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Journal ArticleDOI

Nonviral Vectors for Gene Delivery

01 Feb 2009-Chemical Reviews (American Chemical Society)-Vol. 109, Iss: 2, pp 259-302
TL;DR: Two nonviral gene delivery systems using either biodegradable poly(D,Llactide-co-glycolide) (PLG) nanoparticles or cell penetrating peptide (CPP) complexes have been designed and studied using A549 human lung epithelial cells.
Abstract: The development of nonviral vectors for safe and efficient gene delivery has been gaining considerable attention recently. An ideal nonviral vector must protect the gene against degradation by nuclease in the extracellular matrix, internalize the plasma membrane, escape from the endosomal compartment, unpackage the gene at some point and have no detrimental effects. In comparison to viruses, nonviral vectors are relatively easy to synthesize, less immunogenic, low in cost, and have no limitation in the size of a gene that can be delivered. Significant progress has been made in the basic science and applications of various nonviral gene delivery vectors; however, the majority of nonviral approaches are still inefficient and often toxic. To this end, two nonviral gene delivery systems using either biodegradable poly(D,Llactide-co-glycolide) (PLG) nanoparticles or cell penetrating peptide (CPP) complexes have been designed and studied using A549 human lung epithelial cells. PLG nanoparticles were optimized for gene delivery by varying particle surface chemistry using different coating materials that adsorb to the particle surface during formation. A variety of cationic coating materials were studied and compared to more conventional surfactants used for PLG nanoparticle fabrication. Nanoparticles (~200 nm) efficiently encapsulated plasmids encoding for luciferase (80-90%) and slowly released the same for two weeks. After a delay, moderate levels of gene expression appeared at day 5 for certain positively charged PLG particles and gene expression was maintained for at least two weeks. In contrast, gene expression mediated by polyethyleneimine (PEI) ended at day 5. PLG particles were also significantly less
Citations
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Journal ArticleDOI
TL;DR: The biological barriers to gene delivery in vivo are introduced and recent advances in material sciences, nanotechnology and nucleic acid chemistry that have yielded promising non-viral delivery systems are discussed, some of which are currently undergoing testing in clinical trials.
Abstract: Gene-based therapy is the intentional modulation of gene expression in specific cells to treat pathological conditions This modulation is accomplished by introducing exogenous nucleic acids such as DNA, mRNA, small interfering RNA (siRNA), microRNA (miRNA) or antisense oligonucleotides Given the large size and the negative charge of these macromolecules, their delivery is typically mediated by carriers or vectors In this Review, we introduce the biological barriers to gene delivery in vivo and discuss recent advances in material sciences, nanotechnology and nucleic acid chemistry that have yielded promising non-viral delivery systems, some of which are currently undergoing testing in clinical trials The diversity of these systems highlights the recent progress of gene-based therapy using non-viral approaches

2,460 citations

Journal ArticleDOI
TL;DR: Chemistries that Facilitate Nanotechnology Kim E. Sapsford,† W. Russ Algar, Lorenzo Berti, Kelly Boeneman Gemmill,‡ Brendan J. Casey,† Eunkeu Oh, Michael H. Stewart, and Igor L. Medintz .
Abstract: Chemistries that Facilitate Nanotechnology Kim E. Sapsford,† W. Russ Algar, Lorenzo Berti, Kelly Boeneman Gemmill,‡ Brendan J. Casey,† Eunkeu Oh, Michael H. Stewart, and Igor L. Medintz*,‡ †Division of Biology, Department of Chemistry and Materials Science, Office of Science and Engineering Laboratories, U.S. Food and Drug Administration, Silver Spring, Maryland 20993, United States ‡Center for Bio/Molecular Science and Engineering Code 6900 and Division of Optical Sciences Code 5611, U.S. Naval Research Laboratory, Washington, D.C. 20375, United States College of Science, George Mason University, 4400 University Drive, Fairfax, Virginia 22030, United States Department of Biochemistry and Molecular Medicine, University of California, Davis, School of Medicine, Sacramento, California 95817, United States Sotera Defense Solutions, Crofton, Maryland 21114, United States

1,169 citations

Journal ArticleDOI
TL;DR: This work presents a new generation of high-performance liquid chromatography platforms for selective separation of Na6(CO3) from Na4(SO4) through Na2SO4 and shows real-world applications in drug discovery and treatment of central nervous system disorders.
Abstract: Diagnostics and Therapy Guanying Chen,‡,† Indrajit Roy,†,§ Chunhui Yang,*,‡ and Paras N. Prasad*,† †Institute for Lasers, Photonics, and Biophotonics and Department of Chemistry, University at Buffalo, State University of New York, Buffalo, New York 14260, United States ‡School of Chemical Engineering and Technology, Harbin Institute of Technology, Harbin, Heilongjiang 150001, China Department of Chemistry, University of Delhi, Delhi 110007, India

1,123 citations

Journal ArticleDOI
TL;DR: This review gives a brief overview about some types of stimuli-responsive nanocarriers with the main focus on organic polymer-based systems.

963 citations

Journal ArticleDOI
20 Sep 2010-Small
TL;DR: The latest research on the pathways of entry into live mammalian and plant cells together with intracellular trafficking are described, and the current research progress on the biocompatibility of this material in vitro and in vivo is discussed.
Abstract: The application of nanotechnology in the field of drug delivery has attracted much attention in the latest decades. Recent breakthroughs on the morphology control and surface functionalization of inorganic-based delivery vehicles, such as mesoporous silica nanoparticles (MSNs), have brought new possibilities to this burgeoning area of research. The ability to functionalize the surface of mesoporous-silica-based nanocarriers with stimuli-responsive groups, nanoparticles, polymers, and proteins that work as caps and gatekeepers for controlled release of various cargos is just one of the exciting results reported in the literature that highlights MSNs as a promising platform for various biotechnological and biomedical applications. This review focuses on the most recent progresses in the application of MSNs for intracellular drug delivery. The latest research on the pathways of entry into live mammalian and plant cells together with intracellular trafficking are described. One of the main areas of interest in this field is the development of site-specific drug delivery vehicles; the contribution of MSNs toward this topic is also summarized. In addition, the current research progress on the biocompatibility of this material in vitro and in vivo is discussed. Finally, the latest breakthroughs for intracellular controlled drug release using stimuli-responsive mesoporous-silica-based systems are described.

915 citations

References
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Journal ArticleDOI
TL;DR: Together, these properties make PEI a promising vector for gene therapy and an outstanding core for the design of more sophisticated devices because its efficiency relies on extensive lysosome buffering that protects DNA from nuclease degradation, and consequent lysOSomal swelling and rupture that provide an escape mechanism for the PEI/DNA particles.
Abstract: Several polycations possessing substantial buffering capacity below physiological pH, such as lipopolyamines and polyamidoamine polymers, are efficient transfection agents per se--i.e., without the addition of cell targeting or membrane-disruption agents. This observation led us to test the cationic polymer polyethylenimine (PEI) for its gene-delivery potential. Indeed, every third atom of PEI is a protonable amino nitrogen atom, which makes the polymeric network an effective "proton sponge" at virtually any pH. Luciferase reporter gene transfer with this polycation into a variety of cell lines and primary cells gave results comparable to, or even better than, lipopolyamines. Cytotoxicity was low and seen only at concentrations well above those required for optimal transfection. Delivery of oligonucleotides into embryonic neurons was followed by using a fluorescent probe. Virtually all neurons showed nuclear labeling, with no toxic effects. The optimal PEI cation/anion balance for in vitro transfection is only slightly on the cationic side, which is advantageous for in vivo delivery. Indeed, intracerebral luciferase gene transfer into newborn mice gave results comparable (for a given amount of DNA) to the in vitro transfection of primary rat brain endothelial cells or chicken embryonic neurons. Together, these properties make PEI a promising vector for gene therapy and an outstanding core for the design of more sophisticated devices. Our hypothesis is that its efficiency relies on extensive lysosome buffering that protects DNA from nuclease degradation, and consequent lysosomal swelling and rupture that provide an escape mechanism for the PEI/DNA particles.

6,213 citations

Journal ArticleDOI
TL;DR: Depending upon the cell line, lipofection is from 5- to greater than 100-fold more effective than either the calcium phosphate or the DEAE-dextran transfection technique.
Abstract: A DNA-transfection protocol has been developed that makes use of a synthetic cationic lipid, N-[1-(2,3-dioleyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA). Small unilamellar liposomes containing DOTMA interact spontaneously with DNA to form lipid-DNA complexes with 100% entrapment of the DNA, DOTMA facilitates fusion of the complex with the plasma membrane of tissue culture cells, resulting in both uptake and expression of the DNA. The technique is simple, highly reproducible, and effective for both transient and stable expression of transfected DNA. Depending upon the cell line, lipofection is from 5- to greater than 100-fold more effective than either the calcium phosphate or the DEAE-dextran transfection technique.

5,434 citations


Additional excerpts

  • ...(A) Gel electrophoresis of plasmid DNA extracted from PLG nanoparticles, (1) marker, (2) naked pDNA, (3) PLG-PVA, (4) PLG-PluronicF-127, (5) PLG-PVAm, (6) PLG-Chitosan, (7) PLG-DC-Chol, (8) PLG-Cetrimide, (9) PLG-Protamine, and (10) PLG-DODAB nanoparticles....

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Journal ArticleDOI
23 Mar 1990-Science
TL;DR: RNA and DNA expression vectors containing genes for chloramphenicol acetyltransferase, luciferase, and beta-galactosidase were separately injected into mouse skeletal muscle in vivo and expression was comparable to that obtained from fibroblasts transfected in vitro under optimal conditions.
Abstract: RNA and DNA expression vectors containing genes for chloramphenicol acetyltransferase, luciferase, and beta-galactosidase were separately injected into mouse skeletal muscle in vivo. Protein expression was readily detected in all cases, and no special delivery system was required for these effects. The extent of expression from both the RNA and DNA constructs was comparable to that obtained from fibroblasts transfected in vitro under optimal conditions. In situ cytochemical staining for beta-galactosidase activity was localized to muscle cells following injection of the beta-galactosidase DNA vector. After injection of the DNA luciferase expression vector, luciferase activity was present in the muscle for at least 2 months.

4,022 citations

Journal ArticleDOI
TL;DR: Starburst polymers as mentioned in this paper are a class of topological macromolecules which are derived from classical monomers/oligomers by their extraordinary symmetry, high branching and maximized terminal functionality density.
Abstract: This paper describes the first synthesis of a new class of topological macromolecules which we refer to as “starburst polymers.” The fundamental building blocks to this new polymer class are referred to as “dendrimers.” These dendrimers differ from classical monomers/oligomers by their extraordinary symmetry, high branching and maximized (telechelic) terminal functionality density. The dendrimers possess “reactive end groups” which allow (a) controlled moelcular weight building (monodispersity), (b) controlled branching (topology), and (c) versatility in design and modification of the terminal end groups. Dendrimer synthesis is accomplished by a variety of strategies involving “time sequenced propagation” techniques. The resulting dendrimers grow in a geometrically progressive fashion as shown: Chemically bridging these dendrimers leads to the new class of macromolecules—”starburst polymers” (e.g., (A)n, (B)n, or (C)n).

3,372 citations