Polyester Dendritic Systems for Drug Delivery Applications:  In Vitro and In Vivo Evaluation

Abstract

High molecular weight polymers (> 20 000 Da) have been widely used as soluble drug carriers to improve drug targeting and therapeutic efficacy. Dendritic polymers are exceptional candidates for the preparation of near monodisperse drug carriers due to their well-defined structure, multivalency, and flexibility for tailored functionalization. We evaluated various dendritic architectures composed of a polyester dendritic scaffold based on the monomer unit 2,2-bis(hydroxymethyl)propanoic acid for their suitability as drug carriers both in vitro and in vivo. These systems are both water soluble and nontoxic. In addition, the potent anticancer drug, doxorubicin, was covalently bound via a hydrazone linkage to a high molecular weight 3-arm poly(ethylene oxide)-dendrimer hybrid. Drug release was a function of pH, and the release rate was more rapid at pH < 6. The cytotoxicity of the DOX-polymer conjugate measured on multiple cancer lines in vitro was reduced but not eliminated, indicating that some active doxorubicin was released from the drug polymer conjugate under physiological conditions. Furthermore, biodistribution experiments show little accumulation of the DOX-polymer conjugate in vital organs, and the serum half-life of doxorubicin attached to an appropriate high molecular weight polymer has been significantly increased when compared to the free drug. Thus, this new macromolecular system exhibits promising characteristics for the development of new polymeric drug carriers.

Enhancement of Cytotoxicity by Combining Pyrenyl-Dendrimers and Arene Ruthenium Metallacages

“…13 For example, a fourth generation polyester dendron attached to a trisphenolic core derived from the monomeric unit bis-MPA has been evaluated for drug delivery applications. 14 Cell proliferation studies have suggested that the dendritic scaffold did not exhibit a significant toxic effect. The attachment of poly(ethylene glycol) to the surface of this type of dendrimer has also been successful for therapeutic applications, 10b,15 and structure− activity relationships have shown that both generation and steric effect are important.…”

Polyester Dendrimers: Smart Carriers for Drug Delivery

“…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]. The systems were found to be water soluble and nontoxic.…”

“…One strategy to overcome these shortcomings is to use polyester dendrimers which have been shown to be non-toxic and biocompatible [19,[56][57][58][59][60]. By attaching a drug to a suitable carrier, it is possible to enhance its aqueous solubility, increase its circulation half-life, target certain tissues, improve drug transit across biological barriers, and slow drug metabolism [61][62][63][64][65][66]. Optimization of these features to maximize drug bioavailability to diseased tissues while minimizing drug exposure to healthy tissues, results in improved therapeutic efficacy.…”

Synthesis and MALDI-ToF characterization of dendronized poly(ethylene glycol)s

“…In this investigation, the dendritic component of linear dendritic hybrids is a divergently grown dendron, a "wedge-like" dendritic segment. Although numerous dendritic syntheses have been reported (Frechet, Tomalia, 2001), the polyester dendrimers and dendrons based on 2,2-bis(hydroxymethyl)propionic acid (bis-MPA (Ihre et al, 1996;Ihre et al, 2001) are the most promising given their ease of synthesis, exceptional structural purity, and biocompatible nature (Padilla de Jesus et al, 2002;Lundberg et al, 2011).…”

“…These characteristics are particularly important when considering polymers for biomedical applications. One example of the useful modularity of the linear-dendritic hybrid system is that, while the linear PEG provides increased plasma half-life, low toxicity, and overall stability from enzymatic or hydrolytic degradation, the dendrons provide a multiplicity of functional groups to increase the drug payload or targeting groups (Padilla de Jesus et al, 2002).…”