Application of polymersomes engineered to target p32 protein for detection of small breast tumors in mice
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Lorena Simón-Gracia1, Pablo Scodeller1, Sergio Salazar Fuentes2, Vanessa Gómez Vallejo3, Xabier Ríos3, Eneko San Sebastián3, Valeria Sidorenko1, Desirè Di Silvio4, Meina Suck5,6, Federica De Lorenzi5, Larissa Yokota Rizzo5, Saskia von Stillfried5, Kalle Kilk7, Twan Lammers5,6, Sergio E. Moya4 and Tambet Teesalu1,8,9
1Laboratory of Cancer Biology, Institute of Biomedicine and Translational Medicine, University of Tartu, 50411 Tartu, Estonia
2Animal Unit, CIC Biomagune, 20009 Donostia, Spain
3Laboratory of Radiochemistry, CIC Biomagune, 20009 Donostia, Spain
4Soft Matter Laboratoy, CIC Biomagune, 20009 Donostia, Spain
5Institute for Experimental Molecular Imaging, RWTH Aachen University Clinic, 52074 Aachen, Germany
6Department of Targeted Therapeutics, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, 7500 AE Enschede, The Netherlands
7Department of Biochemistry, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, 50411, Estonia
8Cancer Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92097, USA
9Center for Nanomedicine, University of California Santa Barbara, Santa Barbara, California 93106, USA
Tambet Teesalu, email: firstname.lastname@example.org
Sergio E. Moya, email: email@example.com
Lorena Simón-Gracia, email: Lorena.Simon.Gracia@ut.ee
Keywords: PET; tumor-penetrating peptide; polymersomes; triple negative breast cancer; p32
Received: November 22, 2017 Accepted: February 10, 2018 Published: April 10, 2018
Triple negative breast cancer (TNBC) is the deadliest form of breast cancer and its successful treatment critically depends on early diagnosis and therapy. The multi-compartment protein p32 is overexpressed and present at cell surfaces in a variety of tumors, including TNBC, specifically in the malignant cells and endothelial cells, and in macrophages localized in hypoxic areas of the tumor. Herein we used polyethylene glycol-polycaprolactone polymersomes that were affinity targeted with the p32-binding tumor penetrating peptide LinTT1 (AKRGARSTA) for imaging of TNBC lesions. A tyrosine residue was added to the peptide to allow for 124I labeling and PET imaging. In a TNBC model in mice, systemic LinTT1-targeted polymersomes accumulated in early tumor lesions more than twice as efficiently as untargeted polymersomes with up to 20% ID/cc at 24 h after administration. The PET-imaging was very sensitive, allowing detection of tumors as small as ~20 mm3. Confocal imaging of tumor tissue sections revealed a high degree of vascular exit and stromal penetration of LinTT1-targeted polymersomes and co-localization with tumor-associated macrophages. Our studies show that systemic LinTT1-targeted polymersomes can be potentially used for precision-guided tumor imaging and treatment of TNBC.
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