Biotinylated and Chelated Poly-L-Lysine as Effector for Pretargeting in Cancer Therapy and Imaging

Abstract

Objective: The aim of this study was to synthesise and evaluate polylysine-based effectors for pretargeted radioimmunotherapy and imaging. These molecules can readily be size-modified and charge-modified to decrease the renal uptake of radioactivity, which is often a major problem for small radiolabeled molecules. Several chelators and biotin molecules (for antibody-streptavidin-binding in vivo) are also easily incorporated into one structure because of the polylysine. Methods:The effectors were synthesised using poly-L-lysine, NHS-LC-biotin, CHX-A''-DTPA or p-SCN-Bn-DOTA and succinic anhydride. They were characterised, labelled with Results: Radiochemical purities between 97.4±0.6 % and 99.6±0.1 % and decay-corrected yields of 80.2±2.4 % after purification were achieved with the radiolabeled molecules, as well as a specific activity of 7.6 × 10 3 Keywords: Pretargeting, Radiometals, Polylysine, Radioimmunotherapy, Radioimmunoimaging, Kidney GBq/µmol. The avidin binding capacity was 94.4±1.9%. The kidney uptake study demonstrated a reduction of renal absorbed dose by 80% when modifying the molecular size and charge. Conclusion:The synthesised polylysine-based effectors show potential for further in vivo evaluation in pretargeted radioimmunotherapy and imaging.

Therapeutic Applications of Pretargeting

“…It has become apparent from previous studies that in contrast to the hematologic toxicity of conventional RIT, the main limitation of alpha PRIT is the risk of nephrotoxicity [117,118]. Several alternative strategies have been suggested to reduce nonspecific radioactivity uptake in the kidneys, such as adjusting the charge and size of the small molecule [119], an oral administration route [110], chelate therapy [120], dose fractionation, or the use of longer lived radionuclides to reduce the percentage of decay in the kidneys. Recently, investigators have examined the use of the longer lived alpha-particle emitting radionuclide, actinium-225, for pancreatic ductal adenocarcinoma.…”

Pretargeted Alpha Therapy of Disseminated Cancer Combining Click Chemistry and Astatine-211

“…Today, several pretargeting strategies can be used to combine antibodies and radioligands in vivo; some of them utilize a noncovalent interaction such as streptavidinbiotin [9][10][11], and some utilize the hybridization of complementary oligonucleotides [12,13] or the ability of bispecific antibodies [14,15] to bind an antigen and a radiolabeled hapten. Last but not least, there is the biorthogonal inverse electron demand Diels-Alder (IEDDA) click reaction, which utilizes the fast and highly specific reaction that occurs between a diene, such as 1,2,4,5-tetrazine (Tz), and a dienophile, particularly trans-cyclooctene (TCO), which appears to be seven times more reactive than the cis-cyclooctene (CCO) in the IEDDA reaction [15][16][17][18][19].…”