酶切肽肿瘤特异性改性脂质体与聚环酯增载亲脂药物控释纳米粒的制备及性能研究

Solid lipid nanoparticles (SLNs) are considered as a new delivery system for the controlled release of lipophilic drugs. This carrier system has potential and significant applications in clinical and pharmaceutical fields like gene therapy, tumor clinic and new-drug discovery. However, SLNs always suffer some drawbacks like the low loading capacity and entrapment efficiency, the short retention and circulation time, and limited tumor-specific properties as well as the difficult to control particle sizes. Therefore, it is needed to explore new delivery systems and preparation methods for SLNs. In this application, we intend to develop a novel SLN system for the delivery of lipophilic drugs by using star-cyclic ester polymer and liposomes modified with tumor-specific enzymatic-cleavable peptide and poly(ethylene glycol)lation (PEGlation) as the matrix. The PEGlation of lipids will be used to increase the retention and long circulation time and the cleavable peptide will be used to specify the system to tumor tissue. The star-cyclic ester polymer will be employed to enhance the drug loading capacity, while the microchannel formation method is to be used for the continuous production of SLNs with narrow and controllable size distributions. As an example, the anti-tumor drug, Curcumin, will be used as the model lipophilic drug and the Curcumin-SLNs will be prepared by the microchannel method mentioned above. The in vitro to in vivo release performance, the anti-tumor active properties, the stability as well as the safety of the obtained Curcumin-SLNs will be investigated. It is therefore, by the present investigation, hopeful to obtain a new SLNs system with good stability, safety, satisfied drug entrapment efficiency and loading capacity, tumor specificity and controllable sizes, which could be effective for the controlled release of Curcumin, and thus fundamental for the future clinic study and applications.

固体脂质纳米粒（SLN）是亲脂性难溶药物控释给药的新载体系统,在基因治疗、肿瘤等重大疾病治疗及新药研究领域有重要应用前景。然而，现有SLN存在载药量低、体内驻留时间短、肿瘤靶向性低及粒径控制难等问题，研究新型SLN释放平台及相应制备新方法有重要意义。 本项目拟研究一种基于蛋白内切酶特异性多肽和亲水嵌段改性脂质体和星状聚环酯为载体的亲脂性难溶药物控释SLN新系统；通过亲水嵌段修饰脂质提高SLN体内驻留时间和稳定性，利用酶促内切肽特异性靶向肿瘤，通过星状聚环酯增载提高载药量，并以微系统连续纳米粒成粒技术进行SLN制备和粒径控制。项目以具有抗肿瘤活性的姜黄素为脂溶性药物模型，对其体内体外释药特性、抗肿瘤活性、稳定性及安全性等进行研究，以形成稳定性好、载药量和包封率高、对肿瘤具有特异靶向性及粒径可控的SLN给药新平台，建立其制备新方法，得到姜黄素控释给药的优良剂型，为进一步临床研究和应用打下基础。

传统的癌症药物对癌细胞的选择性低，且毒副作用大，疗效差。同时大量的药物水溶性差，限制了其药理作用的发挥。本项目选择具有抗肿瘤活性的姜黄素为模型药物，设计以可降解星状聚酯作为药物包载材料提高药物的载药量。同时根据金属蛋白酶在肿瘤组织中分布很广，利用蛋白酶内切特异性多肽与PEG对材料进行修饰。利用剪切肽提高纳米粒的靶向肿瘤特异性。通过PEG端链提高固体脂质纳米粒的体内驻留时间和稳定性，实现药物在体内的缓控释释放。并利用微通道连续纳米粒成粒技术进行粒径控制和成粒，形成一种载药量高、对肿瘤组织具有特异性及粒径可控的新型脂质纳米粒给药系统。并对所得脂质纳米粒给药系统的药物稳定性、药效学特性作研究。相关实验结果显示：相关靶向性和体内长循环的设计目标都得以实现，该纳米给药系统能有效控制肿瘤细胞增殖。