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

使用光响应缀合物进行光生物调节的位点特异性药物递送

• 批准号: 10735978
• 负责人: Youngjae You
• 金额: $ 34.23万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735978
• 关键词: Amines; Animal Cancer Model; Biological Process; Breast Cancer Model; Cancer Vaccine Related Development; Cancer Vaccines; Cells; Chemicals; Chemistry; Clinical; Colon Carcinoma; Development; Disease; Disseminated Malignant Neoplasm; Drug Controls; Drug Delivery Systems; Drug Kinetics; Evaluation; Glioblastoma; Goals; Immune; Immune checkpoint inhibitor; Immune response; Immune system; Immunologic Adjuvants; Immunologic Stimulation; Immunotherapeutic agent; In Situ; Kinetics; Light; Lighting; Localized Disease; Location; Malignant Neoplasms; Malignant neoplasm of pancreas; Malignant neoplasm of urinary bladder; Mathematics; Mechanics; Metastatic/Recurrent; Modeling; Mus; Neoplasm Metastasis; Organ; PUVA Photochemotherapy; Patients; Pharmaceutical Preparations; Pharmacodynamics; Photochemistry; Photosensitizing Agents; Physiological; Pre-Clinical Model; Rattus; Reaction; Recurrence; Resolution; Singlet Oxygen; Site; System; Testing; Therapeutic; Time; Tissues; Treatment Side Effects; Tumor Antigens; Ultraviolet Rays; Vaccination; Validation; Visible Radiation; anti-cancer; anti-tumor immune response; antitumor effect; biomaterial compatibility; body system; chemical conjugate; chemical synthesis; chemotherapy; clinical application; cytokine; design; disorder control; immune activation; immunogenic; immunoregulation; in situ vaccination; innovation; insight; interstitial; malignant breast neoplasm; melanoma; pharmacodynamic model; pharmacologic; photobiomodulation; prophylactic; response; side effect; spatiotemporal; tool; tumor; tumor microenvironment; tumor-immune system interactions; vaccination strategy

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.

项目摘要/摘要 光是疾病治疗中的特殊工具，在治疗时间和位置提供了精确的可控性。 与紫外线不同，可见较长且接近红外（IR）光无毒，并且比紫外线更深入组织 临床应用。但是，这种生物相容性光可以分解的化学接头非常稀缺。 长期目标是开发通过可见的和近红外光线裂解的化学连接器 药物输送，并设计和合成用于pho-biomomomogulation的化学共轭物。在 以前的项目，毒品共轭平台和特定场地药物交付的照片释放策略是 已确立的。单击和图片无需单击的化学反应，其中单线氧（SO）可分开的链接器 通过胺 - yne点击反应合成并裂解。药物结合物由药物组成， 可裂解的接头，光敏剂和癌症靶向组。当用红灯照亮（690 nm）时 共轭物仅在照明区域中产生SO并释放药物，并在当地治疗该疾病。在下一个 5年，将使用轻响应性药物共轭制定更大胆的光量调节策略 平台。总体假设是使用可见的和近红外响应性的局部光量调节 结合物可以通过激活免疫系统产生系统性的药理作用。其中的主要目标 应用是设计和准备免疫刺激性药物的可溶剂缀合物，并证明这一点 可见光的响应性缀合物可用于产生全身和肿瘤特异性抗癌作用。 共轭物是通过聚焦的局部照明激活的，特定于现场释放药物，并刺激 免疫系统触发全身和肿瘤特异性免疫反应。系统性抗肿瘤效应是 通过与非重叠机制的系统施用的药物结合进一步增强 与局部光二聚体调节。目标以3个特定目的实现：（1）设计和准备SO- 可激活的免疫刺激药物的结合物并确定全身抗肿瘤作用，（2）确定 光分子调节的全身效应机制并建立免疫 - 药效学，（3） 通过添加临床可用 检查点抑制剂。药代动力学和免疫药动力学建模用于分析和 模拟各种组织中结合物，释放药物和免疫细胞的动态变化以获得 在系统层面上的机械洞察力。主要的可交付成果是（i）红灯响应式缀合物 免疫刺激药物，（ii）光学调节后的免疫 - 剂量动力学模型和（iii）验证 我们的本地光量调节用于全身效应。使用乳腺癌和结肠癌动物测试该策略 模型，但可以使用间隙或外部照明适用于广泛的肿瘤。

项目成果

Anticancer drug released from near IR-activated prodrug overcomes spatiotemporal limits of singlet oxygen.

近红外激活原药释放的抗癌药物克服了单线态氧的时空限制。

• DOI: 10.1016/j.bmc.2016.02.025
• 发表时间: 2016-04-01
• 期刊: Bioorganic & medicinal chemistry
• 影响因子: 3.5
• 作者: Rajaputra P;Bio M;Nkepang G;Thapa P;Woo S;You Y
• 通讯作者: You Y

Quantitative modeling of the dynamics and intracellular trafficking of far-red light-activatable prodrugs: implications in stimuli-responsive drug delivery system.

• DOI: 10.1007/s10928-017-9543-z
• 发表时间: 2017-12
• 期刊: Journal of pharmacokinetics and pharmacodynamics
• 影响因子: 2.5
• 作者: Li M;Thapa P;Rajaputra P;Bio M;Peer CJ;Figg WD;You Y;Woo S
• 通讯作者: Woo S

Folate-PEG Conjugates of a Far-Red Light-Activatable Paclitaxel Prodrug to Improve Selectivity toward Folate Receptor-Positive Cancer Cells.

• DOI: 10.1021/acsomega.7b01105
• 发表时间: 2017-10-31
• 期刊: ACS omega
• 影响因子: 4.1
• 作者: Thapa P;Li M;Karki R;Bio M;Rajaputra P;Nkepang G;Woo S;You Y
• 通讯作者: You Y

Local and Systemic Antitumor Effects of Photo-activatable Paclitaxel Prodrug on Rat Breast Tumor Models.

• DOI: 10.1111/php.13202
• 发表时间: 2020-05
• 期刊: Photochemistry and photobiology
• 影响因子: 3.3
• 作者: Subramaniyan B;Rajaputra P;Nguyen L;Li M;Peer CJ;Kindrick J;Figg WD;Woo S;You Y
• 通讯作者: You Y

Far-Red Light-Activatable Prodrug of Paclitaxel for the Combined Effects of Photodynamic Therapy and Site-Specific Paclitaxel Chemotherapy.

• DOI: 10.1021/acs.jmedchem.5b01971
• 发表时间: 2016-04-14
• 期刊: JOURNAL OF MEDICINAL CHEMISTRY
• 影响因子: 7.3
• 作者: Thapa, Pritam;Li, Mengjie;Bio, Moses;Rajaputra, Pallavi;Nkepang, Gregory;Sun, Yajing;Woo, Sukyung;You, Youngjae
• 通讯作者: You, Youngjae