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Affibody-Derived Dr...
Affibody-Derived Drug Conjugates Targeting HER2 : Effect of Drug Load on Cytotoxicity and Biodistribution
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- Ding, Haozhong (författare)
- KTH,Proteinvetenskap,KTH Royal Inst Technol, Dept Prot Sci, Roslagstullsbacken 21, S-11417 Stockholm, Sweden
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- Xu, Tianqi (författare)
- Uppsala universitet,Medicinsk strålningsvetenskap
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- Zhang, Jie (författare)
- KTH,Proteinvetenskap,KTH Royal Inst Technol, Dept Prot Sci, Roslagstullsbacken 21, S-11417 Stockholm, Sweden
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- Tolmachev, Vladimir (författare)
- Uppsala universitet,Medicinsk strålningsvetenskap,Tomsk Polytech Univ, Res Sch Chem & Appl Biomed Sci, Res Ctr Oncotheranost, Tomsk 634050, Russia
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- Oroujeni, Maryam, PhD, 1982- (författare)
- Uppsala universitet,Medicinsk strålningsvetenskap
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- Orlova, Anna (författare)
- Uppsala universitet,Theranostics,Tomsk Polytech Univ, Res Sch Chem & Appl Biomed Sci, Res Ctr Oncotheranost, Tomsk 634050, Russia
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- Gräslund, Torbjörn (författare)
- KTH,Proteinvetenskap,KTH Royal Inst Technol, Dept Prot Sci, Roslagstullsbacken 21, S-11417 Stockholm, Sweden
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- Vorobyeva, Anzhelika (författare)
- Uppsala universitet,Medicinsk strålningsvetenskap,Tomsk Polytech Univ, Res Sch Chem & Appl Biomed Sci, Res Ctr Oncotheranost, Tomsk 634050, Russia
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(creator_code:org_t)
- 2021-03-23
- 2021
- Engelska.
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Ingår i: Pharmaceutics. - : MDPI AG. - 1999-4923. ; 13:3
- Relaterad länk:
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https://doi.org/10.3...
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https://www.mdpi.com...
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https://uu.diva-port... (primary) (Raw object)
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https://urn.kb.se/re...
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https://doi.org/10.3...
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https://urn.kb.se/re...
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Abstract
Ämnesord
Stäng
- Affibody molecules hold great promise as carriers of cytotoxic drugs for cancer therapy due to their typically high affinity, easy production, and inherent control of the drug molecules' loading and spatial arrangement. Here, the impact of increasing the drug load from one to three on the properties of an affibody drug conjugate targeting the human epidermal growth factor receptor 2 (HER2) was investigated. The affibody carrier was recombinantly expressed as a fusion to an albumin-binding domain (ABD) for plasma half-life extension. One or three cysteine amino acids were placed at the C-terminus to which cytotoxic mcDM1 molecules were conjugated. The resulting drug conjugates, Z(HER2)-ABD-mcDM1 and Z(HER2)-ABD-mcDM1(3), were characterized in vitro, and their biodistribution in mice carrying HER2-overexpressing SKOV3 xenografts was determined. Increasing the drug load from one to three led to a decrease in affinity for HER2, but a significantly more potent cytotoxic effect on SKOV3 cells with high HER2 expression. The difference in cytotoxic effect on other cell lines with high HER2 expression was not significant. In vivo, an increase in drug load led to a 1.45-fold higher amount of cytotoxic mcDM1 delivered to the tumors. The increase in drug load also led to more rapid hepatic clearance, warranting further optimization of the molecular design.
Ämnesord
- NATURVETENSKAP -- Biologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
Nyckelord
- affibody molecule
- human epidermal growth factor receptor 2
- HER2
- emtansine
- DM1
- albumin binding domain
- DAR
- affibody drug conjugate
- AffiDC
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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