in clinical trials in inoperable recurrent head/neck cancers using the conjugate Cetuximab-IR700. A Phase I study has demonstrated minimal adverse events with substantial effects on the tumor including several complete responses. Our strategy relies on silicon carbide (SiC) nanostructures to enable deep-tissue treatment of cancer via NIR-PIT. While a single exposure of APC followed by a single dose of NIR light is effective in knocking down cancer cells, it is not adequate to completely kill the tumor likely due to incomplete penetration of the APC within the tumor. However, multiple exposures of light separated by hours to days are effective and have often resulted in cures in models. The APC demonstrates a relatively long circulation time thus, after first light exposure, additional circulating APCs enter the tumor and bind to remaining tumor cells. Since NIR-PIT kills tumor cells but not vascular endothelium, the vessels are left intact with a 24 fold increase in the permeability of tumor vessels to macromolecules as large as 200nm, an effect termed Super Enhanced Permeability and Retention (SUPR). This project takes advantage of SUPR after an initial NIR- PIT treatment for delivering x-ray activatable nanoparticles to the tumor.