Nanotheranostics 2020; 4(3):142-155. doi:10.7150/ntno.44562

Research Paper

Preclinical evaluation of cationic DOTA-triarginine-lipid conjugates for theranostic liquid brachytherapy

Wenbo Wang1,4, Frederikke P. Fliedner2, Anders E. Hansen1,2,4, Rasmus Eliasen1,4, Fredrik Melander1,4, Andreas Kjaer2, Thomas L. Andresen1,4, Andreas I. Jensen3,4✉, Jonas R. Henriksen1,4✉

1. Department of Health Technology, Technical University of Denmark, Produktionstorvet Building 423, DK 2800 Lyngby, Denmark
2. Rigshospitalet and University of Copenhagen, Dept. of Clinical Physiology, Nuclear Medicine & PET, Cluster for Molecular Imaging, 2100 Copenhagen, Denmark
3. The Hevesy Laboratory, Department of Health Technology, Technical University of Denmark, Frederiksborgvej 399, DK, 4000 Roskilde, Denmark
4. Center for Nanomedicine and Theranostics, Technical University of Denmark, 2800 Lyngby, Denmark

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Citation:
Wang W, Fliedner FP, Hansen AE, Eliasen R, Melander F, Kjaer A, Andresen TL, Jensen AI, Henriksen JR. Preclinical evaluation of cationic DOTA-triarginine-lipid conjugates for theranostic liquid brachytherapy. Nanotheranostics 2020; 4(3):142-155. doi:10.7150/ntno.44562. Available from http://www.ntno.org/v04p0142.htm

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Abstract

Liquid brachytherapy is an emerging technology for internal radiation therapy where liquids containing radionuclides are administered directly into solid tumors. These technologies are less invasive than conventional brachytherapy, and can potentially improve the dose coverage and homogeneity of the radioactivity distribution within the tumor. For this purpose, we have developed a novel cationic micelle system for delivery of a range of radionuclides. The system is applicable for emitters of alpha, beta or photon radiation, and enables dose-mapping via theranostic nuclear imaging.

Methods: The cationic micelles were developed as linear surfactants comprising the chelator DOTA, a triarginine sequence and a palmitoyl or stearoyl fatty acid chain. The critical micelle concentration of the surfactants was determined, and the micelles were radiolabelled with 64Cu or 177Lu in high radiochemical purity (>95%). The tumor retention and biodistribution of the 64Cu-radiolabeled surfactants, administered as micelles or formulated in liposomes, were investigated in vivo by PET/CT in a tumor bearing mouse model.

Results: The interaction of the micelles with anionic lipid membranes was demonstrated to be favourable, using a liposome partition assay. In vivo, the surfactants formulated both as cationic micelles and liposomes displayed the best intratumoral retention, with micelles providing more homogeneous activity distribution.

Conclusion: A cationic, surfactant-based drug delivery system was developed and demonstrated promise as a vehicle for liquid brachytherapy when formulated as micelles or in liposomes. The system enables accurate dosimetry due to the flexible radiochemistry of DOTA.

Keywords: brachytherapy, radiotherapy, cancer, intratumoral, micelles