Dr. Sabrina Santos Oliveira
Cell Biology, Department of Biology – Hugo R. Kruytgebouw, Z511 (Mon, Wed, Fri)
Pharmaceutics, Department of Pharmaceutical Sciences – David de Wiedgebouw, room 3.86 (Tue, Thu)
Faculty of Science, Utrecht University – Padualaan 8, 3584 CH Utrecht, The Netherlands
Tel: +31 6 34 10 34 60
Sabrina Oliveira was introduced to Utrecht University through an internship at the department of Pharmaceutical Sciences (2004) during her studies at the Faculty of Pharmacy of Coimbra University in Portugal. After graduation, she obtained an individual doctoral grant from the Portuguese Foundation for Science and Technology (FCT) to return to this department to do her PhD research on Targeted Cancer Therapies (2004-2008). She then worked as a postdoc on the development of tracers based on nanobodies for optical molecular imaging, in the group of Cell Biology, department of Biology (2008-2010) and the department of Pathology from the University Medical Center Utrecht (2010-2012). In 2012, she was awarded a VENI grant from the Netherlands Organisation for Research (NWO-STW), giving her the opportunity to start her own research line, which focuses on rendering photodynamic therapy more selective to cancer cells by using nanobodies. In 2016, she has received a Starting Grant from the European Research Council (ERC) to continue her line of research. In July 2016, Sabrina was appointed Assistant Professor, and in May 2019 Associate Professor, with a shared position between the division of Cell Biology, Neurobiology and Biophysics, department of Biology and the division of Pharmaceutics, department of Pharmaceutical Sciences.
The research in the “Molecular Targeted Therapies” group is focused on the development and evaluation of improved therapies that are directed to relevant molecular targets. Understanding the biological role of molecular targets – that are particularly relevant in certain diseases – is essential to design and develop effective targeted therapies. In cancer, for instance, the epidermal growth factor receptor (EGFR) is a recognized target for cancer imaging and therapy. Current therapies (e.g. photodynamic therapy, chemotherapy) can be ameliorated by improving their selectivity to cancer cells using vehicles that guide them to relevant targets on these cells. Targeting moieties or targeted nanoparticles are possibilities of such vehicles. Nanobodies are the targeting moiety employed in this research group and correspond to small antibody fragments derived from heavy chain antibodies that exist in animals from the camelidae family.
Nanobody-targeted photodynamic therapy
One of the main focuses of this small team is on rendering photodynamic therapy (PDT) more selective to cancer cells using nanobodies. PDT is a treatment option which makes use of a laser light (harmless on its own) to locally activate a chemical (i.e. photosensitizer) and produce reactive oxygen species that are toxic to cells. Although PDT is nowadays used in some hospitals to treat cancer, it is not a standard treatment. One of the reasons for this is the limited selectivity of the treatment, which employs hydrophobic photosensitizers that can interact with all cell types. Dr. Oliveira has introduced nanobody-targeted PDT, making use of the small size and great binding specificity of nanobodies to specifically target more hydrophilic photosensitizers to cancer cells and kill these specifically.
Two of the objectives of the current research are: a) to better understand the mechanism of this new therapeutic approach, in particular its effects on, and the involvement of the immune system, and b) to evaluate this approach in larger animals (e.g. dogs that enter the clinic with cancer), to understand the chances of this treatment to be effective also in humans. Overall, rendering PDT more selective to cancers cells could greatly improve its current clinical application and thereby increase therapeutic options for cancer patients.
Take a look at the article on our KILLCANCER project on the 1st issue of the EDMA’s Project Repository Journal (dissemination of European Research Projects).
Nanobodies for imaging and therapy
Nanobodies are very promising tracers, as they can a. distribute very rapidly through tissues, b. be retained at the tumor, and c. be cleared when unbound, thereby allowing tumor detection 1-2 h post injection. Although some characteristic of an ideal tracer (such as rapid distribution and rapid clearance) are not shared with characteristics of an ideal drug (preferably, long tumor retention and long half-life), within Cell Biology and together with Dr. van Bergen en Henegouwen, we have been investigating approaches to more efficiently convert a good tracer into a targeted therapy.
Nanobodies have been employed conjugated to the surface of several types of nanocarriers (liposomes, polymeric nanoparticles, micelles, etc) to promote specific cell uptake and allow the delivery of drugs into the target cells. This research is mostly performed in collaboration with colleagues from the Pharmaceutics group https://www.uu.nl/en/research/pharmaceutics.
Martínez-Jothar L, Beztsinna N, van Nostrum CF, Hennink WE, Oliveira S, Selective Cytotoxicity to HER2 Positive Breast Cancer Cells by Saporin-Loaded Nanobody-Targeted Polymeric Nanoparticles in Combination with Photochemical Internalization. Mol Pharm. 2019 Mar 12. doi: 10.1021/acs.molpharmaceut.8b01318.
Beltrán Hernández I, Rompen R, Rossin R, Xenaki KT, Katrukha EA, Nicolay K, van Bergen En Henegouwen P, Grüll H, Oliveira S. Imaging of Tumor Spheroids, Dual-Isotope SPECT, and Autoradiographic Analysis to Assess the Tumor Uptake and Distribution of Different Nanobodies. Mol Imaging Biol. 2019 Mar 11. doi: 10.1007/s11307-019-01320-x.
Peng W, de Bruijn HS, Farrell E, Sioud M, Mashayekhi V, Oliveira S, van Dam GM, Roodenburg JLN, Witjes MJH, Robinson DJ, Epidermal growth factor receptor (EGFR) density may not be the only determinant for the efficacy of EGFR-targeted photoimmunotherapy in human head and neck cancer cell lines. Lasers Surg Med. 2018 Jul;50(5):513-522.
Martínez-Jothar L, Doulkeridou S, Schiffelers RM, Sastre Torano J, Oliveira S, van Nostrum CF, Hennink WE. Insights into maleimide-thiol conjugation chemistry: Conditions for efficient surface functionalization of nanoparticles for receptor targeting. J Control Release. 2018 Jul 28;282:101-109.
Xenaki KT, Oliveira S, van Bergen En Henegouwen PMP. Antibody or Antibody Fragments: Implications for Molecular Imaging and Targeted Therapy of Solid Tumors. Front Immunol. 2017 Oct 12;8:1287.
van Straten D, Mashayekhi V, de Bruijn HS, Oliveira S, Robinson DJ, Oncologic Photodynamic Therapy: Basic Principles, Current Clinical Status and Future Directions. Cancers (Basel). 2017, 9(2):19
Koch M, de Jong JS, Glatz J, Symvoulidis P, Lamberts LE, Adams AL, Kranendonk ME, Terwisscha van Scheltinga AG, Aichler M, Jansen L, de Vries J, Lub-de Hooge MN, Schröder CP, Jorritsma-Smit A, Linssen MD, de Boer E, van der Vegt B, Nagengast WB, Elias SG, Oliveira S, Witkamp AJ, Mali WP, Van der Wall E, Garcia-Allende PB, van Diest PJ, de Vries EG, Walch A, van Dam GM, Ntziachristos V, Threshold analysis and biodistribution of fluorescently labeled bevacizumab in human breast cancer, Cancer Res. 2017, 77(3):623-631
Lamberts LE, Koch M, de Jong JS, Adams ALL, Glatz J, Kranendonk MEG, Terwisscha van Scheltinga AGT, Jansen L, de Vries J, Lub-de Hooge MN, Schröder CP, Jorritsma-Smit A, Linssen MD, de Boer E, van der Vegt B, Nagengast WB, Elias SG, Oliveira S, Witkamp AJ, Mali WPTM, Van der Wall E, van Diest PJ, de Vries EGE, Ntziachristos V, van Dam GM, Tumor-specific uptake of fluorescent bevacizumab-IRDye800CW microdosing in patients with primary breast cancer: a phase I feasibility study, Clin Cancer Res. 2017, 23(11):2730-2741
van Driel PB, Boonstra MC, Slooter MD, Heukers R, Stammes MA, Snoeks TJA, de Bruijn HS, van Diest PJ, Vahrmeijer AL, van Bergen en Henegouwen PMP, van de Velde CJH, Löwik CWGM, Robinson DJ, Oliveira S (2016): EGFR targeted nanobody-photosensitizer conjugates for photodynamic therapy in a pre-clinical model of head and neck cancer, J Control Release 229, 93-105
Kijanka MM, van Brussel AS, van der Wall E, Mali WP, van Diest PJ, van Bergen En Henegouwen PM, Oliveira S (2016): Optical imaging of pre-invasive breast cancer with a combination of VHHs targeting CAIX and HER2 increases contrast and facilitates tumour characterization, EJNMMI Res. 6(1):14
Broekgaarden M, van Vught R, Oliveira S, Roovers RC, van Bergen En Henegouwen PM, Pieters RJ, Van Gulik TM, Breukink E, Heger M (2016): Site-specific conjugation of single domain antibodies to liposomes enhances photosensitizer uptake and photodynamic therapy efficacy, Nanoscale. 8(12):6490-4
Oliveira S (2015): Considerations on the Advantages of Small Tracers for Optical Molecular Imaging. J Mol Biol & Mol Imaging, 2(2):1016.
van Brussel AS, Adams A, Oliveira S, Dorresteijn B, El Khattabi M, Vermeulen JF, van der Wall E, Mali WP, Derksen PW, van Diest PJ, van Bergen En Henegouwen PM. Hypoxia-Targeting Fluorescent Nanobodies for Optical Molecular Imaging of Pre-Invasive Breast Cancer. Mol Imaging Biol. 2015
van Driel PB, van de Giessen M, Boonstra MC, Snoeks TJ, Keereweer S, Oliveira S, van de Velde CJ, Lelieveldt BP, Vahrmeijer AL, Löwik CW, Dijkstra J (2015): Characterization and evaluation of the artemis camera for fluorescence-guided cancer surgery, Mol Imaging Biol, 17(3):413-23
Kijanka M, Dorresteijn B, Oliveira S, van Bergen en Henegouwen PM (2015): Nanobody-based cancer therapy of solid tumors, Nanomedicine (Lond). 10(1):161-74
Heukers R, van Bergen En Henegouwen PM, Oliveira S (2014): Nanobody-photosensitizer conjugates for targeted photodynamic therapy, Nanomedicine, 10(7):1441-51
van Driel PB, van der Vorst JR, Verbeek FP, Oliveira S, Snoeks TJ, Keereweer S, Chan B, Boonstra MC, Frangioni JV, van Bergen en Henegouwen PM, Vahrmeijer AL, Lowik CW (2014): Intraoperative fluorescence delineation of head and neck cancer with a fluorescent anti-epidermal growth factor receptor nanobody, Int J Cancer, 134(11):2663-73
Haselberg R, Oliveira S, van der Meel R, Somsen GW, de Jong GJ. (2014): Capillary electrophoresis-based assessment of nanobody affinity and purity, Anal Chim Acta, 818:1-6
Oliveira S, Heukers R, Sornkom J, Kok RJ, van Bergen En Henegouwen PM (2013): Targeting tumors with nanobodies for cancer imaging and therapy, J Control Release, 172(3):607-17
Kijanka M, Warnders FJ, El Khattabi M, Lub-de Hooge M, van Dam GM, Ntziachristos V, de Vries L, Oliveira S, van Bergen En Henegouwen PM (2013): Rapid optical imaging of human breast tumour xenografts using anti-HER2 VHHs site-directly conjugated to IRDye 800CW for image-guided surgery, EJNMMI, 40(11):1718-29
Talelli M, Oliveira S, Rijcken CJ, Pieters EH, Etrych T, Ulbrich K, van Nostrum RC, Storm G, Hennink WE, Lammers T (2013): Intrinsically active nanobody-modified polymeric micelles for tumor-targeted combination therapy, Biomaterials, 34(4):1255-60
van der Meel R, Oliveira S, Altintas I, Heukers R, Pieters EH, van Bergen en Henegouwen PM, Storm G, Hennink WE, Kok RJ, Schiffelers RM (2013) Inhibition of tumor growth by targeted anti-EGFR/IGF-1R nanobullets depends on efficient blocking of cell survival pathways, Mol Pharm, 10(10):3717-27
van Brussel AS, Adams A, Vermeulen JF, Oliveira S, van der Wall E, Mali WP, van Diest PJ, van Bergen En Henegouwen PM (2013): Molecular imaging with a fluorescent antibody targeting carbonic anhydrase IX can successfully detect hypoxic ductal carcinoma in situ of the breast, Breast Cancer Res Treat. 140(2):263-72
Oliveira S, Cohen R, Walsum MS, van Dongen GA, Elias SG, van Diest PJ, Mali W, van Bergen En Henegouwen PM (2012): A novel method to quantify IRDye800CW fluorescent antibody probes ex vivo in tissue distribution studies, EJNMMI Res, 2(1):50
Oliveira S, van Dongen GAMS, Stigter-van Walsum M, Roovers RC, Stam JC, Mali W, van Diest PJ, van Bergen en Henegouwen PMP (2012): Rapid visualization of human tumor xenografts through optical imaging with a near-infrared fluorescent anti-EGFR nanobody, Molecular Imaging, 11(1):33-46
van der Meel R, Oliveira S, Altintas I, Haselberg R, van der Veeken J, Roovers RC, van Bergen en Henegouwen PM, Storm G, Hennink WE, Schiffelers RM, Kok RJ (2012): Tumor-targeted Nanobullets: Anti-EGFR nanobody-liposomes loaded with anti-IGF-1R kinase inhibitor for cancer treatment, J Control Release. 159(2):281-9
Talelli M, Rijcken CJF, Oliveira S, van der Meel R, van Bergen en Henegouwen PM, van Nostrum CF, Lammers T, Storm G, Hennink WE (2011): Nanobody-shell functionalized thermosensitive core-crosslinked polymeric micelles for active drug targeting, J Control Release, 153(1):93-102
Oliveira S, Schiffelers RM, van der Veeken J, van der Meel R, Vongpromek R, van Bergen En Henegouwen PM, Storm G, Roovers RC (2010): Downregulation of EGFR by a novel multivalent nanobody-liposome platform, Journal of Controlled Release, 145(2):165-75
van der Meel R, Gallagher WM, Oliveira S, O’Connor AE, Schiffelers RM, Byrne AT (2010): Recent advances in molecular imaging biomarkers in cancer: application of bench to bedside technologies, Drug Discovery Today, 15(3-4):102-14
van der Veeken J, Oliveira S, Schiffelers RM, Storm G, van Bergen En Henegouwen PM, Roovers RC (2009): Crosstalk between epidermal growth factor receptor- and insulin-like growth factor-1 receptor signaling: implications for cancer therapy, Current Cancer Drug Targets, 9(6):748-60
Oliveira S, Høgset A, Storm G, Schiffelers RM (2008): Delivery of siRNA to the target cell cytoplasm: photochemical internalization facilitates endosomal escape and improves silencing efficiency, in vitro and in vivo, Current Pharmaceutical Design, 14(34):3686-97
Oliveira S, Fretz MM, Høgset A, Storm G, Schiffelers RM (2007): Photochemical internalization enhances silencing of epidermal growth factor receptor through improved endosomal escape of siRNA, Biochimica et Biophysica Acta 1768: 1211-1217
Oliveira S, van Rooy I, Kranenburg O, Storm G, Schiffelers RM (2007): Fusogenic peptides enhance endosomal escape improving siRNA-induced silencing of oncogenes, International Journal of Pharmaceutics, 331: 211-214
Sutter M, Oliveira S, Sanders NN, Lucas B, van Hoek A, Hink MA, Visser AJ, De Smedt SC, Hennink WE, Jiskoot W (2007): Sensitive spectroscopic detection of large and denatured protein aggregates in solution by use of a fluorescent dye Nile red, Journal of Fluorescence 17: 181-192
Oliveira S, Storm G, Schiffelers RM (2006): Targeted Delivery of siRNA, Journal of Biomedicine and Biotechnology 2006: 1-9
Oliveira S, van Bergen en Henegouwen PM, Storm G, Schiffelers RM (2006): Molecular biology of epidermal growth factor receptor inhibition for cancer therapy, Expert Opinion on Biological Therapy 6: 605-617