基于BRET原理的自敏化光动力治疗体系的构建及活性研究

批准号:
21571105
项目类别:
面上项目
资助金额:
60.0 万元
负责人:
周家宏
依托单位:
学科分类:
B0702.生物分子的化学生物学
结题年份:
2019
批准年份:
2015
项目状态:
已结题
项目参与者:
魏少华、周林、王傲、袁秀雪、桂利、陈恩懿、靳维维、林东梅
国基评审专家1V1指导 中标率高出同行96.8%
结合最新热点,提供专业选题建议
深度指导申报书撰写,确保创新可行
指导项目中标800+,快速提高中标率
微信扫码咨询
中文摘要
光动力疗法是临床治疗肿瘤的新型疗法,目前临床应用主要受限于静脉给药难(光疗药物绝大多数属于脂溶性化合物)、治疗光源组织穿透深度浅和可到达肿瘤细胞内部的光剂量不足等问题。本项目拟运用具有良好生理相容性且对pH敏感的纳米磷酸钙来分层负载生物发光系统及光疗药物,该治疗体系不仅实现了在血液中的有效传输和在EPR效应作用下实现肿瘤组织部位的靶向富集,而且在肿瘤细胞内涵体内的酸性作用下,触发生物发光共振能量转移,使体系能自敏化光疗药物,发挥抗肿瘤活性。通过探讨和分析该体系的构建条件及结构对血液中的传输性能、肿瘤组织部位的摄取率、生物发光共振能量转移敏化光敏药物的效率和抗肿瘤细胞的活性等的影响规律,优化该体系构建条件,获得具有自主知识产权、适用于体内实体肿瘤治疗的新型光动力治疗体系,同时建立利用生物发光共振能量转移原理来构建光动力治疗体系的新方法。以期推动光动力疗法在实体肿瘤治疗领域中的临床应用进程。
英文摘要
Photodynamic therapy is a new type of therapy in clinical treatment of tumors, the clinical application of main current is limited by intravenous dosing difficult (phototherapy drugs most belong to the fat-soluble compounds), treatment source tissue penetration depth is shallow and can be reached such problems as insufficient light dose within the tumor cells.This project intends to use with good biological compatibility and sensitive to pH nano calcium phosphate of layered load bioluminescent system and phototherapy drugs, the treatment system not only implements the effective transmission in the blood and in the EPR effect under the action of tumor tissue targeting enrichment, and the connotation of the tumor cells under the action of acid in the body, triggering bioluminescent resonance energy Photodynamic therapy (PDT) utilizes a combination of photosensitizers (PSs) and specific light sources for the treatment of various diseases. The use of PDT as a treatment modality is gradually gaining acceptance but it is not widely used in solid tumor treatment for several reasons, including the hydrophobic property of PSs, the penetration depth limitation and the inadequate light dose inside cancer cells. This project intends to use calcium phosphate nanoparticles, with good biological compatibility and pH sensitive property, to encapsulate bioluminescence system and PSs in separate part of nanoparticle. Such complex can be delivered in the blood and targeted to tumor tissue because of the enhanced permeability and retention effect (EPR). After entrapped inside cancer cells, calcium phosphate nanoparticles can be destroyed in the acid environment inside endosome, which triggering bioluminescent resonance energy transfer (BRET) and sensitizing PSs, simultaneously. The reactive oxygen species generated by the sensitized PSs can destroy the membrane of endosome to release bioluminescence system and PSs into cytoplasm to show PDT activity. By analyzing the relationship between the structure of drug delivery system and the delivery performance in the blood, tumor tissue uptake rate, BRET efficiency and anti-cancer activity, the ideal self-illuminate PDT system can be selected to be used in solid tumor treatment. Furthermore, a new method of photodynamic therapy system based on BRET principle can be built. Above research can promote the clinical application in solid tumor treatment by PDT.
光动力疗法(PDT)是一种极具应用前景的肿瘤治疗方法。其原理是光照激发富集于肿瘤组织的光敏剂产生活性氧(ROS)杀灭肿瘤细胞。但多数光敏剂的激发波长位于可见光区,该区域所对应的光源组织穿透深度浅,无法满足体内实体肿瘤治疗的要求。为解决该问题,项目设计构建含绿色蛋白(GFP)及荧光素酶(Luciferase)序列的质粒DNA。用纳米磷酸钙(CaP)来共载生物发光系统(质粒DNA与底物D-虫荧光素钠盐,D-luciferin)及光疗药物(金丝桃素,hypericin)。项目组设计的质粒DNA携带绿色荧光蛋白及荧光素酶基因,经细胞机制转录和翻译后,表达为在蓝光的激发下发出强烈的绿色荧光及能够催化底物发光的荧光素酶。CaP具有良好的生物相容性,且其结构的稳定性依赖于环境的pH值,是一种应用广泛的纳米载体。因此利用CaP-PEI为转染载体,将外源DNA转染进细胞内。PEI其外层带有正电荷,可与带有负电荷的DNA更有效地结合。为确保药物同步肿瘤摄取及同步发挥活性,先将底物D-luciferin、光敏剂Hypericin装载于CaP内,再修饰上聚乙烯亚胺(PEI),最后将DNA装载于Hypericin&D-luciferin@CaP-PEI内,形成纳米复合物DNA&Hypericin&D-luciferin@CaP-PEI(DHDC)。通过瘤内注射使纳米复合物DHDC富集于肿瘤,肿瘤组织的酸性环境(pH=5~6)使得CaP崩解,释放D-luciferin、Hypericin及DNA。在细胞内ATP及Mg2+的存在下,经DNA转录及翻译的荧光素酶催化D-luciferin产生520~680 nm的荧光,该波长范围与Hypericin吸收光谱完美匹配,从而有效激发Hypericin产生ROS,发挥PDT活性,实现有效肿瘤治疗。
期刊论文列表
专著列表
科研奖励列表
会议论文列表
专利列表
One-pot method to prepare a theranostic nanosystem with magnetic resonance imaging function and anticancer activity through multiple mechanisms
一锅法通过多种机制制备具有磁共振成像功能和抗癌活性的治疗诊断纳米系统
DOI:10.1039/c7dt00489c
发表时间:2017
期刊:Dalton Transactions
影响因子:4
作者:Chen Enyi;Chen Xin;Yuan Xiuxue;Wei Shaohua;Zhou Lin;Zhou Jiahong;Shen Jian
通讯作者:Shen Jian
A smart copper-phthalocyanine framework nanoparticle for enhancing photodynamic therapy in hypoxic conditions by weakening cells through ATP depletion
一种智能铜酞菁框架纳米颗粒,通过 ATP 耗竭来削弱细胞,从而增强缺氧条件下的光动力治疗
DOI:10.1039/c8tb00334c
发表时间:2018-04-14
期刊:JOURNAL OF MATERIALS CHEMISTRY B
影响因子:7
作者:Gui, Li;Zhou, Jiahong;Wei, Shaohua
通讯作者:Wei, Shaohua
Breaking the reduced glutathione-activated antioxidant defence for enhanced photodynamic therapy
打破还原型谷胱甘肽激活的抗氧化防御以增强光动力疗法
DOI:10.1039/c7tb01233k
发表时间:2017
期刊:Journal of Materials Chemistry B
影响因子:7
作者:Zhan Qi chen;Shi Xian qing;Yan Xiao hong;Liu Qian;Zhou Jia hong;Zhou Lin;Wei Shao hua
通讯作者:Wei Shao hua
Monomer zinc phthalocyanine/upconversion nanoparticle coated with hyaluronic acid crosslinked gel as NIR light-activated drug for in vitro photodynamic therapy
单体酞菁锌/透明质酸交联凝胶包覆的上转换纳米粒子作为近红外光激活药物用于体外光动力治疗
DOI:10.1039/c6dt01929c
发表时间:2016
期刊:Dalton Transactions
影响因子:4
作者:Zhou Lin;Chen Enyi;Jin Weiwei;Wang Yue;Zhou Jiahong;Wei Shaohua
通讯作者:Wei Shaohua
Use of an NIR-light-responsive CO nanodonor to improve the EPR effect in photothermal cancer treatment
使用近红外光响应 CO 纳米供体提高光热癌症治疗中的 EPR 效果
DOI:--
发表时间:2018
期刊:CHEMICAL COMMUNICATIONS
影响因子:4.9
作者:Chongchong Wang;Yanqing Li;Xianqing Shi;Jiahong Zhou;Lin Zhou;Shaohua Wei
通讯作者:Shaohua Wei
通过结构修饰改善痂囊腔菌素A类光敏剂的光动力活性研究
- 批准号:20603018
- 项目类别:青年科学基金项目
- 资助金额:25.0万元
- 批准年份:2006
- 负责人:周家宏
- 依托单位:
国内基金
海外基金
