Site Specific Drug Delivery with Light-responsive Conjugates for Photo-biomodulation

项目摘要/摘要 光是疾病治疗中的一种特殊工具，可以精确地控制治疗时间和位置。 与紫外线不同，较长的可见光和近红外(IR)光是无毒的，比紫外线能到达更深的组织 临床应用。然而，能够被这种生物相容的光切割的化学连接物非常稀少。 长期目标是开发可被可见光和近红外光切割的化学连接物，用于光控制 药物输送，以及设计和合成用于光生物调节的化学偶联物。在 之前的项目，药物结合平台和现场特定药物释放的光释放策略是 已经成立了。演示了点击和光解点击化学，其中单线态氧(SO)可裂解连接物 通过胺-炔点击反应合成，并被SO裂解。药物结合物是由药物组成的，所以- 可切割连接体，光敏剂和癌症靶向基团。当用红光(690 Nm)照明时， 结合物产生SO，只在照明区域释放药物，并在局部治疗疾病。在下一个 5年后，将使用光响应性药物结合物建立更大胆的光生物调节策略 站台。最重要的假设是利用可见光和近红外光响应的局部光生物调节 结合物可通过激活免疫系统发挥全身药理作用。这一行动的主要目标 应用是设计和制备免疫刺激药物的可切割结合物，并证明这一点 可见光反应结合物可用于产生全身性和肿瘤特异性抗癌效应。 结合物被聚焦的局部照明激活，释放特定部位的药物，并刺激 免疫系统触发全身性和肿瘤特异性免疫反应。全身性抗肿瘤作用是 通过与非重叠机制的系统给药相结合而进一步加强 与当地的光生物调节有关。这些目标的实现有三个具体目标：(1)设计和准备SO-2 免疫刺激药物的可激活结合物并确定全身抗肿瘤效果，(2)确定 光生物调节的系统效应机制及免疫药效学的建立 通过添加临床可用药物确定局部光生物调节增强全身抗肿瘤效果 检查点抑制药。药代动力学和免疫药效学模型用于分析和 模拟不同组织中结合物、释药和免疫细胞的动态变化，获得 在系统层面上的机械洞察力。主要交付成果是(I)红灯响应的共轭 免疫刺激药物，(Ii)光生物调节后的免疫药效学模型，以及(Iii)验证 我们的局部光生物调节系统的影响。该策略在乳腺癌和结肠癌动物身上进行了测试。 模型，但它可以适用于使用间质或外部照射的广泛肿瘤。

Project Summary/ Abstract Light is an exceptional tool in disease treatment, offering precise controllability in treatment time and location. Unlike UV light, longer visible and near infrared (IR) light is not toxic and reaches deeper tissues than UV for clinical applications. However, chemical linkers that are cleavable by such biocompatible light are very scarce. Long term goals are to develop chemical linkers that are cleaved by visible and near IR light for light-controlled drug delivery, and to design and synthesize chemical conjugates that are used for pho-biomodulation. In the previous project, a drug conjugate platform and photo-release strategy for site specific drug delivery were established. Click and photo-unclick chemistry was demonstrated, where singlet oxygen (SO)-cleavable linker is synthesized via amine-yne click reaction and cleaved by SO. The drug conjugates are composed of drug, SO- cleavable linker, photosensitizer and cancer-targeting group. When illuminated with red light (690 nm), the conjugates generate SO and release drug only in the illuminated region and treat the disease locally. In the next 5 years, a bolder photo-biomodulation strategy will be established using the light-responsive drug conjugate platform. Overarching hypothesis is that local photo-biomodulation using visible and near IR light-responsive conjugates can make systemic pharmacological effects via activation of immune system. Main goals in this application are to design and prepare SO-cleavable conjugates of immunostimulant drugs and to prove that this visible-light responsive conjugates can be used for generating systemic and tumor-specific anticancer effects. The conjugates are activated by a focused local illumination, release drugs site-specifically, and stimulate immune system to trigger systemic and tumor-specific immune responses. The systemic antitumor effect is further enhanced by the combination with systemically administered drugs with non-overlapping mechanisms with the local photo-biomodulation. The goals are realized with 3 specific aims: (1) Design and prepare SO- activatable conjugates of immune-stimulating drugs and determine systemic antitumor effects, (2) Determine the mechanisms of systemic effects of the photo-biomodulation and establish the immuno-pharmacodynamics, (3) Determine the enhanced systemic antitumor effect of the local photo-biomodulation by adding clinically available checkpoint inhibitors. Pharmacokinetic and immune-pharmacodynamic modeling is used for analyzing and simulating dynamic changes of conjugates, released drugs, and immune cells in various tissues to gain mechanistic insight at the systemic level. Major deliverables are (i) red-light responsive conjugates of immunostimulant drugs, (ii) immune-pharmacodynamic models following photo-biomodulation, and (iii) validation of our local photo-biomodulation for systemic effects. The strategy is tested using breast and colon cancer animal models but it could be applicable for a wide range of tumors using interstitial or external illumination.