Abstract 2161: Development of radiolabelled drug carrier systems for molecularly targeted radiotherapy
Authors: Menon Jyothi U. , Owen Joshua , Carlisle Robert , Vallis Katherine A. 
Published: July 2016

Abstract
Introduction
Tagging of radioisotopes to targeting moieties such as peptides, antibodies and nucleotides aids in more precise delivery of these isotopes to cancer cells for treatment. However some of the obstacles to successful delivery of these radiolabelled molecules include poor circulation half-life and inefficient tumour extravasation and penetration. Liposomal drug carrier systems have extended circulation profiles but would benefit from enhanced binding and entry into target cancer cells. To address some of these challenges, liposomes encapsulating a chemotherapeutic agent (doxorubicin) and tagged with radiolabelled targeting moieties were designed, formulated and then tested for specific binding to and killing of cancer cell lines.
Experimental Procedures
Distearoylphosphatidylethanolamine-poly ethylene glycol (DSPE-PEG) based liposomes were developed and surface modified with epidermal growth factor-diethylenetriamine pentaacetate (EGF-DTPA) followed by 111In radiolabelling. The EGF-tagged liposomes were characterised using zetasizer and transmission electron microscopy (TEM). Direct particle cytotoxicity was assessed using the MTT assay and uptake kinetics was determined by treating EGF+ve MDA-MB-468 (1.3 × 10⁁6 EGFR/cell) and EGFR-ve MCF7 cells (1.5 × 10⁁4 EGFR/cell) with Nile red-containing liposomes and quantifying Nile red fluorescence in the cell lysates. Payload delivery capabilities were studied by exposing EGFR+ve luciferase-expressing MDA-MB-231 or EGFR-ve luciferase expressing MCF7 breast cancer cells to EGF-tagged or non-tagged particles containing the model drug luciferin. Therapeutic efficacy of Doxorubicin-containing EGF-tagged liposomes to MDA-MB-468 and MCF7 cells was then assessed by the MTT assay.
Results
The particles were spherical in morphology with a diameter of 140-160 nm. More than 95% of the 111In added was tagged to the particles. The liposomes did not show intrinsic cytotoxicity and were taken up by cells in a dose-dependent manner with greater uptake observed in MDA-MB-468 than in MCF7s. Greater delivery (2-fold increase, p&lt;0.05) of EGF-tagged luciferin-containing particles was observed in MDA-MB-231 cells than in MCF7 cells, this was not the case for non-tagged particles. EGF-tagged particles also gave better delivery (3.5-fold increase, p&lt;0.05) than non-tagged particles in MDA-MB-231 cells, this was not the case in MCF7 cells. Doxorubicin-loaded EGF-tagged liposomes had an IC50 of 0.02 mg/ml with MDA-MB-468 and 0.04 mg/ml with MCF7s.
Conclusions
This work, using 111In- and EGF-tagged liposomes has shown promising in vitro targeted cellular uptake and drug delivery. Receptor binding kinetics and the feasibility of using these systems in vivo for ultrasound-assisted radiopharmaceutical delivery will follow.
Citation Format: Jyothi U. Menon, Joshua Owen, Robert Carlisle, Katherine A. Vallis. Development of radiolabelled drug carrier systems for molecularly targeted radiotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2161.