In vitro evaluation and biodistribution of HER2-targeted liposomes loaded with an ¹²⁵I-labelled DNA-intercalator

Abstract

Background: Increasing attention is currently focussed on the issue of finding strategies for the delivery of Auger-electron-emitting radionuclides into tumor cell nuclei.

Purpose: In this study, we investigated tumor-cell uptake and cell-killing ability in vitro as well as in vivo biodistribution of an ¹²⁵I-labelled anthracycline derivative administered by means of HER2-targeted liposomes.

Methods: Anthracycline derivative Comp1 was radiolabelled with Auger-emitting ¹²⁵I and encapsulated in liposomes (DSPC:Chol:DSPE-PEG) using pH-gradient loading. Single-chain fragment F5 was anchored to the liposomes as targeting device for HER2. Uptake and specificity of ¹²⁵I-Comp1 delivered via targeting and non-targeting liposomes were analysed in cultured HER2-overexpressing cells. Cell-killing efficacy was evaluated in SKOV3 cells and biodistribution for up to 48 h was studied after intraperitoneal injection in tumor-bearing female BALB/c nu/nu mice.

Results: ¹²⁵I-Comp1 was specifically taken up by the cultured cells when administered by means of HER2-targeted liposomes and a clear dose-effect correlation in survival of cells was seen with increasing specific activity. The biodistribution studies revealed that ¹²⁵I-Comp1 accumulated in tumors when distributed using HER2-targeted liposomes and that this effect was absent when using non-targeting liposomes.

Conclusion: The HER2-targeted liposomes possess the properties needed to bring about tumor-specific delivery and therapeutic effect of ¹²⁵I-Comp1.

Keywords::

• HER2
• liposome
• intercalator
• Auger
• tumor-targeting

Acknowledgments

The authors thank Prof. Jörgen Carlsson, Prof. Stefan Sjöberg, Qichun Wei and Jacob Spross, Uppsala University, for their contribution to the project. The authors further thank Dr Jörgen Elgqvist at Sahlgrenska Academy, Göteborg University for introduction to the animal model, Veronika Asplund for technical assistance with animals and Jonny Eriksson for technical assistance with Cryo-TEM.

Declaration of interest

Funding was provided by the Swedish Cancer Society, the Swedish Research Council and Stiftelsen Olle Engkvist Byggmästare.