Impact of Conjugation Chemistry on the Pharmacokinetics of Peptide-Polymer Conjugates in a Model of Traumatic Brain Injury.

IF 4 2区 化学 Q1 BIOCHEMICAL RESEARCH METHODS
Jason Ren Wu, Akash Canjels, Rei Miyauchi, Ester J Kwon
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Abstract

Traumatic brain injury (TBI) remains a leading cause of long-term disability and mortality; however, there are no effective therapies to mitigate secondary injury and long-term neurological impairments. After the initial mechanical insult, there is a secondary injury that leads to neuroinflammation and blood-brain barrier (BBB) disruption, both of which are linked to changes in the extracellular matrix (ECM). A short peptide sequence, CAQK (Cys-Ala-Gln-Lys), targets upregulated ECM proteoglycans after TBI and has exhibited therapeutic properties in preclinical TBI studies. However, like many peptides, CAQK has poor pharmacokinetics, with rapid systemic clearance limiting its therapeutic potential. To overcome these limitations, we investigated a peptide-polymer conjugate using a poly(ethylene glycol) (PEG) scaffold to improve the peptide pharmacokinetics of CAQK. We synthesized materials using two conjugation chemistries, maleimide-thiol Michael-type addition and dibenzocyclooctyne (DBCO)-azide strain-promoted azide-alkyne cycloaddition. The impact of linker selection on biodistribution and clearance was distinct. We first showed that conjugation of CAQK to PEG, irrespective of linkers, significantly extended the peptide's blood half-life by 90-fold and increased brain accumulation. In the analysis of off-target organs, we observed longer retention of DBCO conjugates in the liver, kidney, and spleen compared to maleimide conjugates. Given the high incidence of TBI in populations such as military personnel and athletes, we explored whether our long-circulating material could be given as a prophylaxis. We demonstrated the accumulation of 4.5%ID/g CAQK in the injured brain when the conjugate was delivered prophylactically 24 h before injury. Our work underscores the advantage of long-circulating peptide-polymer conjugates in the context of TBI and the impact of conjugation chemistry on pharmacokinetics.

偶联化学对外伤性脑损伤模型中肽-聚合物偶联物药代动力学的影响。
创伤性脑损伤(TBI)仍然是导致长期残疾和死亡的主要原因;然而,目前还没有有效的治疗方法来减轻继发性损伤和长期神经损伤。在最初的机械损伤之后,会发生继发性损伤,导致神经炎症和血脑屏障(BBB)破坏,这两者都与细胞外基质(ECM)的变化有关。短肽序列CAQK (Cys-Ala-Gln-Lys)靶向脑外伤后上调的ECM蛋白多糖,并在临床前脑外伤研究中显示出治疗特性。然而,像许多多肽一样,CAQK具有较差的药代动力学,快速全身清除限制了其治疗潜力。为了克服这些局限性,我们研究了一种使用聚乙二醇(PEG)支架的肽-聚合物偶联物来改善CAQK的肽药代动力学。采用马来酰亚胺-硫醇迈克尔型加成和二苯并环辛基(DBCO)-叠氮化物菌株促进叠氮化物-炔环加成两种共轭化学方法合成了材料。连接体选择对生物分布和清除率的影响是明显的。我们首先发现,CAQK与PEG结合,无论连接物如何,都显著延长了肽的血液半衰期90倍,并增加了脑蓄积。在脱靶器官的分析中,我们观察到与马来酰亚胺偶联物相比,DBCO偶联物在肝脏、肾脏和脾脏中的滞留时间更长。鉴于TBI在军事人员和运动员等人群中的高发病率,我们探讨了我们的长期流通材料是否可以作为预防措施。我们证实,在损伤前24小时预防性给药时,损伤脑组织中累积了4.5%ID/g CAQK。我们的工作强调了长循环肽-聚合物偶联物在脑损伤背景下的优势以及偶联化学对药代动力学的影响。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Bioconjugate Chemistry
Bioconjugate Chemistry 生物-化学综合
CiteScore
9.00
自引率
2.10%
发文量
236
审稿时长
1.4 months
期刊介绍: Bioconjugate Chemistry invites original contributions on all research at the interface between man-made and biological materials. The mission of the journal is to communicate to advances in fields including therapeutic delivery, imaging, bionanotechnology, and synthetic biology. Bioconjugate Chemistry is intended to provide a forum for presentation of research relevant to all aspects of bioconjugates, including the preparation, properties and applications of biomolecular conjugates.
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