The effect of subcellular localization on the efficiency of EGFR-targeted VHH photosensitizer conjugates
Tiedosto(t)
Rinnakkaistallenteen versio
published versionPäivämäärä
2018Tekijä(t)
Yksilöllinen tunniste
10.1016/j.ejpb.2017.12.009Metadata
Näytä kaikki kuvailutiedotLisätietoa
Rinnakkaistallenne
Viittaus
van Lith SAM. van den Brand D. Wallbrecher R. Wübbeke L. van Duijnhoven SMJ. Mäkinen PI. Hoogstad-van Evert JS. Massuger L. Ylä-Herttuala S. Brock R. Leenders WPJ. (2018). The effect of subcellular localization on the efficiency of EGFR-targeted VHH photosensitizer conjugates. EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, 124, 63-72. 10.1016/j.ejpb.2017.12.009.Oikeudet
Tiivistelmä
Photodynamic therapy (PDT) is an emerging method to treat light-accessible malignancies. To increase specificity and allow dose reduction, conjugates of photosensitizers (PS) with antibodies against tumor-associated antigens have been developed for photoimmunotherapy (PIT). However, so far it is unclear whether cellular internalization of these conjugates after binding affects PIT efficacy.
The use of low molecular weight llama single domain antibodies (VHHs, nanobodies) for PIT is preferred above full size antibodies because of better tumor penetration. Therefore, we functionalized the VHH 7D12, directed against the epidermal growth factor receptor (EGFR), with a PS (IRDye700DX). To assess the impact of cellular internalization on activity, the VHHs were additionally conjugated to a cell-penetrating peptide (VHH[PS]-CPP).
Here we show that upon illumination with near-infrared (NIR) light, both VHH[PS] and VHH[PS]-CPP conjugates specifically induce cell death of EGFR expressing cancer cell lines and of EGFR-expressing cells derived from surgically obtained ascites from patients with high-grade serous ovarian cancer. However, VHH[PS] conjugates were significantly more effective compared to internalizing VHH[PS]-CPP suggesting that cell surface association is required for optimal therapeutic activity.
Avainsanat
Linkki alkuperäiseen julkaisuun
http://dx.doi.org/10.1016/j.ejpb.2017.12.009Julkaisija
Elsevier BVKokoelmat
- Terveystieteiden tiedekunta [1735]