不同分子量的MPEG-PLGA纳米药物载体的体外降解和药物释放行为研究

发布时间：2018-04-16 20:40

  本文选题：10-羟基喜树碱 + 聚乙二醇-聚丙交酯-乙交酯　； 参考：《吉林大学》2014年硕士论文

【摘要】：药物制剂的传递可以通过使用药物传递系统来改善，包括脂质体，胶束和聚合物纳米粒子。另外，考虑到安全性，这些药物传递系统必须具备高的载药量，并在病灶部位具有长效循环和累积效果。相比于其它的载体系统，，聚合物纳米粒子有很多优点。其可控的药物释放行为，稳定性以及较好的生物相容性。尽管其唯一的缺点是使用对组织有一定毒性的有机溶剂，但是价格便宜，制备过程简单可以用于大规模工业生产。用于可控的聚合物纳米粒子中生物可降解性和生物兼容性良好的PLGA已经被研究作为生物活性分子治疗剂的传递载体。且已经被广泛应用很多年，并通过美国食品药品监督管理局批准用于人类疾病治疗。 PEG由于其不带电荷，亲水和无免疫原性等特点，是一种作为纳米粒子表面修饰的最佳材料，可以减少调理素作用。 PLGA-PEG纳米粒子可以避免肾脏清除，以延长其血浆半衰期。而且，这些长效循环纳米粒子通过增强的渗透和保留效应（EPR）优先地累积在肿瘤组织和炎症部位。PEG的这种能力也依赖于一些参数，例如分子重量、密度、PEG链的构象和灵活性。另外，PLGA的生物分散特性也受粒子大小，PEG损失率等条件的影响。与其他长效循环系统相比，PEG纳米粒子的主要优势在于它的壳稳定性以及其控释能力。 本文主旨是通过四种不同分子量比例的MPEG-PLGA包裹抗肿瘤药物10-羟基喜树碱（10-HCPT）形成纳米药物载体。并对其胶束载体进行流体动力学（DLS）、红外（FITR）表征，对其载药量、包封率进行测定，体外药物释放情况和体外降解情况进行研究，最后对其抗肿瘤效果也进行了研究。初步观察、分析在双亲性嵌段共聚物形成的纳米药物载体中，分子大小以及亲水嵌段与疏水嵌段比例对以上性质的影响。 我们首先成功合成了MEPG(5k)-PLGA(3k)、 MPEG(5k)-PLGA(9k)、MPEG(5k)-PLGA(11k)、MPEG(5k)-PLGA(16k)四种不同的嵌段共聚物，通过透析法成功装载10-HCPT。其中，MPEG(5k)-PLGA(9k)形成胶束的载药量最高，MPEG(5k)-PLGA(11k)次之。且各组具有均一的粒径，良好的分散性。体外释放行为中，MPEG-PLGA(5k/11k)为药物释放动力学实验中最优组。其第一阶段的突释最不明显，直到36h总释放量达到89.13％，而后持续释放到第72h，最终药物的释放量为91.06％。在缓释行为和累积释放量上都是四组中最好的。另外在体外释放过程中，亲水嵌段MPEG的比例越大，PBS介质中pH下降越多。而在此过程中，各分子量的纳米药物胶束载体的大小基本未发生明显变化，只是在纳米药物载体表面出现了裂隙。在降解过程中MPEG(5k)-PLGA(16k)降解为小片段的速度应该是最慢的，且MPEG的比例越小，材料降解的越慢。纳米药物载体在释放过程中的质量变化与其亲水嵌段和疏水嵌段组成的比例不同有关。并且随着MPEG比例的减少，这种质量损失的速度在下降，且总的质量损失量减小。四种载体的体外抗肿瘤效果也有差异，其中MPEG(5k)-PLGA(9k)形成的胶束表现出较强的肿瘤杀伤能力，MPEG(5k)-PLGA(11k)仅次之。
[Abstract]:Drug delivery can through the use of a drug delivery system to improve, including liposomes, polymer micelles and nanoparticles. In addition, taking into account the safety of the drug delivery system must have high drug loading, and has long cycle and cumulative effect on the focus. Compared to other vector systems, polymer nanoparticles have many advantages. The release behavior of the drug control, stability and good biocompatibility. Although its only drawback is the use of organic solvents have a certain toxicity to the organization, but the price is cheap, simple preparation process can be used for large-scale industrial production. For polymer nanoparticles in controllable biodegradability and good biological compatibility has been studied as a PLGA delivery of biologically active molecules. The treatment agent and has been widely used for many years, and by the U.S. Food and drug supervision and management It was approved for use in human disease treatment.
PEG due to its uncharged, hydrophilic and non immunogenic characteristics, is one of the best materials for the surface modification of the nanoparticles, can reduce opsonization. PLGA-PEG nanoparticles can prevent renal clearance, to prolong the half-life of plasma. Moreover, the long-acting circulation nanometer particles through enhanced permeability and retention effect (EPR) the ability of.PEG preferentially accumulated in tumor tissue and inflammatory sites also depends on some parameters, such as molecular weight, density, PEG chain conformation and flexibility. In addition, PLGA is also affected by the dispersion characteristics of biological particle size and influence conditions of PEG loss rate. Compared with other long-acting circulation system, the main advantage of PEG nanoparticles it is the shell stability and its controlled release ability.
The purpose of this paper is the antitumor drug 10- hydroxycamptothecin through four different molecular weight ratio of the MPEG-PLGA package (10-HCPT). The formation of nano drug carrier and fluid dynamics on the micelle carrier (DLS), infrared (FITR) characterization, the drug loading, encapsulation efficiency was determined to study the in vitro drug release and in vitro degradation, finally the anti-tumor effect was also studied. Preliminary observation, analysis of amphiphilic block copolymer nano drug carrier formation, molecular size and hydrophilic block ratio on properties of the above effects of block and hydrophobic.
鎴戜滑棣栧厛鎴愬姛鍚堟垚浜哅EPG(5k)-PLGA(3k), MPEG(5k)-PLGA(9k),MPEG(5k)-PLGA(11k),MPEG(5k)-PLGA(16k)鍥涚�嶄笉鍚岀殑宓屾�靛叡鑱氱墿,閫氳繃閫忔瀽娉曟垚鍔熻�呰�

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