Dendrimers in gene delivery

doi:10.1016/j.addr.2005.09.017

Advanced Drug Delivery Reviews

Volume 57, Issue 15, 14 December 2005, Pages 2177-2202

https://doi.org/10.1016/j.addr.2005.09.017 Get rights and content

Abstract

Dendrimers have unique molecular architectures and properties that make them attractive materials for the development of nanomedicines. Key properties such as defined architecture and a high ratio of multivalent surface moieties to molecular volume also make these nanoscaled materials highly interesting for the development of synthetic (non-viral) vectors for therapeutic nucleic acids. Rational development of such vectors requires the link to be made between dendrimer structure and the morphology and physicochemistry of the respective nucleic acid complexes and, furthermore, to the biological performance of these systems at the cellular and systemic level. The review focuses on the current understanding of the role of dendrimers in those aspects of synthetic vector development. Dendrimer-based transfection agents have become routine tools for many molecular and cell biologists but therapeutic delivery of nucleic acids remains a challenge.

Section snippets

Gene therapy

The initial promise that the combination of understanding of the molecular pathways of disease and the complete human genome sequence would yield safer and more efficient medicines and revolutionise the way we treat patients, has not been fulfilled to date. Nevertheless there is little doubt that genetic therapies will make an important contribution to our therapeutic armamentarium once some of the key challenges, such as specific and efficient delivery, have been solved. The fact that an

Dendrimers

Since their conception in the late 1970s and early 1980s the unique properties of dendrimers have spawned a whole range of new research areas ranging from drug and gene delivery applications to processing, diagnostics, and nanoengineering [19].

In comparison to the traditional polymers that initiated a materials revolution in the second half of the last century, dendrimers are relative newcomers. Nevertheless, their special properties have made these highly branched three dimensional

Dendrimer–nucleic acid interaction

The complexation process between dendrimers and nucleic acids does not seem to differ fundamentally from other cationic polymers with high charge density: dendrimers interact with various forms of nucleic acids, such as plasmid DNA or antisense oligonucleotides, to form complexes which protect the nucleic acid from degradation [57], [78], [80]. The interaction between dendrimer and nucleic acids is based on electrostatic interactions [81] and lacks any sequence specificity [80].

During the

In vivo gene expression and experimental therapy

The ability of non-viral systems such as Superfect™ to efficiently transfect various cells in vitro has made synthetic vectors a routine tool in molecular biology. Yet, they have had little impact on the translation of genetic therapies into the clinic to date. It remains a significant challenge to make valid predictions on the in vivo behaviour of synthetic vectors. When one considers the vastly increase complexity of the system that is being introduced by the range of possible interactions

Conclusion

The holy grail for the rational design of synthetic gene delivery systems would clearly be to link chemical structure of cationic complexation agents to the morphology and physicochemistry of the respective nucleic acid complexes and then to further link this to the biological properties on a cellular and systemic level. However, our understanding of each of these steps is still very much incomplete and a large proportion of research remains based on empiricism.

Conceptually the way synthetic

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^☆: This review is part of the Advanced Drug Delivery Reviews theme issue on “Dendrimers: a Versatile Targeting Platform”, Vol. 57/15, 2005.

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Dendrimers in gene delivery☆

Abstract

Section snippets

Gene therapy

Dendrimers

Dendrimer–nucleic acid interaction

In vivo gene expression and experimental therapy

Conclusion

Int. J. Pharm.

Molec. Ther.

Biomed. Pharmacother.

J. Pharm. Sci.

Drug Discov. Today

Pharm. Sci. Technol. Today

Curr. Opin. Chem. Biol.

J. Control. Release

Int. J. Pharm.

Biomaterials

Biochim. Biophys. Acta

Int. J. Pharm.

J. Control. Release

J. Colloid Interface Sci.

Int. J. Pharm.

J. Control. Release

J. Control. Release

Biochim. Biophys. Acta

J. Biol. Chem.

J. Biol. Chem.

China approves first gene therapy

Nat. Biotechnol.

Virus treatment questioned after gene therapy death

Nature

Gene therapy. Panel urges limits on X-SCID trials

Science

Nonviral vectors in the new millennium: delivery barriers in gene transfer

Hum. Gene Ther.

Human gene therapy

Nature

A new DNA vehicle for nonviral gene delivery: supercoiled minicircle

Gene Ther.

Non-viral vectors in cancer gene therapy: principles and progress

Anticancer Drugs

Direct gene transfer into mouse muscle in vivo

Science

Gene expression following direct injection of DNA into liver

Hum. Gene Ther.

Direct gene transfer to mouse melanoma by intratumor injection of free DNA

Gene Ther.

Nonviral gene delivery: techniques and implications for molecular medicine

Expert Rev. Mol. Med.

Evidence for the role of proteoglycans in cation-mediated gene transfer

Proc. Natl. Acad. Sci. U. S. A.

Tumour targeted drug and gene delivery: principles and concepts

Expert Rev. Mol. Med.

Targeting of synthetic gene delivery systems

J. Biomed. Biotechnol.

Discovery of dendrimers and dendritic polymers: a brief historical perspective

J. Polym. Sci., Part A: Polym. Chem.

Synthesis

A new class of polymers—starburst-dendritic macromolecules

Polym. J.

Dendritic macromolecules—synthesis of starburst dendrimers

Macromolecules

Cascade molecules: 2. Synthesis and characterization of a benzene[9]3-arborol

J. Am. Chem. Soc.

Micelles: 1. Cascade molecules—a new approach to micelles — a [27]-arborol

J. Org. Chem.

Dendrimers in drug research

Chem. Soc. Rev.

Catalysis inside dendrimers

Chem. Soc. Rev.

Boron neutron capture therapy of primary and metastatic brain tumors

Mol. Chem. Neuropathol.

Dendritic encapsulation of function: applying nature's site isolation principle from biomimetics to materials science

Angew. Chem., Int. Ed. Engl.

Dendrimeric supramolecular and supramacromolecular assemblies

J. Macromol. Sci.-Polym. Rev. C

preparation of polymers with controlled molecular architecture—a new convergent approach to dendritic macromolecules

J. Am. Chem. Soc.

Polynitrile-functional and polyamine-functional poly(trimethylene imine) dendrimers