Abstract
This study proposes liposomes as a new tool for pretargeted radioimmunotherapy (RIT) in solid tumors. Tumor pretargeting is obtained by using a bispecific monoclonal antibody [BsmAb, anti-CEA × anti-DTPA-indium complex (DTPA-In)] and pegylated radioactive liposomes containing a lipid-hapten conjugate (DSPE-PEG-DTPA-In). In this work, the immunospecificity of tumor targeting is demonstrated both in vitro by fluorescence microscopy and in vivo by biodistribution studies. Carcinoembryonic antigen (CEA)-expressing cells (LS174T) were used either in cell culture or as xenografts in nude mice. Doubly fluorescent liposomes or doubly radiolabeled liposomes were, respectively, used for in vitro and in vivo studies. In each case, a tracer of the lipid bilayer [rhodamine or indium-111 ((111)In)] and a tracer of the aqueous phase [fluorescein or iodine-125 ((125)I)] were present. The targeting of liposomes was assessed with BsmAb for active targeting or without for passive targeting. Data obtained with the lipid bilayer tracer showed a fluorescent signal on cell membranes two to three times higher for active than for passive targeting. This immunospecificity was confirmed in vivo with tumor uptake of 7.5 ± 2.4% ID/g (percentage of injected dose per gram of tissue) for active targeting versus 4.5 ± 0.45% ID/g for passive targeting (p = 0.03). Regarding the aqueous phase tracer, results are slightly more contrasted. In vitro, the fluorescent tracer seems to be released in the extracellular matrix, which can be correlated with the in vivo data. Indeed, the tumor uptake of (125)I is lower than that of (111)In: 5.1 ± 2.5% ID/g for active targeting and 2.7 ± 0.6% ID/g for passive targeting, but resulted in more favorable tumor/organs ratios. This work demonstrated the tumor targeting immunospecificity of DSPE-PEG-DTPA-In liposomes by two different methods. This original and new approach suggests the potential of immunospecific targeting liposomes for the RIT of solid tumors.
Highlights
The main purpose of radioimmunotherapy (RIT) is to kill cancer cells by immunospecific targeting radionuclides to specific antigens expressed at their surface
One of the pretargeting approaches is the affinity enhancement system (AES), which is based on bispecific monoclonal antibodies (BsmAb) and radiolabeled bivalent haptens [5]
Once the radiolabeling technique was finalized and the best formulation was selected by Surface plasmon resonance (SPR) [11], we were able to test these liposomes on a cellular model, using carcinoembryonic antigen (CEA)-expressing LS174T cells, in order to characterize the specific interactions between liposomes and target cells
Summary
The main purpose of radioimmunotherapy (RIT) is to kill cancer cells by immunospecific targeting radionuclides to specific antigens expressed at their surface. One of the pretargeting approaches is the affinity enhancement system (AES), which is based on bispecific monoclonal antibodies (BsmAb) and radiolabeled bivalent haptens [5] This approach has been extensively tested in the clinic and has shown an increase of overall survival of patients with progressive metastatic Medullary Thyroid Carcinoma, which provided the first evidence of survival improvement by RIT in solid tumors [6, 7]. The specific activity of developed haptens labeled with available radionuclides does not exceed 100–150 MBq/nmol and even less for radionuclides with a long half-life, which limits the activity delivered to tumor cells In this context, liposomes, which up to now have been especially developed for drug targeting, can represent a new and original method of radiotherapy of cancers. The development of imaging applications with radioactive liposomes is widely described [9, 10], but their advantages for carrying therapeutic radionuclides for cancer therapy could be further exploited
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