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.

项目概要/摘要 光是疾病治疗的一种特殊工具，可以精确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) 光无毒，并且可以比紫外线到达更深的组织 临床应用。然而，可被这种生物相容性光裂解的化学接头非常稀有。 长期目标是开发可被可见光和近红外光裂解的化学接头，用于光控 药物递送，以及设计和合成用于光生物调节的化学缀合物。在 之前的项目，药物缀合物平台和用于位点特异性药物递送的光释放策略 已确立的。演示了点击和光解点击化学，其中单线态氧 (SO) 可裂解连接体 通过胺-炔点击反应合成并被SO裂解。药物缀合物由药物、SO- 可裂解接头、光敏剂和癌症靶向基团。当用红光（690 nm）照射时， 结合物产生 SO 并仅在照明区域释放药物并局部治疗疾病。在接下来的 5年内，将使用光响应药物缀合物建立更大胆的光生物调节策略 平台。总体假设是使用可见光和近红外光响应的局部光生物调节 缀合物可以通过激活免疫系统产生全身药理作用。这方面的主要目标 应用是设计和制备免疫刺激药物的SO-可裂解缀合物，并证明这一点 可见光响应缀合物可用于产生系统性和肿瘤特异性的抗癌作用。 结合物通过聚焦的局部照明激活，特定位点释放药物，并刺激 免疫系统触发全身和肿瘤特异性免疫反应。全身抗肿瘤作用为 通过与具有非重叠机制的全身给药药物组合进一步增强 与局部光生物调节。这些目标通过 3 个具体目标来实现：(1) 设计和准备 SO- 免疫刺激药物的可激活缀合物并确定全身抗肿瘤作用，（2）确定 光生物调节的系统效应机制并建立免疫药效学，(3) 通过添加临床上可用的物质，确定局部光生物调节增强的全身抗肿瘤作用 检查点抑制剂。药代动力学和免疫药效学模型用于分析和 模拟各种组织中缀合物、释放的药物和免疫细胞的动态变化以获得 系统层面的机制洞察。主要成果是 (i) 红光响应缀合物 免疫刺激药物，(ii) 光生物调节后的免疫药效模型，以及 (iii) 验证 我们的局部光生物调节对系统效应的影响。该策略使用乳腺癌和结肠癌动物进行了测试 模型，但它可以适用于使用间质或外部照明的多种肿瘤。

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.

紫杉醇的远红色轻度前药，用于光动力疗法和特定部位特异性紫杉醇化学疗法的综合作用。

• 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