基于近红外光响应型纳米载体的肿瘤诊断治疗学研究

发布时间：2018-10-12 09:36

【摘要】：在抗肿瘤疗法的研究中,有多种因素制约着其发展:(1)最主要的问题是抗肿瘤制剂在体内的靶向性较低,易引起严重的全身毒副作用;(2)药物从载体的释放过程,通常是缓慢且不可控的;(3)单一疗法并非对肿瘤具有普适性,且难以实现肿瘤的完全消除;(4)在治疗过程中,通常需要结合诊断手段判断肿瘤的位置、大小,并监测治疗成分在体内的分布情况。为了克服以上限制因素,本研究采用金纳米棒(Gold Nanorods,GNR)与载体共同给药,使其在光热作用下加强增强渗透和保留(Enhanced Permeability and Retention,EPR)效应的被动靶向作用;此外,一种低pH嵌入肽链(pH(Low)Insertion Peptide,pHLIP)被用于修饰载体,在肿瘤的酸性微环境下发挥主动靶向作用。在载体靶向聚集于肿瘤部位后,采用光作为无刺激可穿透的远程调控诱导源,结合应用近红外(Near Infrared,NIR)光响应型载体,在光热剂的作用下提供热能,实现光热控制释药。整体研究内容以单一疗法如光热治疗(Photothermal Therapy,PTT)为基础,联合应用负载化学药物或光敏剂的光热响应释药载体,实现PTT/化学治疗或PTT/光动力治疗(Photodynamic Therapy,PDT)多重协同治疗体系。此外,本研究将具有不同成像机制的成像剂负载于光响应载体上,如荧光物质,或直接作为载体使用,如金纳米载体,实现诊断治疗一体化的抗肿瘤体系。综上所述,本研究分别设计以下两种治疗体系发挥协同抗肿瘤作用:(1)本研究设计了基于GNR和温敏性脂质体(Thermosensitive Liposomes,TSL)的肿瘤靶向转运和靶位释药的抗肿瘤体系,在NIR光条件下,可以实现PTT、化学治疗和活体荧光成像三重诊断治疗目的;(2)本课题进一步探究了一种新型NIR光诱导的三重响应抗肿瘤体系,采用空心金纳米球(Hollow Gold Nanospheres,HAuNS)表面吸附靶向多肽pHLIP和光敏剂二氢卟酚e6(Chlorin e6,Ce6),实现NIR光诱导下的PTT-药物释放-PDT的步进式治疗过程。
[Abstract]:In the research of antitumor therapy, there are many factors restricting its development: (1) the most important problem is the low targeting of antitumor agents in vivo, which is liable to cause serious systemic toxic side effects; (2) the release process of drugs from the carrier. Usually slow and uncontrollable; (3) monotherapy is not universal to the tumor, and it is difficult to completely eliminate the tumor; (4) in the course of treatment, the location and size of the tumor usually need to be judged in combination with diagnostic methods. The distribution of therapeutic components in vivo was monitored. In order to overcome the above limitations, gold nanorods (Gold Nanorods,GNR) and the carrier were used to enhance the passive targeting effect of enhanced permeation and retention of (Enhanced Permeability and Retention,EPR under photothermal action. A low pH intercalated peptide chain (pH (Low) Insertion Peptide,pHLIP) is used to modify the vector and play an active targeting role in the acidic microenvironment of the tumor. After the carrier was targeted at the tumor site, light was used as a non-stimulative and penetrating remote regulatory inducer, combined with the near-infrared (Near Infrared,NIR) photo-responsive carrier to provide thermal energy under the action of photothermal agent to realize the photothermal controlled drug release. Based on monotherapy such as photothermal therapy (Photothermal Therapy,PTT) and photothermal response drug delivery carrier loaded with chemotherapeutic agents or Guang Min, the system of PTT/ chemotherapy or PTT/ photodynamic therapy (Photodynamic Therapy,PDT) was realized. In addition, imaging agents with different imaging mechanisms were loaded on photoresponse carriers, such as fluorescent substances, or directly used as carriers, such as gold nano-carrier, to achieve an integrated anti-tumor system of diagnosis and treatment. To sum up, the following two treatment systems were designed to play synergistic antitumor effects: (1) in this study, the anti-tumor systems based on GNR and thermo-sensitive liposomes (Thermosensitive Liposomes,TSL) were designed for tumor targeted transport and target drug release. Under NIR light conditions, The aim of triple diagnosis of PTT, chemotherapy and in vivo fluorescence imaging can be achieved. (2) A novel NIR photo-induced triple response antitumor system is further explored. The surface adsorption targeting polypeptide (pHLIP) of hollow gold nanospheres (Hollow Gold Nanospheres,HAuNS) and Chlorin e6 (Chlorin e6) were used to realize the stepwise treatment of PTT- drug release-PDT induced by NIR.
【学位授予单位】：天津大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R73-3;O657.33

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