期刊
PHARMACEUTICAL RESEARCH
卷 39, 期 7, 页码 1509-1521出版社
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s11095-022-03282-2
关键词
affibody; transferrin receptor; transferrin receptor mediated transcytosis (RMT); protein brain delivery
资金
- Uppsala University
- Swedish Research Council [2017-02413, 2018-02715, 2021-01083, 2021-03524]
- Alzheimerfonden
- Hjarnfonden
- Torsten Soderbergs stiftelse
- Ahlenstiftelsen
- Stiftelsen for gamla tjanarinnor
- Stohnes stiftelse
- Magnus Bergvalls stiftelse
- Konung Gustaf V:s och Drottning Victorias frimuarestiftelse
- Innovative Medicines Initiative 2 (IMI2) Joint Undertaking [807015]
- Swedish Research Council [2021-01083, 2021-03524] Funding Source: Swedish Research Council
Affibodies targeting amyloid-beta (A beta) show potential as therapeutic and diagnostic agents in Alzheimer's disease. Fusion of Affibodies with the blood-brain barrier shuttle scFv8D3 improves brain delivery and retention. However, the specificity of affibodies for A beta deposits needs further confirmation.
Affibodies targeting amyloid-beta (A beta) could potentially be used as therapeutic and diagnostic agents in Alzheimer's disease (AD). Affibodies display suitable characteristics for imaging applications such as high stability and a short biological half-life. The aim of this study was to explore brain delivery and retention of A beta protofibril-targeted affibodies in wild-type (WT) and AD transgenic mice and to evaluate their potential as imaging agents. Two affibodies, Z5 and Z1, were fused with the blood-brain barrier (BBB) shuttle single-chain variable fragment scFv8D3. In vitro binding of I-125-labeled affibodies with and without scFv8D3 was evaluated by ELISA and autoradiography. Brain uptake and retention of the affibodies at 2 h and 24 h post injection was studied ex vivo in WT and transgenic (tg-Swe and tg-ArcSwe) mice. At 2 h post injection, [I-125]I-Z5 and [I-125]I-Z1 displayed brain concentrations of 0.37 +/- 0.09% and 0.46 +/- 0.08% ID/g brain, respectively. [I-125]I-scFv8D3-Z5 and [I-125]I-scFv8D3-Z1 showed increased brain concentrations of 0.53 +/- 0.16% and 1.20 +/- 0.35%ID/g brain. At 24 h post injection, brain retention of [I-125]I-Z1 and [I-125]I-Z5 was low, while [I-125]I-scFv8D3-Z1 and [I-125]I-scFv8D3-Z5 showed moderate brain retention, with a tendency towards higher retention of [I-125]I-scFv8D3-Z5 in AD transgenic mice. Nuclear track emulsion autoradiography showed greater parenchymal distribution of [I-125]I-scFv8D3-Z5 and [I-125]I-scFv8D3-Z1 compared with the affibodies without scFv8D3, but could not confirm specific affibody accumulation around A beta deposits. Affibody-scFv8D3 fusions displayed increased brain and parenchymal delivery compared with the non-fused affibodies. However, fast brain washout and a suboptimal balance between A beta and mTfR1 affinity resulted in low intrabrain retention around A beta deposits.
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