磁靶向-缓释型层状复合氢氧化物给药系统研究

The existing magnetic targeted delivery system (MTDS) employs ferroferric oxide as magnetic material which must be modified before carrying drugs, and the MTDS can't integrate magnetic targeted performance and slow-release function on carrier's core level. Layered double hydroxides (LDH), when stays at the level of nonmagnetic Mg(Zn,Ni,Li)Al-LDH intercalated assembly with drugs, it, the LDH drug carrying system, possesses only slow-release performance but not magnetic targeting function. In view of this above, it has come into being the entirely new ideology of design that features constructing magnetic targeted slow release merged type of drug delivery system by utilizing the magnetic layered double hydroxide (MLDH) as carriers. Through supramolecular assembly, dosage form transformation, physical- chemical characterization,cell biologic technology, molecular biologic technology and animal experiment, research will be conducted to study and clarify such specific details as construction, cell transmission, gene transfer, magnetic targeted slow release function of the MLDH delivery systems plus the preparation conditions, pharmacodynamics and magnetic targeted treatment effect of the MLDH-drug dosage form. The research aims to solve the key and major technical problems in relation to the construction of MLDH delivery systems, and the preparation of MLDH-drug dosage form. It aims, in addition, to testify and best demonstrate scientificness of the hypothesis to integrate the magnetic performance of Fe(OH)x with slow-release effect of LDH layered structure, which, we believe, would be an ideal and a constructive solution for developing an entirely new multifunctional MTDS, and would therefore makes it possible for developing this new targeted slow release merged type of MLDH-drug dosage form. The effort in this innovative research will lead to a still further advance of the existing MTDS. Findings obtained through the research would be valuable for revealing the transport law of MLDH system. And the techniques to be developed through the research should be of greatly significant and theoretically helpful for expediting the dosage form process of the MLDH drug delivery system.

现有磁靶向给药系统用四氧化三铁作磁性材料,须先行改性才能载药,不能从运载核心整合靶向与缓释功能;层状复合氢氧化物(layered double hydroxide,LDH)停滞在MgZnNiLiAl-LDH运载水平,只有缓释而无磁靶向功能.我们针对这一现状提出以磁性层状复合氢氧化物（magnetic LDH,MLDH）为载体构建磁靶向-缓释兼融系统的方案;用超分子组装、剂型改造、理化表征、细胞及分子生物学技术与动物实验方法研究MLDH运载系统的构建与细胞传输、基因转运、磁靶向-缓释特征,及给药系统的制剂化条件、药效和磁靶向疗效等内容;解决磁靶向-缓释兼融系统的构建与制剂化问题,验证"整合Fe(OH)x的顺磁结构与LDH的缓释作用设计多功能运载系统、开发新型靶向-缓释制剂"设想的科学性.这对改进现有磁靶向给药系统设计,揭示MLDH转运规律、推进制剂化进程有重要的理论价值与实际意义.

以“磁性层状LDH超分子组装与磁靶向缓控释作用(20961008)”为基础，针对“MLDH-DNA基因转运，MLDH细胞传输，右旋糖酐-磁性层状复合氢氧化物-氟尿嘧啶(DMF)磁靶向缓控释给药系统的制剂化途径，制剂药效学及靶向疗效学，DMF系统的智能化途径探索”等内容开展研究，解决“构筑磁靶向-缓控释兼融型MLDH运载系统、实现DMF给药系统的制剂化”等关键技术问题，取得化学、制剂学、细胞及分子生物学与动物实验数据，验证“整合Fe(OH)x的顺磁结构与LDH的控释作用构建多功能广谱磁靶向运载系统，汇集传统辅料、剂型效应及MLDH磁靶向运载优势开发新型靶向-缓释制剂”的科学构想，在基础理论、技术开发和人才培养方面取得比较丰硕的成果，发表论文13篇，取得7项专利授权，培养研究生6名，获宁夏医学优秀学术论文、宁夏自然科学优秀学术论文、宁夏科学技术进步奖及中国发明专利优秀奖等奖项。. 通过细胞生物学和分子生物学研究，发现MLDH系统的细胞核靶向转运特性，例如，MLDH-DNA在0.5 h内完成与细胞膜的融合、跨膜传输，在 1h内实现细胞内化、逼近细胞核，2 h内到达细胞核、富集至核仁；MLDH-FLOUR在5 min内完成细胞内化，30 min后大量富集于细胞核仁；通过对DMF给药系统的制剂化及疗效学研究，证明MLDH运载系统的磁靶向-缓控释兼融性，检验DMF脂质体的抗肿瘤效果－腹腔注射的抑瘤率60.7%，磁靶向干预时上升至73.3%，接近乃至超过文献报道瘤体内直接给药或血管注射药物的抑瘤率；Ki-67阳性表达降至0.1647 ± 0.0119，加磁干预至0.1424 ± 0.0264；肿瘤组织微血管密度降至29.78 ± 7.09，加磁干预低至22.78 ± 4.85，为DMF制剂的商业开发与临床前研究提供了充足的理论根据；通过对DMF系统的量子点嫁接、热敏性组装等探索研究，取得丰富实验数据，为开展“磁性荧光纳米粒子的诊疗一体化功能”、“磁热双敏性DMF智能化给药系统”等方向的纵深研究，奠定了扎实的前期基础。. 项目取得的理论成果对指导新型靶向转运系统的生物医学研究及化学生物学研究有重要的学术价值；技术成果，有助于推进现代给药系统的设计创新，开发高效广谱靶向-缓释制剂，具有潜在的经济社会效益。