Synthesis, Radiolabeling, and Bio-imaging of High-Generation Polyester Dendrimers

Abstract

A series of aliphatic polyester dendrons, generations 1 through 8, were prepared with a core p-toluenesulfonyl ethyl (TSe) ester as an easily removable protecting group that can be efficiently replaced with a variety of nucleophiles. Using amidation chemistry, a tridentate bis(pyridyl)amine ligand which is known to form stable complexes with both Tc(I) and Re(I) was introduced at the dendrimer core. Metalation of the core ligand with (99m)Tc was accomplished for generations 5 through 7, and resulted in regioselective radiolabeling of the dendrimers. The distribution of the radiolabeled dendrimers was evaluated in healthy adult Copenhagen rats using dynamic small-animal single photon emission computed tomography (SPECT). The labeled dendrimers were cleanly and rapidly eliminated from the bloodstream via the kidneys with negligible nonspecific binding to organs or tissues being observed. These data were corroborated by a quantitative biodistribution study on the generation 7 dendrimer following necropsy. The quantitative biodistribution results were in excellent agreement with the data obtained from the dynamic SPECT images.

Polyester Dendrimers

“…The anhydrides of acetal-protected 2,2-bis-(hydroxymethyl)propanoic acid have been used often [127,128]. Restricting the mobility of the alcohol-terminated chains through formation of a cyclic acetal decreases steric hindrance during ester formation, allowing facile access to high generation dendrimers [129]. Using NMR parameters, we have recently established that the configuration of the O-benzylidene derivative of 2,2'-bis(hydroxymethyl)propanoic acid is cis [130].…”

“…The amount of anhydride used was only 1.25 equiv per hydroxyl group. Further evidence of the effectiveness of this route was obtained by Parrott et al who prepared up to eighth generation dendrons using this method achieving yields of >90% at every stage without altering reaction conditions [129]. …”

“…Polyester dendrimers were prepared up to the fourth generation using even sterically congested cores like pentaerythritol in good yields using DMAP and DCC to promote ester formation. Since then, a number of research groups have utilized the benzylidene-protected bis-HMPA as a convenient building block [127,129,130,146,[150][151][152][153]. Synthesis of a dendritic macro-initiator for atom transfer radical polymerization [146].…”

“…Synthesis of second generation unsymmetrical polyester dendrimer [203]. Parrott et al recently introduced a new carboxylic acid protecting group for the synthesis of polyester dendrons based on bis-HMPA [129], the 2-p-toluenesulfonylethyl group [129]. Dendrons up to the eighth generation were prepared in excellent yields using benzylidene-protected bis-HMPA as the unit being added as shown in Scheme 44 [129].…”

Polyester Dendrimers: Smart Carriers for Drug Delivery

“…In addition, polyester dendrimers have labile ester functionalities which are steadily hydrolyzed in vivo to release entrapped or covalently attached drugs. Higher generation polyester dendrimers can easily be prepared with facile synthesis of other dendrimers and a variety of methods have been reported for ester bond formation [126][127][128][129][130][131][132][133][134][135]. The synthesis of polyester dendrimers in general [135] and those derived from bis-2,2-hydroxymethylpropanoic acid (bis-HMPA) in particular [58] have been reviewed.…”