Phosphate-containing poly(ethylene glycol) hydrogel nanoparticles for prevention of gutderived sepsis
May 10-15, 2015
Patients exposed to immunodeficiency, extreme surgical intervention, or subjected to radiation therapy for the treatment of abdominal and pelvic cancers are often prone to lethal gut-derived sepsis. During these extreme conditions of physiological stress, the intestinal tract is transformed into an environment characterized by variations in oxygen, pH, and phosphate concentration. Specifically, phosphate depletion in the surgically stressed host has been identified to promote virulence of the lethal bacterial pathogen P. aeruginosa which is present in 50% of patients’ intestinal tracts with 30% of strains being resistant to multiple antibiotics.[1, 3] To address this issue we have developed an inverse mini-emulsion process for producing phosphate-loaded cross-linked poly(ethylene glycol) PEG hydrogel nanoparticles (NPs) capable of releasing phosphate over a time period of several days. Two nanoparticle (NP) variants have been prepared, one involving phosphate (NP-Pi), the other hexa-metaphosphate, or polyphosphate (NP-PPi). In vitro assays were used to detect virulence expression by P. aeruginosa under low phosphate conditions with suspended NPs. To ensure appropriate control groups, phosphate-free nanoparticles (NP) served as one control and two dissolved salt formulations (phosphate, Pi, and polyphosphate, PPi) were used as additional controls. In all experiments a blank control, with only a fixed concentration of bacteria in the media was utilized. Results indicate that polyphosphate-loaded hydrogel nanoparticles (NP-PPi) are the most effective in suppressing virulence. The bacteriostatic effect of all samples were also tested and incorporated in this comparison of normalized signals. Current efforts are aimed at testing the feasibility of this drug delivery approach in septic animal models.
1. Zaborin A, Romanowski K, Gerdes S, Holbrook C, Lepine F, Long J, Poroyko V, Diggle SP, Wilke A, Righetti K, Morozova I, Babrowski T, Liu DC, Zaborina O, and Alverdy JC. PNAS, 106 (5): 6327-6332, 2009. 2. Romanowski K, Zaborin A, Fernandez H, PoroykoV, Valuckaite V, Gerdes S, Liu DC, Zaborina OY, and Alverdy JC. BMC Microobiology, 11(212): 1-14, 2011. 3. Zaborina O, Holbrook C, Chen Y, Long J, Zaborin A, MorozovaI, Fernandez H, Wang Y, Turner JR, and Alverdy JC. PLOS Pathogens, 4(2): 0001-0014, 2008.