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首页> 外文会议>World biomaterials congress >Stability and release of two peptides in a novel peptide-based drugs for local intra-articular purpose in osteoarthritis
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Stability and release of two peptides in a novel peptide-based drugs for local intra-articular purpose in osteoarthritis

机译：用于骨关节炎的局部关节内新型基于肽的药物中两种肽的稳定性和释放

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Introduction: Knee osteothritis (OA) is a leading cause of disability in older adults, research into the specific therapies of OA, is a priority in health sciences. In this project a novel peptide-based nanoparticles (NPs) are proposed to satisfy an unmet clinical need; sustained drug delivery to the knee joint. The objective is to develop a delivery system R- 954 from nanogels hyaluronic acid (HA) /chitosan (CH), either by encapsulation (without covalent bond), or by grafting to the HA (with covalent bond). The peptide r9S4 is an antagonist of the bradykinin receptor (BKB1R) and BQ123 is an antagonist of the endothelin receptor (ETA-R). Kaufman et al. and Moldovan et al. showed that both endotelin-1 (ET-1) and bradykinin play crucial role in vivo in OA pathophysiology, through their catabolic functions in cartilage degradation and inflammation involving metalloproteases MMPs (MMP1-and MMP-13), nitric oxide (NO), and prostaglandins (PGE2). Hyaluronic acid and chitosan based nanohydrogels were chosen as carriers for the two peptides because they could provide an enhanced protection against biochemical aggression and sustained release. Materials and Methods: In the first part, the peptide coupling of the r954 petide and hyaluronic acid (HA) was carried out. The conjugation of the peptide to HA was performed using the well established coupling chemistry of pH sensitive linkers. The carboxylic and primary amine groups present on the peptides allow for simple ligation. To quantify the release and stability of this novel peptide-based drug, a fast and accurate liquid chromatography -tandem mass spectrometry (LC-MS/MS) method was developed. In this method the proteins of the HSF are simply precipitated with acetonitrile, the sample is diluted with mobile phase and injected directly without further purification steps. The method was validated according to the EMA guideline on bioanalytical method validation. Results and discusssion: Peptide release and degradation kinetics study of the coupled composite in human synovlal fluid (HSF) and buffer solutions. We found that a 23% of r954 was released in hsf from the coupled composite in 77 hrs, it means in 39 days the total release. However the release of the peptide bq123 under the same conditions takes a very long time. The degradation kinetics of the peptide r954 and bq123 in the physiological matrix human synovial fluid and under various pH conditions were investigated. The stability testing of the peptide r954 was carry out to provide evidence on how the quality of the drug substance varies with time under the influence of the temperature. When r9S4 was incubated in hsf at 37 °C, was stable during the first 77 hrs. Conclusion: Results are very encouraging and show that the vectorization strategy is feasible. The main perspective: Synthesize sterile synthetic nanogels containing both peptides (encapsulated or grafted) to assess the cytotoxicity and the effects on human cartilage.
机译：简介：膝关节骨关节炎（OA）是老年人致残的主要原因，对OA特定疗法的研究是健康科学中的优先领域。在该项目中，提出了一种新型的基于肽的纳米颗粒（NPs），以满足尚未满足的临床需求。持续将药物输送到膝关节。目的是通过封装（无共价键）或接枝到HA（有共价键），由纳米凝胶透明质酸（HA）/壳聚糖（CH）开发一种递送系统R-954。肽r9S4是缓激肽受体（BKB1R）的拮抗剂，而BQ123是内皮素受体（ETA-R）的拮抗剂。考夫曼（Kaufman）等人。和摩尔多瓦（Moldovan）等人。表明内皮素-1（ET-1）和缓激肽在体内OA病理生理中起着至关重要的作用，它们在金属蛋白酶MMP（MMP1和MMP-13），一氧化氮（NO）和金属蛋白酶的软骨降解和炎症中具有分解代谢功能。前列腺素（PGE2）。选择基于透明质酸和壳聚糖的纳米水凝胶作为这两种肽的载体，因为它们可以提供增强的抗生化攻击和持续释放的保护作用。材料和方法：在第一部分中，进行了r954肽与透明质酸（HA）的肽偶联。肽与HA的缀合是使用pH敏感接头的公认的偶联化学方法进行的。肽上存在的羧基和伯胺基允许简单的连接。为了量化这种基于肽的新型药物的释放和稳定性，开发了一种快速，准确的液相色谱-串联质谱（LC-MS / MS）方法。在这种方法中，HSF的蛋白质仅用乙腈沉淀，样品用流动相稀释，无需进一步纯化即可直接注射。该方法根据有关生物分析方法验证的EMA指南进行了验证。结果与讨论：偶联复合物在人滑液（HSF）和缓冲液中的肽释放和降解动力学研究。我们发现，r954中23％的r954在77小时内从偶联的复合物中以hsf释放，这意味着在39天内全部释放。然而，在相同条件下肽bq123的释放花费很长时间。研究了r954和bq123肽在生理基质人滑液中和不同pH条件下的降解动力学。进行了r954肽段的稳定性测试，以提供证据证明原料药的质量在温度的影响下如何随时间变化。当r9S4在hsf中于37°C孵育时，在最初的77小时内是稳定的。结论：结果令人鼓舞，表明矢量化策略是可行的。主要观点：合成包含两种肽（封装或嫁接）的无菌合成纳米凝胶，以评估细胞毒性和对人软骨的影响。

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