New Class of Polymers for the Delivery of Macromolecular Therapeutics (original) (raw)
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Development and Characterization of New Cyclodextrin Polymer-Based DNA Delivery Systems
Bioconjugate Chemistry, 2008
In this study, we investigated whether a cyclodextrin polymer (poly CD) complexed with cationic adamantyl derivatives (Ada) could be used as a vector for gene delivery. DNA compaction as a function of adamantyl/DNA phosphate ratio (A/P) by this new class of vector was demonstrated using surface enhanced Raman spectroscopy, potential measurements, and DNA retardation assays. Transfection data highlight the relationship between in Vitro gene delivery efficiency and the combination of several physical properties of the poly CD/Ada/DNA polyplexes, including cationic polar headgroup valency and chemical structure of the spacer arm of Ada connectors, the adamantyl/DNA phosphate ratio (A/P) of the poly CD/Ada/DNA polyplexes, and the ionic strength of the medium. Finally, when associating the best formulation with a fusogenic peptide, we reached transfection levels which were of the same order as those obtained with DOTAP.
Biomaterials, 2007
A series of novel cationic star polymers were synthesized by conjugating multiple oligoethylenimine (OEI) arms onto an a-cyclodextrin (a-CD) core as nonviral gene delivery vectors. The molecular structures of the a-CD-OEI star polymers, which contained linear or branched OEI arms with different chain lengths ranging from 1 to 14 ethylenimine units, were characterized by using size exclusion chromatography, 13 C and 1 H NMR, and elemental analysis. The a-CD-OEI star polymers were studied in terms of their DNA binding capability, formation of nanoparticles with plasmid DNA (pDNA), cytotoxicity, and gene transfection in cultured cells. All the a-CD-OEI star polymers could inhibit the migration of pDNA on agarose gel through formation of complexes with pDNA, and the complexes formed nanoparticles with sizes ranging from 100 to 200 nm at N/P ratios of 8 or higher. The star polymers displayed much lower in vitro cytotoxicity than that of branched polyethylenimine (PEI) of molecular weight 25K. The a-CD-OEI star polymers showed excellent gene transfection efficiency in HEK293 and Cos7 cells. Generally, the transfection efficiency increased with an increase in the OEI arm length. The star polymers with longer and branched OEI arms showed higher transfection efficiency. The best one of the star polymers for gene delivery showed excellent in vitro transfection efficiency that was comparable to or even higher than that of branched PEI (25K). The novel a-CD-OEI star polymers with OEI arms of different chain lengths and chain architectures can be promising new nonviral gene delivery vectors with low cytotoxicity and high gene transfection efficiency for future gene therapy applications. r
Macromolecules, 2018
A family of mPEG-b-polycarbonate (mPEG-PC) diblock pendant polymers were synthesized from trimethylene carbonate and other cyclic carbonate monomers bearing hydrophobic guest ligands via organocatalytic ringopening polymerization using 1,4,5-triazabicyclo[4.4.0]dec-5ene catalyst or 1,8-diazabicyclo[5.4.0]undec-7-ene/thiourea cocatalyst. Diblock copolymers composed of a methoxypoly-(ethylene oxide) (mPEG) block and a polycarbonate block containing either homopolymer or mixed polycarbonates (PC) were prepared by homopolymerization or copolymerization of the cyclic carbonate monomers in the presence of mPEG2000 or mPEG5000 initiator to give materials having a tunable pendant group density along the polycarbonate backbone. Polycarbonate blocks targeting the 2.4−10 kDa range were prepared with good molecular weight control and modest polydispersities (averaging ∼1.3). Complexation of plasmid DNA with β-cyclodextrin−polyethylenimine2.5 kDa produced nanoparticle cores that were then coated with the mPEG−PC diblock copolymers to produce transfection complexes in the 100−250 nm size range. Stable transfection complexes prepared at N/P ratios >10 had slightly positive ζ potentials and showed comparable or modestly better transfection efficiencies in HeLa cells than the commercial transfection agent, Lipofectamine2000. Transfection efficiencies were not dependent on polycarbonate block molecular weights. The mPEG-PC constructs displayed similar efficacy for adamantyl and cholesteryl pendants that strongly bind to β-cyclodextrin; however, slightly better performance was observed for the weakly bound pendant, benzyl. These findings suggest that pDNA release is largely mediated by hydrolysis of the ester-bound pendant ligand within the endolysosomal compartment of the cell, with desorption of the mPEG−PC layer also contributing to plasmid release and activation in the case of weak binding pendant groups. We infer from these results that mPEG-PC may be an effective degradable transfection agent for in vivo applications.
Current Trends in the Use of Cationic Polymer Assemblies for siRNA and Plasmid DNA Delivery
Pharmaceutical Nanotechnology, 2013
Gene therapy is a promising approach for disease prevention and therapy. Efficient gene delivery is an important factor limiting gene delivery. Due to the poor stability of nucleotide molecules in vivo, they require an association with delivery systems to overcome extracellular and intracellular barriers and allow access to the site of action. In this review, we discuss the challenges currently encountered in the delivery of DNA and RNAi-based therapies using the most common cationic polymer assemblies including polylysines, chitosan, polyethylenimines, dendrimers, cyclodextrins and illustrate with examples how chemical modification of cationic assemblies may contribute to their successful application in the clinic.
Biomacromolecules, 2012
A cyclodextrin-based supramolecular hydrogel system with supramolecularly anchored active cationic copolymer/plasmid DNA (pDNA) polyplexes was studied as a sustained gene delivery carrier. A few biodegradable triblock copolymers of methoxy-poly(ethylene glycol)-b-poly-(ε-caprolactone)-b-poly[2-(dimethylamino)ethyl methacrylate] (MPEG-PCL-PDMAEMA) with well-defined cationic block lengths were prepared to condense pDNA. The MPEG-PCL-PDMAEMA copolymers exhibit good ability to condense pDNA into 275−405 nm polyplexes with hydrophilic MPEG in the outer corona. The MPEG corona imparted greater stability to the pDNA polyplexes and also served as an anchoring segment when the pDNA polyplexes were encapsulated in α-CD-based supramolecular polypseudorotaxane hydrogels. More interestingly, the resultant hydrogels were able to sustain release of pDNA up to 6 days. The pDNA was released in the form of polyplex nanoparticles as it was bound electrostatically to the cationic segment of the MPEG-PCL-PDMAEMA copolymers. The bioactivity of the released pDNA polyplexes at various durations was further investigated. Protein expression level of pDNA polyplexes released over the durations was comparable to that of freshly prepared PEI polyplexes. Being thixotropic and easily prepared without using organic solvent, this supramolecular in situ gelling system has immense potential as an injectable carrier for sustained gene delivery.
2005
Nucleic acid delivery has many applications in basic science, biotechnology, agriculture, and medicine. One of the main applications is DNA or RNA delivery for gene therapy purposes. Gene therapy, an approach for treatment or prevention of diseases associated with defective gene expression, involves the insertion of a therapeutic gene into cells, followed by expression and production of the required proteins. This approach enables replacement of damaged genes or expression inhibition of undesired genes. Following two decades of research, there are two major methods for delivery of genes. The first method, considered the dominant approach, utilizes viral vectors and is generally an efficient tool of transfection. Attempts, however, to resolve drawbacks related with viral vectors (e.g., high risk of mutagenicity, immunogenicity, low production yield, limited gene size, etc.), led to the development of an alternative method, which makes use of non-viral vectors. This review describes non-viral gene delivery vectors, termed "self-assembled" systems, and are based on cationic molecules, which form spontaneous complexes with negatively charged nucleic acids. It introduces the most important cationic polymers used for gene delivery. A transition from in vitro to in vivo gene delivery is also presented, with an emphasis on the obstacles to achieve successful transfection in vivo.
Biomaterials, 2009
Herein, we report the efficient synthesis of high molecular weight polymers (up to 331 kDa) that contain b-cyclodextrin within the polymer backbone and the examination of these structures for pDNA delivery within cultured mammalian cells. Two series of polymers were synthesized, one with variation in oligoethyleneamine stoichiometry, Cd1 46 , Cd2 44 , Cd3 49 , and Cd4 47 (1-4 oligoethyleneamines in the repeat unit, respectively and similar degree of polymerization, n w ¼ 44-49) and another with variation in polymer length (four ethyleneamines in the repeat unit), Cd4 27 , Cd4 47 , Cd4 93 , and Cd4 200 [n w ¼ 27, 47, 93, 200] via the ''click reaction''. The two series of polymers revealed efficient pDNA binding and compaction through gel electrophoresis, dynamic light scattering, and transmission electron microscopy experiments. The DNase protection assay showed a decrease in pDNA degradation with an increase in the polymer amine stoichiometry, where polymer Cd3 49 and all of the Cd4 analogs completely protected pDNA for up to 8 h in serum. The cellular uptake and gene expression profiles were examined in HeLa cells, which similarly demonstrated that both the series of polymers had high pDNA delivery where, Cd3 49 and Cd4 93 had the most effective luciferase gene expression. In addition, the cell viability profiles were quite high with all of the structures.