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Open AccessArticle

Rapid Target Binding and Cargo Release of Activatable Liposomes Bearing HER2 and FAP Single-Chain Antibody Fragments Reveal Potentials for Image-Guided Delivery to Tumors

1
Department of Experimental Radiology, Institute of Diagnostic and Interventional Radiology, Jena University Hospital, Friedrich Schiller University Jena, Am Klinikum 1, 07747 Jena, Germany
2
Department of Pharmaceutical Technology, Friedrich-Schiller-University Jena, Lessingstrasse 8, 07743 Jena, Germany
3
Center for Electron Microscopy, Jena University Hospital, Friedrich Schiller University Jena, Ziegelmuehlenweg 1, 07743 Jena, Germany
4
Center for Sepsis Control and Care, Institute of Biochemistry II, Jena University Hospital, Friedrich Schiller University Jena, Am Klinikum 1, 07747 Jena, Germany
5
Institute of Cell Biology and Immunology, University Stuttgart, Allmandring 31, 70569 Stuttgart, Germany
*
Authors to whom correspondence should be addressed.
Pharmaceutics 2020, 12(10), 972; https://doi.org/10.3390/pharmaceutics12100972
Received: 25 September 2020 / Revised: 12 October 2020 / Accepted: 13 October 2020 / Published: 15 October 2020
(This article belongs to the Special Issue Nanopharmaceuticals for Image-Guided Cancer Therapy and Diagnosis)
Liposomes represent suitable tools for the diagnosis and treatment of a variety of diseases, including cancers. To study the role of the human epidermal growth factor receptor 2 (HER2) as target in cancer imaging and image-guided deliveries, liposomes were encapsulated with an intrinsically quenched concentration of a near-infrared fluorescent dye in their aqueous interior. This resulted in quenched liposomes (termed LipQ), that were fluorescent exclusively upon degradation, dye release, and activation. The liposomes carried an always-on green fluorescent phospholipid in the lipid layer to enable tracking of intact liposomes. Additionally, they were functionalized with single-chain antibody fragments directed to fibroblast activation protein (FAP), a marker of stromal fibroblasts of most epithelial cancers, and to HER2, whose overexpression in 20–30% of all breast cancers and many other cancer types is associated with a poor treatment outcome and relapse. We show that both monospecific (HER2-IL) and bispecific (Bi-FAP/HER2-IL) formulations are quenched and undergo HER2-dependent rapid uptake and cargo release in cultured target cells and tumor models in mice. Thereby, tumor fluorescence was retained in whole-body NIRF imaging for 32–48 h post-injection. Opposed to cell culture studies, Bi-FAP/HER2-IL-based live confocal microscopy of a high HER2-expressing tumor revealed nuclear delivery of the encapsulated dye. Thus, the liposomes have potentials for image-guided nuclear delivery of therapeutics, and also for intraoperative delineation of tumors, metastasis, and tumor margins. View Full-Text
Keywords: liposomes; fluorescence quenching; optical imaging; molecular targeting; HER2; tumor microenvironment; tumor heterogeneity liposomes; fluorescence quenching; optical imaging; molecular targeting; HER2; tumor microenvironment; tumor heterogeneity
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Tansi, F.L.; Rüger, R.; Böhm, C.; Steiniger, F.; Raasch, M.; Mosig, A.S.; Kontermann, R.E.; Teichgräber, U.K.; Fahr, A.; Hilger, I. Rapid Target Binding and Cargo Release of Activatable Liposomes Bearing HER2 and FAP Single-Chain Antibody Fragments Reveal Potentials for Image-Guided Delivery to Tumors. Pharmaceutics 2020, 12, 972.

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