智能高分子脂质囊泡纳米系统在肿瘤诊疗中的初步应用

发布时间：2018-07-20 12:39

【摘要】：纳米药物投递系统可改善传统化疗的药物非特异性分布、治疗效果差、全身毒副作用大等缺点。如何设计高效的药物投递系统解决上述问题是目前肿瘤治疗领域一个急需解决的问题。本文的目的是开发一种智能响应性高分子脂质囊泡,并以其为基础构建一系列多功能纳米系统应用于肿瘤的诊断与治疗。具体研究内容如下:1.具有敏感化学键的双亲性葡聚糖衍生物的合成。结果表明,双亲性葡聚糖衍生物被成功制备,分子内含有还原性敏感二硫键及pH敏感腙键,可对相应的环境刺激发生响应性断键,并且高分子具有较低的临界聚集浓度,可在水中发生自组装行为;2.智能响应性高分子脂质囊泡(PLVs)的制备及在药物载体方面的研究。结果表明,制备的高分子脂质囊泡粒径在100 nm以下,同时表面有PEG修饰,因而可利用EPR效应实现对肿瘤的被动靶向。到达肿瘤组织后,其可对肿瘤微环境的弱酸性实现响应,表面的PEG修饰层脱落并暴露出靶向基团或正电基团,进而可通过与细胞膜相互作用快速进入细胞,在细胞内还原性环境的刺激下,囊泡实现二重响应,结构发生破坏,迅速释放其中负载的药物,发挥治疗效果;3.磁性载药高分子脂质囊泡(SPIODOX-PPLVs)的制备及在肿瘤诊疗方面的研究。结果表明,制备的纳米载体粒径约为80 nm,具有较好的磁响应性(27.5 emu/g)和较高的横向弛豫效率(213.82 mM-1 s-1),可对还原性环境实现响应,达到药物控释的目的,可在外加磁场作用下携带药物有效进入细胞,并且迅速释放药物,体内实验表明,纳米载体可实现肿瘤部位的磁共振阴性造影与磁靶向化疗;4.智能上转换高分子脂质囊泡(RB-UPPLVs)的制备及在光动力治疗方面的研究。结果表明,RB-UPPLVs具有纳米级核壳结构,粒径约为40 nm,在近红外光照射下可产生活性氧用于光动力治疗,可对不同pH环境实现响应,经pH5.0缓冲液预处理后,可显著提高其细胞内吞效率与光动力治疗效果;5.载药上转换高分子脂质囊泡(MC540DOX-UFPLVs)的制备及在肿瘤协同治疗方面的研究。结果表明,制备的纳米载体粒径约为40 nm,在近红外光照射下可产生活性氧用于光动力治疗,可对不同pH环境响应实现药物控释,可实现化疗与光动力治疗的协同治疗,具有比单一疗法更高的肿瘤治疗效果;综上所述,本文成功构建了一系列基于智能响应性高分子脂质囊泡的多功能纳米粒子,其有望作为一种有效的纳米载体应用于肿瘤的诊断和治疗领域。
[Abstract]:Nano-drug delivery system can improve the non-specific distribution of traditional chemotherapeutic drugs. How to design an efficient drug delivery system to solve these problems is an urgent problem in the field of cancer treatment. The aim of this paper is to develop an intelligent responsive polymer lipid vesicle and to construct a series of multifunctional nanosystems for tumor diagnosis and treatment. The specific contents of the study are as follows: 1. Synthesis of amphiphilic dextran derivatives with sensitive chemical bonds. The results showed that the amphiphilic dextran derivatives were successfully prepared with reductive disulfide bond and pH sensitive Hydrazone bond. Self-assembly behavior can occur in water. Preparation of Intelligent Responsive Polymer Lipid vesicles (PLVs) and their Application in Drug carriers. The results showed that the size of the polymer lipid vesicles was below 100 nm and the surface was modified by PEG. Therefore, the EPR effect could be used to realize the passive targeting of tumor. Upon reaching the tumor tissue, it can respond to the weak acidity of the tumor microenvironment, and the PEG modified layer on the surface falls off and exposes the target group or the positive group, which can quickly enter the cell by interacting with the cell membrane. Under the stimulation of the intracellular reductive environment, the vesicles responded in a double way, the structure was destroyed, the loaded drugs were released rapidly, and the therapeutic effect was exerted. Preparation of Magnetic Drug-loaded Polymer Lipid vesicles (SPIODOX-PPLVs) and its Application in Cancer diagnosis and treatment. The results show that the nanoparticles have a good magnetic response (27. 5 emu/g) and a high transverse relaxation efficiency (213.82 mm -1 s-1), which can respond to the reductive environment and achieve the purpose of controlled release of the drug, and the particle size of the nanoparticles is about 80 nm, and the results show that the nanoparticles have good magnetic response (27. 5 emu/g) and high transverse relaxation efficiency (213.82 mm -1 s-1). It can carry drugs into cells effectively under the action of external magnetic field and release drugs rapidly. In vivo experiments show that nano-carriers can realize magnetic resonance negative contrast imaging and magnetically targeted chemotherapy in tumor sites. Preparation and photodynamic therapy of intelligent up-conversion polymer lipid vesicles (RB-UPPLVs). The results showed that RB-UPPLVs had a nanocrystalline core-shell structure with a particle size of about 40 nm. Reactive oxygen species could be produced for photodynamic therapy under near-infrared irradiation and could respond to different pH conditions. After pretreatment with pH 5.0 buffer solution, RB-UPPLVs could be used in photodynamic therapy. It can improve the efficiency of endocytosis and the effect of photodynamic therapy. Preparation of Drug-loaded Polymer Lipid vesicles (MC540 DOX-UFPLVs) and its Application in the Cooperative Therapy of Cancer. The results showed that the particle size of the nanoparticles was about 40 nm. Reactive oxygen species (Ros) could be produced for photodynamic therapy under near-infrared irradiation. The drug release could be controlled in response to different pH, and the synergistic therapy of chemotherapy and photodynamic therapy could be achieved. In conclusion, we successfully constructed a series of multifunctional nanoparticles based on intelligent responsive polymer lipid vesicles. It is expected to be used as an effective nano-carrier in tumor diagnosis and treatment.
【学位授予单位】：天津大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R730.4;TB383.1

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