Enabling NIR-PIT therapy to treat deep-tissue cancer

总结 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副作用。几种旨在杀死 癌细胞正在发育，而正常细胞则没有。然而，没有这样的疗法 被开发用于局部晚期的深部内脏癌。光免疫疗法（PIT）是一种 基于使用抗体的高度选择性细胞杀伤的癌症靶向治疗， 光吸收剂（IR 700DX）缀合物（APC）和靶向低能量光疗法。开发 在美国国家癌症研究所，这种疗法被称为近红外PIT（NIR-PIT）。述抗体 可以基于其细胞表面表达来选择与特定癌症的最佳结合。 IR 700DX仅在APC与细胞膜结合时对细胞有毒。当暴露于 近红外光（~ 690 nm）可使肿瘤细胞发生快速细胞坏死， 膜渗透性，但在没有或最小的正常细胞中没有观察到损伤 靶抗原的表达。NIR-PIT在无法手术的复发性头颈部的临床试验中 使用缀合物西妥昔单抗-IR 700治疗癌症。一项I期研究表明， 对肿瘤有实质性影响的不良事件，包括几种完全缓解。 我们的策略依赖于碳化硅（SiC）纳米结构，以实现对 癌症通过NIR-PIT。虽然APC的单次暴露随后是单剂量的NIR光， 虽然它能有效地击倒癌细胞，但不足以完全杀死肿瘤，这可能是由于 APC在肿瘤内的不完全渗透。然而，多次曝光的光线 几个小时到几天的间隔是有效的，并且通常导致模型中的治愈。所述APC 因此，在第一次曝光后， APC进入肿瘤并与剩余的肿瘤细胞结合。由于NIR-PIT可以杀死肿瘤细胞， 血管内皮，血管保持完整，渗透性增加24倍， 肿瘤血管的大分子，大到200纳米，这种效果被称为超级增强 渗透性和保留性（SUPR）。该项目利用了初步近红外后的SUPR- 用于将X射线可活化纳米颗粒递送至肿瘤的PIT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.