PEGylation affects cytotoxicity and cell-compatibility of poly(ethylene imine) for lung application: Structure-function relationships

Journal Article · Fri Jan 15 00:00:00 EST 2010 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2009.10.001· OSTI ID:21344835

Beyerle, Andrea ^[1]; Merkel, Olivia ^[2]; Stoeger, Tobias ^[1]; Kissel, Thomas ^[2]

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1. Institute of Lung Biology and Disease, Helmholtz Zentrum Muenchen, German Research, Center for Environmental Health (GmbH) (Germany)
2. Department of Pharmaceutics and Biopharmacy, Philipps-University, Ketzerbach 63, D-35032 Marburg (Germany)

Poly(ethylene imine) (PEI) has widely been used as non-viral gene carrier due to its capability to form stable complexes by electrostatic interactions with nucleic acids. To reduce cytotoxicity of PEI, several studies have addressed modified PEIs such as block or graft copolymers containing cationic and hydrophilic non-ionic components. Copolymers of PEI and hydrophilic poly(ethylene glycol) (PEG) with various molecular weights and graft densities were shown to exhibit decreased cytotoxicity and potential for DNA and siRNA delivery. In this study, we evaluated the cytotoxicity and cell-compatibility of different PEGylated PEI polymers in two murine lung cell lines. We found that the degree of PEGylation correlated with both cytotoxicity and oxidative stress, but not with proinflammatory effects. AB type copolymers with long PEG blocks caused high membrane damage and significantly decreased the metabolic activity of lung cells. In addition, they significantly increased the release of two lipid mediators such as 8-isoprostanes (8-IP) and prostaglandin E{sub 2} (PGE{sub 2}) in a dose-dependent manner. In contrast, the cytokine profiles which indicated high levels of acute-phase cytokines such as TNF-alpha, IL-6, and G-CSF did not follow any clear structure-function relationship. In conclusion, we found that modification of PEI 25kDa with high degree of PEGylation and low PEG chain length reduced cytotoxic and oxidative stress response in lung cells, while the proinflammatory potential remained unaffected. A degree of substitution in the range of 10 to 30 and PEG-chain lengths up to 2000 Da seem to be beneficial and merit further investigations.

• OSTI ID: 21344835
• Journal Information: Toxicology and Applied Pharmacology, Vol. 242, Issue 2; Other Information: DOI: 10.1016/j.taap.2009.10.001; PII: S0041-008X(09)00423-2; Copyright (c) 2009 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
COPOLYMERS
DNA
DOSES
ETHYLENE
IMINES
INFLAMMATION
INTERACTIONS
LUNGS
LYMPHOKINES
MEMBRANES
OXIDATION
POLYETHYLENE GLYCOLS
POLYETHYLENES
PROSTAGLANDINS
RESPIRATORY TRACT CELLS
STRUCTURE FUNCTIONS
TOXICITY
ALCOHOLS
ALKENES
ANIMAL CELLS
BODY
CHEMICAL REACTIONS
FUNCTIONS
GLYCOLS
GROWTH FACTORS
HYDROCARBONS
HYDROXY COMPOUNDS
MITOGENS
NUCLEIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANIC POLYMERS
ORGANS
PATHOLOGICAL CHANGES
POLYMERS
POLYOLEFINS
PROTEINS
RESPIRATORY SYSTEM
SOMATIC CELLS
SYMPTOMS