Maltose- and maltotriose-modified, hyperbranched poly(ethylene imine)s (OM-PEIs): Physicochemical and biological properties of DNA and siRNA complexes
Publikation: Beitrag in Fachzeitschrift › Forschungsartikel › Beigetragen › Begutachtung
Beitragende
Abstract
Polycationic non-viral polymers are widely employed as delivery platforms of plasmid DNA, or of small interfering RNAs (siRNAs) for the induction of RNA interference (RNAi). Among those, poly(ethylene imine)s (PEIs) take a prominent position due to their relatively high efficacy; however, their biodistribution profiles upon systemic delivery and their toxicity pose limitations which can be addressed by the introduction of PEI modifications. In this paper, we systematically analyse physicochemical and biological properties of DNA and siRNA complexes prepared from a set of maltose-, maltotriose- or maltoheptaose-modified hyperbranched PEIs (termed (oligo-)maltose-modified PEIs; OM-PEIs). We show that pH-dependent charge densities of the OM-PEIs correlate with the structure and degree of grafting, and the length of the oligomaltose. Decreased zeta potentials of OM-PEI-based complexes and changes in the thermodynamics of DNA complex formation are observed, while the complex sizes are largely unaffected by maltose grafting and the presence of serum proteins. Furthermore, although complexation efficacies of siRNAs are not altered, complex stabilities are markedly increased in OM-PEI complexes. DNA complex uptake and transfection kinetics are slowed down upon maltose-grafting of the PEI which can be attributed to decreased zeta potentials, and alterations in the uptake mechanisms (clathrin-dependent/clathrin-independent endocytosis) are observed. Independent of the maltose architecture, DNA and siRNA complexes based on maltose-grafted PEI show considerably lower cytotoxicity as compared to PEI complexes. While maltose grafting generally leads to reduced in vitro transfection efficacies, this effect is less profound in some OM-PEI/siRNA complexes as compared to OM-PEI/DNA complexes. Importantly, upon their systemic application in vivo, OM-PEI/siRNA complexes show marked differences in the siRNA biodistribution profile with e.g. substantially decreased siRNA levels in the liver and increased siRNA levels in the muscle. Taken together, we demonstrate that OM-PEI complexes show structure-dependent physicochemical and biological properties and may represent promising, tailor-made platforms for the delivery of siRNAs, particularly for in vivo applications. (C) 2010 Elsevier B.V. All rights reserved.
Details
Originalsprache | Englisch |
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Seiten (von - bis) | 146-158 |
Seitenumfang | 13 |
Fachzeitschrift | Journal of controlled release |
Jahrgang | 149 |
Ausgabenummer | 2 |
Publikationsstatus | Veröffentlicht - 20 Jan. 2011 |
Peer-Review-Status | Ja |
Extern publiziert | Ja |
Externe IDs
PubMed | 20946922 |
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Scopus | 78651376884 |
ORCID | /0000-0002-4531-691X/work/148607828 |
Schlagworte
Schlagwörter
- Gene delivery, Gene targeting, Maltose-grafting, Pei, Poly(ethylene imine), RNAi, siRNA