Synthesis and preliminary evaluation of a ^99mTc‐labeled folate‐PAMAM dendrimer for FR imaging

Abstract

Folate receptor is an ideal target for tumor-specific diagnostic and therapeutic. The aim of this study was to synthesize Tc-labeled folate-polyamidoamine dendrimer modified with 2-hydrazinonicotinic acid ( Tc-HP FA) for FR imaging. The Tc-HP FA conjugate was prepared using N-tris-(hydroxymethyl)-methylglycine and trisodium triphenylphosphine-3,3',3″-trisulfonate as coligands. Physicochemical properties, in vitro cell uptake study, and in vivo micro-single-photon emission computed tomography/CT imaging were performed. The radiolabeled Tc-HP FA conjugate was prepared with high radiolabeling yield, good stability, and water solubility (logP = -1.70 ± 0.21). In cell uptake study, the radiolabeled conjugate showed high uptakes in the FR-abundant KB cells and could be blocked significantly by excess folic acid. The 7721 cells which served as control group substantially had no uptakes. The results of micro-single-photon emission computed tomography/CT imaging exhibited that high accumulation of activity was found in FR-overexpressed KB tumor, and the tumor-to-muscle ratio was approximately 25.78, while, using free FA as inhibitor, the uptakes of Tc-HP FA in KB tumor and kidney were obviously inhibited. In summary, a new radiocompound was synthesized successfully with specific FR targeting ability. The feasibility of Tc-HP FA for early diagnosis of FR-positive tumors with non-invasive single-photon emission computed tomography imaging was demonstrated and the possibility of imaging-guided drug delivery based on multifunctional polyamidoamine will be studied in the future.

Development of a New FR-Targeting Agent 99mTc-HYNFA with Improved Imaging Contrast and Comparison of Multimerization and/or PEGylation Strategies for Radio-Folate Modification

“…The structures of radiofolates are shown in Figure 1a,b, including monomers [ 99m -HYNIC-T-PEG-FA (denoted as 99m Tc-HYNFA)], dimers [ 99m Tc-HYNIC-D 1 -FA 2 , 99m Tc-HYNIC-D 1 -PEG-FA 2 , and 99m Tc-FA-D 1 -HYNIC 2 ], and multimers [ 99m Tc-HYNIC-D 2 -FA 4 and 99m Tc-HP 3 FA]. The HP 3 FA was a PAMAM-based (polyamidoamine-based) folate multimer with seven folate groups reported by Song et al 24 HYNIC-T-FA and HYNIC-D 1 -FA 2 were prepared via click reaction. 25,26 In particular, HYNIC-D 1 -FA 2 was a dimer with two folate moieties, and HYNIC-D 2 -FA 4 was a tetramer with four folate moieties.…”

“…Previously, we reported three 99m Tc-labeled folate conjugates including multimeric 99m Tc-HP 3 FA, monomeric 99m Tc-HYNIC-T-FA, and dimeric 99m Tc-HYNIC-D 1 -FA 2 as FR-targeted agents. In order to further understand the effectiveness of multimerization or PEGylation on the in vivo imaging performance, here, we developed several new 99m Tc-folates with multimerization and/or PEGylation and compared their tumor-targeting properties with those previously reported via biodistribution and SPECT imaging.…”

Single- versus Dual-Targeted Nanoparticles with Folic Acid and Biotin for Anticancer Drug Delivery

“…FA-targeted dendrimers can also be used as carriers of contrast agents [101][102][103] and in radiotherapy [104]. A new therapeutic nanocomplex based on dendrimers modified by FA, carrying two active chemotherapeutic agents-fluorouracil and 99m Tc to breast cancer cells has been achieved.…”

Dendritic metal complexes for bioimaging. Recent advances

“…The generation 3 PAMAM was functionalized with folate and also with 2-hydrazinonicotinic acid for the complexation of 99m Tc, with tricine and trisodium triphenylphosphine-3,3′, 3″-trisulfonate as co-ligands (Figure 24C). SPECT/CT imaging was successfully performed with this dendrimer injected to mice bearing a KB tumor [100].…”