Poly(amidoamine) Polymers: Soluble Linear Amphiphilic drug-delivery Systems for genes, Proteins and Oligonucleotides

Abstract

Polymer–drug and polymer–protein conjugates are emerging as a robust and well-characterized class of therapeutic entity. Although there are no low-molecular-weight soluble polymer conjugates in routine clinical use, there are many examples of routinely used high-molecular-weight drugs conjugated to soluble polymers (e.g., Oncospar®). Advances in synthetic polymer chemistry have fostered the development of linear poly(amidoamine)s (PAA)s that impart both biodegradability, ‘smart’ (pH responsive) biological activity and biocompatibility. In their linear form, such as hyper-branched poly(amidoamine) (PAMAM) dendrimers, linear PAAs can be used to deliver large therapeutic entities such as peptides, proteins and genes to either the cytosol or nucleus. Furthermore, these polymers offer great potential in vivo due to their ability to either target the liver or be directed away from the liver and enter tumor mass via the enhanced permeability and retention (EPR) effect. PAAs also exhibit minimal toxicity (dependent upon backbone chemistry), relative to well-characterized polymers used for gene delivery. The propensity of PAAs to modulate intracellular trafficking resulting in their cytosolic translocation has also recently been quantified in vivo and is the primary focus of this article.

Strategies in Gene Therapy for Glioblastoma

“…These molecules offer several advantages (such as high surface/volume ratio for DNA binding and well-known chemical behavior) [189] that have made them attractive synthetic nanocarriers for gene therapy. A commonly used dendrimer is a hyperbranched polymer of poly-amidoamine (PAMAM) characterized by biocompatibility, controlled biodegradation, low toxicity, and good accumulation in tumors with leaky vasculature [190]. A modified version of PAMAM was conjugated with nanoparticle carriers (see next section) and a viral Tat-peptide to facilitate cell membrane crossing [191].…”

MicroRNAs as Molecular Targets for Cancer Therapy: On the Modulation of MicroRNA Expression

“…Due to the presence of positively charged amino groups on their surface, PAMAM dendrimers can easily interact with nucleic acids to form complexes through charge-based interactions and protect them from nuclease degradation, while exhibiting minimal toxicity [150,155]. Moreover, the open nature of the dendritic architecture enables the entrapment of drugs within their core through electrostatic, hydrophobic and hydrogen bond interactions [156].…”

Biodegradable nanoparticles composed of dendrigraft poly-l-lysine for gene delivery

“…In addition, the electrostatic compaction of DNA by dendrimers was found to protect it from degradation by nucleases and to enhance the cellular uptake of dendrimer-based DNA-containing particles via adsorptive endocytosis or phagocytosis. Polyamidoamine (PAMAM) dendrimers are commercially available macromolecules that can be used as carriers for plasmid DNA, antisense oligonucleotides, and siRNA [5][6][7][8]. However, PAMAM dendrimers are not biodegradable and exhibit strong cytotoxicity [9,10].…”