Recombinant Hydrophobic Polypeptide MBAY Loaded Into SPION-Exosome Realizes Sustained-Release to Improve Type 2 Diabetes Mellitus.

IF 4.7 2区医学 Q1 CHEMISTRY, MEDICINAL

Drug Design, Development and Therapy Pub Date : 2025-04-22 eCollection Date: 2025-01-01 DOI:10.2147/DDDT.S499641

Xinyu Zong, Shangying Xiao, Haishan Xia, Dan Guo, Jiaping Wu, Manjiao Zhuang, Lei Rao

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Abstract

Background: BAY55-9837, a potential therapeutic peptide for the treatment of type 2 diabetes mellitus (T2DM), can induce glucose (GLC)-dependent insulin secretion. Our previous study has demonstrated that the use of superparamagnetic iron oxide nanoparticle-decorated exosome (exosome-SPION) and external magnetic force (MF) enables BAY 55-9837 to target pancreatic islets. However, the initial burst release of BAY 55-9837 loaded within exosome-SPION shortens its in vivo half-life and consequently reduces the frequency of GLC responsiveness. Therefore, in our study, the transmembrane hydrophobic structure of the exosome signature protein CD81 was fused with BAY 55-9837 to obtain MBAY with sustained-release capability.

Methods: MBAY was fabricated via genetic engineering, and the dissociation constant (Kd) was determined to assess its affinity for vasoactive intestinal peptide receptor type 2 (VPACII). Subsequently, MABY was incorporated into exosomes through electroporation to obtain MBAY-exosome, and SPOIN was adorned on MBAY-exosome by means of the self-assembly of transferrin (Tf) and the transferrin receptor (TfR). The in vitro release profile and in vivo pharmacokinetic profile of MBAY-Exosome-SPION were detected using high-performance liquid chromatography (HPLC). The L9(3⁴) orthogonal design approach was utilized to optimize the drug administration mode in vivo. The therapeutic effect of MBAY-exosome-SPIONs/MF on T2DM was assessed both in vitro and in vivo.

Results: In vitro studies showed that the release rate of MBAY from exosome-SPION was slower compared with BAY 55-9837. Meanwhile, MBAY still maintained high affinity and selectivity for VPAC II and MBAY-exosome-SPIONs/MF could effectively promote insulin secretion in response to elevated GLC as BAY-exosome-SPIONs/MF. In vivo studies indicated that MBAY-exosome-SPIONs had a prolonged half-life and improved pharmacokinetic parameters compared to BAY-exosome-SPIONs, which further alleviated the symptoms of T2DM model mice.

Conclusion: Thus, the reconstructed MBAY loaded in SPION-exosome realized sustained-release and exosomes-SPIONS achieved pancreatic targeting which led to ideal therapeutic effect in T2DM mice.

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装载spion -外泌体的重组疏水多肽MBAY实现缓释改善2型糖尿病。

背景：BAY55-9837是一种治疗2型糖尿病（T2DM）的潜在多肽，可诱导葡萄糖（GLC）依赖性胰岛素分泌。我们之前的研究表明，使用超顺磁性氧化铁纳米颗粒修饰的外泌体（exosome- spion）和外部磁力（MF）可以使BAY 55-9837靶向胰岛。然而，装载在spion外泌体中的BAY 55-9837的初始爆发释放缩短了其体内半衰期，从而降低了GLC响应的频率。因此，在我们的研究中，将外泌体特征蛋白CD81的跨膜疏水结构与BAY 55-9837融合，获得具有缓释能力的MBAY。方法：通过基因工程制备MBAY，测定其解离常数（Kd），评价其对血管活性肠肽受体2 （VPACII）的亲和力。随后，通过电穿孔将MABY纳入外泌体，获得mbay -外泌体，并通过转铁蛋白（Tf）和转铁蛋白受体（TfR）的自组装将SPOIN修饰在mbay -外泌体上。采用高效液相色谱法检测MBAY-Exosome-SPION的体外释放谱和体内药动学谱。采用L9（34）正交设计优化体内给药方式。体外和体内评价MBAY-exosome-SPIONs/MF对T2DM的治疗效果。结果：体外研究表明，与BAY 55-9837相比，外泌体spion释放MBAY的速度较慢。同时，MBAY对VPAC II仍保持较高的亲和力和选择性，MBAY-exosome- spions /MF与BAY-exosome-SPIONs/MF一样，在GLC升高时能有效促进胰岛素分泌。体内研究表明，与BAY-exosome-SPIONs相比，MBAY-exosome-SPIONs具有延长半衰期和改善药代动力学参数的作用，从而进一步缓解了T2DM模型小鼠的症状。结论：由此可见，spion -外泌体负载重组MBAY实现了持续释放，外泌体- spions实现了胰腺靶向，对T2DM小鼠具有理想的治疗效果。

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

Drug Design, Development and Therapy CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

9.00

自引率

0.00%

发文量

382

审稿时长

>12 weeks

期刊介绍： Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications. The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas. Specific topics covered by the journal include: Drug target identification and validation Phenotypic screening and target deconvolution Biochemical analyses of drug targets and their pathways New methods or relevant applications in molecular/drug design and computer-aided drug discovery* Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes) Structural or molecular biological studies elucidating molecular recognition processes Fragment-based drug discovery Pharmaceutical/red biotechnology Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products** Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing) Preclinical development studies Translational animal models Mechanisms of action and signalling pathways Toxicology Gene therapy, cell therapy and immunotherapy Personalized medicine and pharmacogenomics Clinical drug evaluation Patient safety and sustained use of medicines.