Application of polymersomes engineered to target p32 protein for detection of small breast tumors in mice.

Lorena Simón-Gracia,Twan Lammers,Valeria Sidorenko,Xabier Ríos,Larissa Yokota Rizzo,Sergio E Moya,Tambet Teesalu,Sergio Salazar Fuentes,Meina Suck,Pablo Scodeller,Saskia Von Stillfried,Eneko San Sebastián,Desirè Di Silvio,Vanessa Gómez Vallejo,Federica De Lorenzi,Kalle Kilk

doi:10.18632/oncotarget.24588

Abstract

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.

Highlights

Triple negative breast cancer (TNBC) is defined by the lack of expression of estrogen receptor, progesterone receptor, and human epidermal growth factor 2
Our studies show that systemic LinTT1-targeted polymersomes can be potentially used for precision-guided tumor imaging and treatment of TNBC
The number of polymersomes was determined by the ZetaView instrument www.oncotarget.com and the functionalization with FAM-labeled peptide was quantified by fluorimetry

Summary

Introduction

TNBC is defined by the lack of expression of estrogen receptor, progesterone receptor, and human epidermal growth factor 2. Cancer diagnosis and treatment can be combined into one modality by dual-use “theranostic” nanocarriers engineered to simultaneously deliver therapeutic and imaging cargoes [6, 7] Imaging payloads, such as fluorescent, MRI, and radio tags can be loaded in the nanosystems or coated on their surface. The high molecular weight of block copolymers results in the formation of highly entangled membranes displaying a high degree of resilience with elastomer-like mechanical properties. This confers the polymersomes a higher flexibility [8, 9] and higher ability for tissue penetration than other vesicles self-assembled from low molecular weight entities, such as liposomes [10]. Polymersomes can be loaded with hydrophilic effector molecules, e.g. low molecular weight drugs [11, 12], proteins [13], nucleic acids [14], and imaging agents [15, 16], in their aqueous lumen and with hydrophobic cargoes within the polymer membrane [11, 17]

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Results

Conclusion