Design and Synthesis of Mono- and Multimeric Targeted Radiopharmaceuticals Based on Novel Cyclen Ligands Coupled to Anti-MUC1 Aptamers for the Diagnostic Imaging and Targeted Radiotherapy of Cancer

Abstract

Targeted radiopharmaceuticals offer the possibility of improved tumor imaging and radiotherapy, with reduced side effects. A variety of monoclonal antibodies and antibody fragments have previously been successfully radiolabeled and used in diagnostic imaging and targeted radiotherapy of cancer. Many such antibodies have been shown to recognize the well-characterized MUC1 tumor marker and have recently been in clinical trials. Furthermore, a number of chelators have been synthesized and are currently used as radiopharmaceuticals for imaging and therapy. We now report the synthesis of a novel, cyclen-based ligand with a sulfur-containing arm that offers increased stability of the ligand-metal complex. We have coupled this ligand with previously selected aptamers to the MUC1 tumor marker to generate a novel targeted radiopharmaceutical with improved properties. We have tested the complex against known, commercially available chelators such as MAG3 in model breast cancer systems. To improve the pharmacokinetic properties of the aptamer-based targeted radiopharmaceutical, we have generated multi-aptamer complexes around a central chelator. Such multi-aptamer complexes have increased retention of the complex in circulation, without affecting the lack of immunogenicity of the complex or altering its superior tumor penetration properties.

Clinical applications of nucleic acid aptamers in cancer

“…In addition, Muc1 is an attractive target, as its overexpression has been associated with various types of cancer and its distribution pattern changes on the cell surface (82,83). DNA aptamers directed against Muc1 (AptA and AptB) were identified in 2006 (84) and have since been implemented in ex vivo imaging and radiotherapy (85). In subsequent studies, when such an DNA aptamer was coupled to the light-activated photodynamic therapy agent chlorine e6, it specifically delivered chlorine e6 into epithelial cancer cells, with a significant enhancement in efficiency (>500-fold increase) compared to that of the drug alone, and achieved cancer-specific cytotoxicity (86).…”

Aptamer-based therapeutics and their potential in radiopharmaceutical design

“…The tumor-to-blood ratio was > 50 three hours post injection, and > 180 after 16 h, while the control antibody required 40 h for a T/B ratio of 5. An anti-MUC1 aptamer was labeled with technetium complexed with four different bifunctional chelators bearing carboxylic acid bioconjugatable functionalities (Borbas et al, 2007). The complexes were formed by reduction of the pertechnetate with sodium borohydride, followed by treatment with a solution of the chelator.…”

Anti-MUC1 aptamers: radiolabelling with 99mTc and biodistribution in MCF-7 tumour-bearing mice

“…Aptamers offer low immunogeniciy, good tumour penetration, rapid uptake and fast systemic clearance, which favour their application as effective vehicles for cytotoxic agents or 4 radioisotopes [15][16][17][18]. To date few examples of radiolabelling of aptamers can be found in literature showing that aptamers can be used as targeting agents in imaging and in radio-therapy [19][20][21]. With regards to the potential efficacy of aptamers as targeted radiopharmaceuticals in cancer therapy, we have previously shown that aptamers have improved tumour penetration, when compared with antibodies [21].…”

“…To date few examples of radiolabelling of aptamers can be found in literature showing that aptamers can be used as targeting agents in imaging and in radio-therapy [19][20][21]. With regards to the potential efficacy of aptamers as targeted radiopharmaceuticals in cancer therapy, we have previously shown that aptamers have improved tumour penetration, when compared with antibodies [21]. It is speculated that radiolabelled aptamers would have great potential as imaging agents, given that the majority of the aptamer not bound to the tumour is cleared rapidly from the system.…”