Nitric Oxide-Releasing Amphiphilic Poly(amidoamine) (PAMAM) Dendrimers as Antibacterial Agents

Abstract

A series of amphiphilic nitric oxide (NO)-releasing poly(amidoamine) (PAMAM) dendrimers with different exterior functionalities were synthesized by a ring-opening reaction between primary amines on the dendrimer and propylene oxide (PO), 1,2-epoxy-9-decene (ED), or a ratio of the two, followed by reaction with NO at 10 atm to produce N-diazeniumdiolate-modified scaffolds with a total storage of ~1 μmol/mg. The hydrophobicity of the exterior functionality was tuned by varying the ratio of PO and ED grafted onto the dendrimers. The bactericidal efficacy of these NO-releasing vehicles against established Gram-negative Pseudomonas aeruginosa biofilms was then evaluated as a function of dendrimer exterior hydrophobicity (i.e., ratio of PO/ED), size (i.e., generation), and NO release. Both the size and exterior functionalization of dendrimer proved important to a number of parameters including dendrimer-bacteria association, NO delivery efficiency, bacteria membrane disruption, migration within the biofilm, and toxicity to mammalian cells. Although enhanced bactericidal efficacy was observed for the hydrophobic chains (e.g., ED), toxicity to L929 mouse fibroblast cells was also noted at concentrations necessary to reduce bacterial viability by 5-logs (99.999% killing). The optimal PO to ED ratios for biofilm eradication with minimal toxicity against L929 mouse fibroblast cells were 7:3 and 5:5. The study presented herein demonstrated the importance of both dendrimer size and exterior properties in determining efficacy against established biofilms without compromising biocompatibility to mammalian cells.

Nitric oxide-releasing poly(lactic-co-glycolic acid)-polyethylenimine nanoparticles for prolonged nitric oxide release, antibacterial efficacy, and in vivo wound healing activity

“…15 To date, several NO-releasing NPs such as silica, gold, liposomes, and dendrimers have been developed by taking advantage of nanotechnology and NO. [16][17][18][19][20][21][22] However, these NO-releasing NPs showed an initial burst release probably due to the NO tethering only to the surface of the NPs. This was accompanied by a relatively short duration of NO release ranging from a few to up to 24 hours.…”

Sustained Nitric Oxide-Releasing Nanoparticles Interfere with Methicillin-Resistant Staphylococcus aureus Adhesion and Biofilm Formation in a Rat Central Venous Catheter Model

“…Several NO-np platforms have been synthesized and used for antibiofilm applications, highlighting the feasibility and importance of developing these technologies to prevent and fight contamination of prosthetic devices (23,25,(28)(29)(30). Here, we used a CVC MRSA biofilm model to study the effectiveness of NO-np in preventing and eradicating MRSA biofilms (31,32).…”

Antibacterial Action of Nitric Oxide-Releasing Chitosan Oligosaccharides against Pseudomonas aeruginosa under Aerobic and Anaerobic Conditions

“…Macromolecular scaffolds capable of effectively storing and releasing NO have been developed to enable local delivery (27,28). The most promising NO release vehicles to date include NO donor-modified N-diazeniumdiolate silica nanoparticles (29)(30)(31), dendrimers (32)(33)(34)(35)(36), and chitosan (15). While silica nanoparticles (14,(37)(38)(39) and dendrimers (32)(33)(34) are effective as antimicrobials, they do not easily break down and thus have limited potential as inhaled therapeutics.…”