Biocompatibility and Efficacy of Oligomaltose-Grafted Poly(ethylene imine)s (OM-PEIs) forin VivoGene Delivery

Abstract

Polycationic polymers like poly(ethylene imine)s (PEIs) are extensively explored for the nonviral transfer of DNA or small RNAs (siRNAs). To enhance biocompatibility and alter pharmacokinetic properties, hyperbranched PEI was recently grafted with the nonligand oligosaccharides maltose or maltotriose at various degrees in a systematic study to yield (oligo-)maltose PEIs (OM-PEIs). In this paper, we investigate the in vivo biocompatibility and efficacy of a whole set of (OM-)PEIs and the corresponding (OM-)PEI-based DNA or siRNA complexes upon systemic (intravenous, i.v.) administration in mice. We determine the overall survival and animal welfare, hepatotoxicity, immune stimulation, erythrocyte aggregation, and the efficacy of DNA delivery in vivo. Higher-degree oligomaltose-grafting of PEI substantially decreases weight loss, abolishes lethality upon repeated treatment with the free polymers or with complexes, and abrogates hepatotoxicity, as determined by serum levels of liver enzymes. Immunostimulatory effects (TNF-α, IFN-γ) and erythrocyte aggregation are mainly observed upon treatment with partially maltotriose-grafted PEI or PEI-based complexes and are largely abolished upon higher-degree grafting. In vivo transfection experiments in mice bearing subcutaneous (s.c.) tumor xenografts reveal a strong dependence of reporter gene expression in a given organ on the mode of complex administration (i.v. vs intraperitoneal injection) and the OM-PEI architecture, with high-level maltose-grafted PEI (PEI-(2-Mal)) being most efficient for DNA delivery. We conclude that distinct differences between different patterns of maltose- or maltotriose-grafting are observed with regard to both biocompatibility and in vivo efficacy and identify optimal oligomaltose-PEIs for therapeutic applications.

Dendritic Glycopolymer as Drug Delivery System for Proteasome Inhibitor Bortezomib in a Calcium Phosphate Bone Cement: First Steps Toward a Local Therapy of Osteolytic Bone Lesions

“…The dendritic glycopolymer PEI‐Mal‐B has been established as promising and biocompatible DDS under in vitro and in vivo conditions . The oligosaccharide architecture B attached to the dendritic PEI scaffold (Scheme ) mainly implemented the necessary biological properties of the PEI‐Mal‐B as DDS in the previous studies.…”

“…Weakly cationic DDS PEI‐Mal‐B is known preferentially to undergo ionic interaction with anionic drug molecules with different size dimensions such as ATP, si‐RNA, or DNA . In a recent study, PEI‐Mal‐B was used to fabricate multicompartment systems based on PEI‐Mal‐B and boronic acid‐containing microgels.…”

Sweet Vector for Gene Delivery: the Sugar Decoration of Polyplexes Reduces Cytotoxicity with a Balanced Effect on Gene Expression

“…Indeed, glucose‐functionalized nanoparticles were reported to show enhanced cellular uptake compared to their naked equivalents . Similarly, the cellular uptake of ATP molecules was shown to be enhanced using oligosaccharide‐shelled hyperbranched PEI as a carrier system, and the same approach can be considered to increase the biocompatibility of polyplexes, for instance, by the grafting of maltose or maltotriose moieties . The sugar decoration of polyplexes also provides a hydrophilic corona to the nanocomplexes, making them less susceptible to opsonization and offering the robust serum stability required for systemic delivery .…”

Characterization of oligosaccharide-functionalized hyperbranched poly(ethylene imine) and their complexes with retinol in aqueous solution

“…Though an enhancement of biocompatibility can be achieved through the incorporation of water-soluble and biocompatible surface groups in the outer shell of the dendritic architecture consisting of poly(propylene imine) (PPI) dendrimers, poly(amido amine) (PAMAM) dendrimers, hyperbranched poly(ethylene imine) (PEI), and other dendritic scaffolds [13][14][15][16][17][18]. In recent studies [19][20][21][22][23], the coupling of mono-and oligosaccharide units has successfully been accomplished. Hence, these dendritic glycoarchitectures have been considered as nanocarriers for drugs [19,20,23].…”

“…In recent studies [19][20][21][22][23], the coupling of mono-and oligosaccharide units has successfully been accomplished. Hence, these dendritic glycoarchitectures have been considered as nanocarriers for drugs [19,20,23]. For instance, dendritic glycoarchitectures based on PEI core [19,23] outlines enhanced biocompatibility and reduced cytotoxicity compared with the bare hyperbranched PEI.…”