Conjugation of Polyamidoamine Dendrimers on Biodegradable Microparticles for Nonviral Gene Delivery

Zhang, Xueqing; Intra, Janjira; Salem, Aliasger K.

doi:10.1021/bc070116l

Cited by 74 publications

(70 citation statements)

References 46 publications

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“…[18,26,27] The positive charge of the PEI results in effective binding to the negatively charged plasmid DNA (pDNA), and this condensation protects the pDNA from digestion in serum and as the nanoparticle complex enters cells. [28,29] Once in the endosomal compartment, PEI can act as a buffer or "proton sponge" to induce osmotic swelling and cause release from the endosome. This is necessary to avoid degradation of the plasmid DNA when the endosome fuses with the lysosome.…”

Section: Introductionmentioning

confidence: 99%

Characterization of the transgene expression generated by branched and linear polyethylenimine-plasmid DNA nanoparticles in vitro and after intraperitoneal injection in vivo

Intra¹,

Salem²

2008

Journal of Controlled Release

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125

119

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Polyethylenimine (PEI) is a cationic polymer that has shown significant potential for delivering genes in vitro and in vivo. Mixing cationic PEI with negatively charged plasmid DNA (pDNA) results in the spontaneous electrostatic formation of stable nanoparticle complexes. The structure of PEI can be branched or linear. In this study, we show that branched PEI has a stronger electrostatic interaction with pDNA than linear PEI, which accounts for greater compaction, higher zeta potentials and smaller nanoparticle sizes at equivalent pDNA concentrations. For both linear and branched PEI, increasing the concentration of pDNA mixed in the same volume and at the same nitrogen to phosphate (N:P) ratio results in larger average particle sizes. Increasing the N:P ratio increases luciferase activity generated by branched PEI-pDNA nanoparticles and linear PEI-pDNA nanoparticles in HEK293, COS7 and HeLa cell lines. Increasing the N:P ratio at which branched PEI-pDNA nanoparticles are prepared also increases luciferase expression in HepG2 cells but does not increase luciferase expression generated by linear PEI-pDNA nanoparticles. In all of the cell lines, branched PEI-pDNA nanoparticles prepared at N:P ratios of 10 and above generated significantly higher luciferase activity than linear PEI-pDNA nanoparticles. Luciferase activity was highest in the HEK293 cells and luciferase expression in each of the cell lines followed the order of HEK293

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Section: Introductionmentioning

confidence: 99%

Characterization of the transgene expression generated by branched and linear polyethylenimine-plasmid DNA nanoparticles in vitro and after intraperitoneal injection in vivo

Intra¹,

Salem²

2008

Journal of Controlled Release

Self Cite

125

119

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“…There have been a few studies in the literature that have reported the formulation of dendrimers into particulate carriers [36]. Most of those studies have focused on the encapsulation of G3-NH 2 -plasmid DNA complex (dendriplexes) into PLGA microparticles [36].…”

Section: Resultsmentioning

confidence: 99%

“…Most of those studies have focused on the encapsulation of G3-NH 2 -plasmid DNA complex (dendriplexes) into PLGA microparticles [36]. One of the important findings from those studies was the ability to sustain the release of these dendriplexes from the polymeric core over extended periods of time, suggesting that formulating dendrimer conjugates into polymeric matrices can be a potential strategy to further enhance their efficacy as drug delivery agents [36]. To the best of our knowledge, there have been no previous articles reporting the encapsulation of dendrimers into polymeric NPs.…”

Section: Resultsmentioning

confidence: 99%

“…Calu-3 cells (passages [35][36][37][38][39][40][41][42][43][44][45] were seeded at a density of 1×10 6 cells per well in 24-well plates, and allowed to grow to confluence. The monolayer confluence was confirmed by staining select wells for ZO-1 and subjecting them to fluorescence spectrometry as detailed earlier, a day before commencing the uptake studies.…”

Section: Flow Cytometrymentioning

confidence: 99%

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Polymeric Nanocarriers for Transport Modulation across the Pulmonary Epithelium: Dendrimers, Polymeric Nanoparticles, and their Nanoblends

Bharatwaj

Dimovski

Conti

et al. 2014

AAPS J

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Abstract. The purpose of this study was to (a) Determine the cellular transport and uptake of amineterminated generation 3 (G3) poly(amido amine) (PAMAM) dendrimers across an in vitro model of the pulmonary epithelium, and the ability to modulate their transport by forming nanoblends of the dendrimers with biodegradable solid polymeric nanoparticles (NPs) and (b) to formulate dendrimer nanocarriers in portable oral inhalation devices and evaluate their aerosol characteristics. To that end, fluorescein isothiocyanate (FITC)-labeled G3 PAMAM dendrimer nanocarriers (DNCs) were synthesized, and also encapsulated within poly lactide-co-glycolide nanoparticles (NPs). Transport and uptake of both DNCs encapsulated within NPs (nanoblends) and unencapsulated DNCs were tracked across polarized monolayers of airway epithelial cells, Calu-3. DNCs were also formulated as core-shell microparticles in pressurized metered-dose inhalers (pMDIs) and their aerodynamic properties evaluated by Andersen cascade impaction. The apparent permeability of DNCs across the airway epithelial model was similar to that of a paracellular marker of comparable molar mass-order of 10 −7 cm s −1 . The transport and cellular internalization of the DNCs can be modulated by formulating them as nanoblends. The transport of the DNCs across the lung epithelium was completely suppressed within the time of the experiment (5 h) when formulated as blends. The encapsulation also prevents saturation of the cellular internalization profile. Nanoblending may be a potential strategy to modulate the rate of transport and cellular uptake of DNCs, and thus be used as a design strategy to achieve enhanced local or systemic drug delivery.

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“…25 A positive surface charge of untargeted polyplexes was necessary for binding to the negatively charged cellular membrane, which in turn facilitated uptake into the cell. [26][27][28] Figure 5A showed that at a w/w ratio of 0.5, the particle size of PEI-Et/pDNA complexes was 379 nm, the zeta potential was 2 mV, indicating poor complexation between pDNA and PEI-Et. However, with an increase in w/w ratio from 1 to 30, PEI-Et could efficiently condense pDNA into nanoparticles with relatively constant diameters ranging from 130 nm to 180 nm, suggesting the formation of stable complexes with a size appropriate for gene delivery.…”

Section: Characterization Of Pei-et/pdna Complexesmentioning

confidence: 99%

Biscarbamate cross-linked polyethylenimine derivative with low molecular weight, low cytotoxicity, and high efficiency for gene delivery

Wang¹,

Su²,

Wu³

et al. 2012

IJN

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Polyethylenimine (PEI), especially PEI 25 kDa, has been widely studied for delivery of nucleic acid drugs both in vitro and in vivo. However, it lacks degradable linkages and is too toxic for therapeutic applications. Hence, low-molecular-weight PEI has been explored as an alternative to PEI 25 kDa. To reduce cytotoxicity and increase transfection efficiency, we designed and synthesized a novel small-molecular-weight PEI derivative (PEI-Et, Mn: 1220, Mw: 2895) with ethylene biscarbamate linkages. PEI-Et carried the ability to condense plasmid DNA (pDNA) into nanoparticles. Gel retardation assay showed complete condensation of pDNA at w/w ratios that exceeded three. The particle size of polymer/pDNA complexes was between 130 nm and 180 nm and zeta potential was 5-10 mV, which were appropriate for cell endocytosis. The morphology of PEI-Et/pDNA complexes observed by atomic force microscopy (AFM) was spherically shaped with diameters of 110-190 nm. The transfection efficiency of polymer/pDNA complexes as determined with the luciferase activity assay as well as fluorescence-activated cell-sorting analysis (FACS) was higher than commercially available PEI 25 kDa and Lipofectamine 2000 in various cell lines. Also, the polymer exhibited significantly lower cytotoxicity compared to PEI 25 kDa at the same concentration in three cell lines. Therefore, our results indicated that the PEI-Et would be a promising candidate for safe and efficient gene delivery in gene therapy.

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Conjugation of Polyamidoamine Dendrimers on Biodegradable Microparticles for Nonviral Gene Delivery

Cited by 74 publications

References 46 publications

Characterization of the transgene expression generated by branched and linear polyethylenimine-plasmid DNA nanoparticles in vitro and after intraperitoneal injection in vivo

Characterization of the transgene expression generated by branched and linear polyethylenimine-plasmid DNA nanoparticles in vitro and after intraperitoneal injection in vivo

Polymeric Nanocarriers for Transport Modulation across the Pulmonary Epithelium: Dendrimers, Polymeric Nanoparticles, and their Nanoblends

Biscarbamate cross-linked polyethylenimine derivative with low molecular weight, low cytotoxicity, and high efficiency for gene delivery

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