PEGylated Dendrimers with Core Functionality for Biological Applications

Abstract

The synthesis of a variety of core functionalized PEGylated polyester dendrimers and their in vitro and in vivo properties are described in this report. These water-soluble dendrimers have been designed to carry eight functional groups on their dendritic core for a variety of biological applications such as drug delivery and in vivo imaging as well as eight solubilizing groups. Using a common symmetrical aliphatic ester dendritic core and trifunctional amino acid moieties, a library of dendrimers with phenols, alkyl alcohols, alkynes, ketones, and carboxylic acid functionalities has been synthesized without the need for column chromatography. The amines were PEGylated, leaving the other functionality of the amino acid available for further manipulation such as the attachment of drugs and/or labels. Radiolabeling experiments with the PEGylated dendrimers showed that they had a long circulation half-life in mice, confirming the potential of this class of dendrimers for therapeutic and/or diagnostic applications. A carboxylic acid functionalized dendrimer was elaborated to carry doxorubicin bound via a hydrazone bond. The drug-loaded carrier accumulated more in tumors and less in healthy organs than the clinically used PEGylated liposomal formulation Doxil. The efficient synthesis, high versatility, and favorable biological properties make these PEGylated polyester dendrimers promising structures for therapeutic and/or imaging applications.

PEGylated polymers for medicine: from conjugation to self-assembled systems

“…6B), with symmetry about the core, generated by divergent growth of a bis-2,2-hydroxymethylpropionic acid (bisHMPA) from a pentaerythritol core. 108 The bisHMPA block was then functionalized using a trifunctional amino acid, by EDC coupling to the carboxylic acid. PEGylation of the terminal amines through carbamate linkages leaves the third functional group available for modification at the dendritic core.…”

“…To examine the capacity of the dendrimers for conjugation with a small molecule drug, DOX was conjugated again by a hydrazone linkage. 108 Biodegradability and biodistribution studies demonstrated increased half-lives relative to unmodified DOX. This drug delivery system was found to be comparable to DOXIL, the current PEGylated version of DOX, in terms of amount of drug delivered to the tumor.…”

Intramolecular Cross-linking of Polymers Using Difunctional Acetylenes via Click Chemistry

“…There has been revitalized interest in the preparation of polymeric nanoparticles due to the use of these tailor-made materials in a variety of applications, such as microelectronics [1,2], drug-delivery systems [3][4][5][6][7] and polymer processing [8][9][10]. Recently, several strategies were employed for the preparation of polymeric nanoparticles, including intramolecular cross-linking of single polymer chains containing cross-linkable groups in ultra-diluted reaction conditions [11][12][13][14][15][16][17] and single-chain collapse of macromolecules containing suitable reactive groups along the chain with bifunctional cross-linkers [18,19].…”

Polyester Dendrimers: Smart Carriers for Drug Delivery

“…Fréchet and coworkers have contributed tremendously to the area of polyester dendrimers [56,57,96,97,126,[142][143][144][145][146][147]. In early 2000, this group prepared and evaluated various dendritic architectures composed of a polyester dendritic scaffold based on the monomer unit bis-HMPA for their suitability as drug carriers both in vitro and in vivo [63].…”