Synthesis of Polyester Dendritic Scaffolds for Biomedical Applications

Abstract

Using a well-defined poly(2,2-bis(hydroxymethyl)propanoic acid) dendrimer scaffold, a series of G1 to G3 dendrons is functionalized at the periphery with alkynes to enable "Click" functionalization via the copper-catalyzed alkyne-azide cycloaddition (CuAAC). The resulting dendrons are further functionalized at the core with a dipicolylamine (DPA) moiety to enable radiolabeling with Tc for molecular imaging applications. Efficient CuAAC coupling is achieved using an azide-functionalized triethylene glycol monomethyl ether (TEG-N ). Removal of copper from the DPA ligand is successfully performed on G1 and G2 dendrimers prior to radiolabeling with Tc. Radiolabeling of the G3 dendrimer is accomplished via transmetallation of the [CuDPA] ligand with Tc, further demonstrating the feasibility of the synthetic strategies in the preparation of dendritic imaging agents. Subsequent attachment of an acyloxymethyl ketone (AOMK) derivative for targeting of cathepsin B is also explored. Despite demonstrating the ability to ligate multiple AOMK ligands, the AOMK-dendrimer conjugates are not able to bind to cathepsin B, which may be attributed to steric hindrance at the dendrimer periphery.

Radiolabelling of nanomaterials for medical imaging and therapy

“…28C). 423,442,443 However, in this case the chelator was conjugated via an alkyl amine to the dendrimer core which had been functionalised with an NHS ester. RCYs of ca.…”

Development of 99mTc-Labeled Human Serum Albumin with Prolonged Circulation by Chelate-then-Click Approach: A Potential Blood Pool Imaging Agent

“…38,39 The main disadvantage of the CuAAC reaction is the contamination of the product with the copper ion and its coordination to targeting biomolecules. 40 Additionally, the use of Cu(I) ions as catalysts hindered their utility in clinical nuclear medicine due to strict current good manufacturing practices. 41 Therefore, other biorthogonal reactions that do not require copper catalysts, have been proposed.…”

“…To circumvent the problem, several new labeling strategies have been developed, the chelate-then-click approach, where the bifunctional chelator is first complexed with [ 99m Tc­(H 2 O) 3 (CO) 3 ] + followed by the copper­(I)-catalyzed azide-alkyne cycloaddition (CuAAC) click reaction with the targeting moiety. As the CuAAC click reaction occurred at physiological temperature and pH, this radiolabeling strategy permits the conjugation of sensitive biomolecules that require harsh radiolabeling conditions. , The main disadvantage of the CuAAC reaction is the contamination of the product with the copper ion and its coordination to targeting biomolecules . Additionally, the use of Cu­(I) ions as catalysts hindered their utility in clinical nuclear medicine due to strict current good manufacturing practices .…”

Click and Bioorthogonal Chemistry: The Future of Active Targeting of Nanoparticles for Nanomedicines?

“…This results in a high functionalization capacity for targeted cancer treatments and bioimaging devices. [22][23][24][25] The high solubility of liposomes and their rapid elimination from systemic circulation could be an advantage for biological applications. Silica (SiO 2 ), gold (Au) and iron oxide (Fe 3 O 4 ) NPs account for 75% of inorganic NPs and offer an interesting click chemistry modification platform for both imaging and therapy.…”