兰州大学机构库 >生命科学学院
成骨细胞靶向的甲状旁腺素1-34多肽偶联药物的设计、合成及活性研究
Alternative TitleThe chemical building of the osteoblast targeting compounds of PTH(1-34) peptide- drug- conjugate and the studies of their biological activities
刘春霞
Thesis Advisor彭雅丽
2016-05-26
Degree Grantor兰州大学
Place of Conferral兰州
Degree Name硕士
Keyword甲状旁腺素1-34 成骨细胞靶向 RANKL 多肽偶联药物
Abstract随着世界人口老龄化,骨质疏松症发病率呈快速增长态势,已成为一项全球性的健康问题。甲状旁腺激素(PTH)是第一个获得美国FDA批准的骨形成剂类新药,这种甲状旁腺激素的衍生物通过每天皮下注射可以增加成骨细胞的数量及骨形成作用,而目前的常规骨质疏松药物只是作用于破骨细胞而减缓或阻断骨质流失。但是由于PTH(1-34)每天一次的皮下注射、骨形成窗口期的限制和骨外副作用严重影响其在临床上的使用。最新的研究表明,PTH(1-34)的主要作用机制是通过成骨细胞和骨细胞所表达的PTHR-1而介导的,PTH(1-34)激活了成骨细胞之外的作用位点导致以上缺点和副作用。 羟磷灰石是骨骼中的主要成分,它可以作为靶向性给药的一个靶点使药物有目的的进入骨组织。研究发现在破骨细胞作用的骨吸收表面以高结晶度的羟磷灰石的形式存在,而在成骨细胞作用的骨形成表面则以低结晶度羟磷灰石的形式集聚。在本课题中我们通过构建一系列成骨细胞靶向的PTH(1-34)多肽偶联药物分子,利用了不同的连接方式(二硫键、硫醚键、腙键),将(DSS)6连接在PTH(1-34)的羧基末端,从而将其主要递送到成骨细胞周围,促进骨形成,而很大程度上不影响RANKL分泌量,从而抑制破骨细胞的激活,突破PTH(1-34)的用药窗口期,并克服由于其不能够靶向骨组织而存在的高钙血症、晕眩、腿部痉挛等副作用。同时设计阿仑膦酸、Asp8等高结晶度骨组织靶向分子连接在PTH(1-34)的羧基末端,比较与(DSS)6连接在体外羟磷灰石的结合性、药理学特性的异同。实验结果表明,三类不同的骨组织靶向偶联药物明显比PTH(1-34)的HA结合性强,同时相较于其他的两类偶联药物,成骨细胞靶向偶联药物对于低结晶度羟磷灰石有显著的结合性,同时cAMP激动活性略有下降。总之,这种成骨细胞靶向偶联药物对于减少PTH(1-34)的骨外副作用,突破骨形成的窗口期有重要作用,同时为骨质疏松症治疗提供了新的策略和思路。
Other AbstractWith continued ageing of the population, the incidence of osteoporosis is growing rapidly and it is becoming a major public health problem in worldwide. PTH(1-34) is the first agent to stimulate bone formation, this parathyroid hormone derivative can increase the number of bone cells and bone formation effect through daily subcutaneous injection. However the current conventional osteoporosis drugs only act on osteoclasts aiming to slow or stop bone loss. ‘Anabolic window’, the inconvenience of daily injections, and the relatively high cost have caused PTH(1-34) remain as a second line medication. The recently research shows, the main mechanism of PTH(1-34) is mediated by PTHR-1 expressed on osteoblasts and osteocytes, while PTH(1-34) activates outer site of osteoblast, leading to the above shortcomings and adverse. Hydroxyapatite as the main ingredient of bone, it can serve as a target for bone-targeted-drug to bring them into the bone tissue. It has been known that bone resorption surfaces characterized by highly crystallized hydroxyapatite are dominantly occupied by osteoclasts and osteoclast precursors, and bone formation surfaces as the form of lowly crystallized hydroxyapatite are accumulated by osteoblasts. In this study, we constructed a series of the osteoblast targeting compounds of PTH(1-34) peptide- drug- conjugate, by using different connections (disulfide bond, thioether bond and hydrazone bond) connected the (DSS)6 to the carboxyl of PTH(1-34), which will deliver it to the osteoblast cells and promote bone formation, and to a large extent not affect RANKL secretion, thereby inhibiting the activation of osteoclasts, breaking ‘anabolic window’ of PTH(1-34), and overcoming the others side effects such as hypercalcemia, dizziness and leg cramps. While we attached the highly crystallized bone-targeting molecules, alendronate and Asp8, specifically targeting osteoclasts to the carboxyl of PTH(1-34), compared them to (DSS)6 drug-conjugate on the pharmacological properties and the hydroxyapatite binding affinity in vitro. Experimental results show that the three different types of bone targeting drug conjugates are significantly stronger than PTH(1-34) on hydroxyapatite binding, but compared to other types of drug conjugates, osteoblasts-targeting of PTH(1-34) peptide drug conjugates is prefer to bind lowly crystallized hydroxyapatite, while cAMP agonist activity is declined slightly. In short, the osteoblast cell targeting drug conjugates fo...
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Language中文
Document Type学位论文
Identifierhttps://ir.lzu.edu.cn/handle/262010/221633
Collection生命科学学院
Recommended Citation
GB/T 7714
刘春霞. 成骨细胞靶向的甲状旁腺素1-34多肽偶联药物的设计、合成及活性研究[D]. 兰州. 兰州大学,2016.
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