Dendrimers are highly branched dendritic molecules that possess unique properties including relatively large molecular size, narrow size distribution, well-defined globular structure, and ease of derivatization via the peripheral functional groups. These properties have attracted great interest in exploring their potential biomedical applications such as drug delivery, gene transfection, and imaging.1
Recent research activities in this area also include the study of antimicrobial activities of dendrimer derivatives.2
In most cases, dendrimers serve as carriers of biologically active agents by encapsulating them in the interior or, more often, tethering them on the periphery of the dendrimers. For example, most dendrimers displaying antimicrobial activities are terminated with antimicrobial agents, including ferrocene,3
Poly(amidoamine) (PAMAM) dendrimers (e.g., the generation 3 (G3) PAMAM in ) are the most extensively studied dendrimers. PAMAM dendrimers with a wide variety of functional groups at the periphery are commercially available. Some of them, including those with amino terminal groups, are shown to have low toxicity to eukaryotic cells.8
Modification of the amino groups with poly(ethylene glycol) (PEG) or lauroyl chains further improves their biocompatibility.9,10
As the number of PEG or lauroyl chains increases, the cytotoxicity of PAMAM to human colon adenocarcinoma cells decreases.10
Shielding of the positive charges of the protonated amino groups on the exterior of the dendrimer by the PEG or lauroyl chains is likely the reason for reduced cytotoxicity.10
Due to their excellent biocompatibility, PEG-modified PAMAM dendrimers have been used as carriers of imaging agents and pharmaceuticals, including antimicrobial agents such as penicillin V and silver.1,11,12
Several proprietary PAMAM dendrimer derivatives are shown to be potent antiviral agents.7f,12b,13
However, their composition has not been disclosed, and it is unclear if the dendrimers alone are inherently antiviral. Despite extensive studies of PAMAM dendrimers for biomedical applications, antimicrobial activity of unmodified PAMAM dendrimers has not been reported.
Figure 1 Structure of the G3 PAMAM dendrimer possessing ~32 amino groups at the periphery, and the reaction used in the present study for modifying the commercial G5 PAMAM dendrimer, possessing ~117 amino groups at its periphery, with PEG consisting (more ...)
Recently, we have been interested in the mechanisms of action of antimicrobial peptides (AMPs) associated with the ocular surface. Bacterial keratitis is a major cause of ocular surface morbidity, particularly among contact lens wearers, that often leads to permanently compromised visual function, sometimes necessitating penetrating keratoplasty (corneal transplant) to restore adequate vision. To date, four AMPs, including LL-37 (a 37 amino acid residue peptide), have been detected in the ocular surface epithelia.14–16
Each of them has potent activity against common ocular pathogens such as Pseudomonas aeruginosa
(PA) and Staphylococcus aureus
There is evidence that a threshold concentration of AMP is needed to cause membrane permeation and eventual cell death.17
We hypothesized that localization of AMP on polymers or substrate surfaces could thus enhance its potency. We selected PAMAM dendrimers to test this idea since we have investigated thin films derived from PAMAM and their functionalization with PEG and ligands.18
In the course of the investigation, we were surprised to find that PAMAM dendrimers themselves were highly toxic to some bacteria.
In this communication, we report the antibacterial properties of generation 5 (G5) PAMAM dendrimers with or without partial PEG coating. We show that these dendrimers are more toxic than LL-37 against PA, a common Gram-negative ocular pathogen involved in keratitis and conjunctivitis. To our knowledge, this is the first report of the inherent high antimicrobial activity of PAMAM dendrimers unmodified with known antimicrobial agents. PEG-coated PAMAM also exhibited low toxicity to human corneal epithelial cells (HCECs). These results suggest the potential use of PAMAM dendrimers as effective antimicrobial agents.