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Abstract
Poly(2-(dimethylamino ethyl)methacrylate) (pDMAEMA) is a cationic polymer with potential
as an antimicrobial agent and as a non-viral gene delivery vector. The aim was to
further elucidate the cytotoxicity of a selected pDMAEMA low molecular weight (MW)
polymer against human U937 monocytes and Caco-2 intestinal epithelial cells using
a novel multi-parameter high content analysis (HCA) assay and to investigate histological
effects on isolated rat intestinal mucosae. Seven parameters of cytotoxicity were
measured: nuclear intensity (NI), nuclear area (NA), intracellular calcium ([Ca(2+)]i),
mitochondrial membrane potential (MMP), plasma membrane permeability (PMP), cell number
(CN) and phospholipidosis. Histological effects of pDMAEMA on excised rat ileal and
colonic mucosae were investigated in Ussing chambers. Following 24-72 h exposure,
25-50 microg/ml pDMAEMA induced necrosis in U937 cells, while 100-250 microg/ml induced
apoptosis in Caco-2. pDMAEMA increased NA and NI and decreased [Ca(2+)]i, PMP, MMP
and CN in U937 cells. In Caco-2, it increased NI and [Ca(2+)]i, but decreased NA,
PMP, MMP and CN. Phospholipidosis was not observed in either cell line. pDMAEMA (10
mg/ml) did not induce any histological damage on rat colonic tissue and only mild
damage to ileal tissue following exposure for 60 min. In conclusion, HCA reveals that
pDMAEMA induces cytotoxicity in different ways on different cell types at different
concentrations. HCA has potential for high throughput toxicity screening in drug formulation
programmes.
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