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  • Review Article
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Design and development of polymers for gene delivery

Nature Reviews Drug Discovery volume 4, pages 581–593 (2005)Cite this article

Key Points

  • Human gene therapy utilizes genetic material – DNA or RNA – as a therapeutic for genetic, acquired and infectious diseases. Gene therapy's potential is great, but the lack of safe and efficient gene delivery methods is a limiting obstacle to clinical implementation.

  • Gene delivery methods include recombinant viruses and synthetic materials such as lipids, polypeptides and polymers. Safety concerns limit the use of viral vectors. Non-viral gene delivery is typically much safer but suffers from generally unsatisfactory delivery efficiency.

  • Gene delivery vectors should protect the genetic material from nucleolytic enzymes, provide potentially long lifetime in the blood, and direct delivery to a specific tissue or cells. Furthermore, the vector must provide a mechanism for entering the target cell, transiting the cytosol, crossing the nuclear membrane and releasing the genetic material at the appropriate point in this process. Non-viral vectors typically lack one or more of the necessary functions.

  • The earliest synthetic vehicles reported in the literature are off-the-shelf materials, not originally designed for gene delivery. These include polylysine, polyethylenimine, and poly(amido amine) dendrimers. The gene delivery efficacy of such materials is serendipitous and, perhaps not surprisingly, typically insufficient for clinical application.

  • In recent years, a variety of polymers have been designed specifically for gene delivery. Often, such polymers are designed to be non-toxic and to address particular steps in the gene delivery process, for example, escape from endocytic vesicles into the cytoplasm. While many of these materials are better than off-the-shelf polymers, their delivery efficiency remains several orders of magnitude below that of recombinant viruses.

  • Based on the large number of studies of off-the-shelf and specifically designed gene delivery polymers, much has been learned about the structure-function relationships of polymer vectors. With growing understanding of polymer gene delivery mechanisms and continued efforts of creative and talented polymer chemists, it is likely that polymer-based gene delivery systems will become an important tool for human gene therapy.

Abstract

The lack of safe and efficient gene-delivery methods is a limiting obstacle to human gene therapy. Synthetic gene-delivery agents, although safer than recombinant viruses, generally do not possess the required efficacy. In recent years, a variety of effective polymers have been designed specifically for gene delivery, and much has been learned about their structure–function relationships. With the growing understanding of polymer gene-delivery mechanisms and continued efforts of creative polymer chemists, it is likely that polymer-based gene-delivery systems will become an important tool for human gene therapy.

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Figure 1: Polyplex formation.
Figure 2: Barriers to intracellular trafficking of polyplexes.
Figure 4: Schematic of the proton-sponge mechanism.
Figure 3: Structures of off-the-shelf gene-delivery polymers.
Figure 5: Structures of several polymers designed for gene delivery.

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Authors and Affiliations

  1. Department of Chemical and Biomolecular Engineering, University of Illinois, Box C-3, 600 South Mathews Avenue, Urbana, 61801, Illinois, USA

    Daniel W. Pack

  2. Department of Bioengineering, University of Washington, Box 352255, Seattle, 98195, Washington, USA

    Allan S. Hoffman, Suzie Pun & Patrick S. Stayton

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FURTHER INFORMATION

American Society of Gene Therapy

Controlled Release Society

Gene Therapy Clinical Trials Worldwide

Glossary

LIPOPLEXES

Nanoparticles similar to polyplexes but formed by complexation of cationic lipids (or liposomes containing cationic lipids) and DNA.

POLYPLEXES

Nanoparticles, typically ∼100 nm in diameter, formed by electrostatic complexation of cationic polymers (or polypeptides) and DNA.

RECEPTOR-MEDIATED ENDOCYTOSIS

The process by which cells internalize various nutrients and signalling molecules. Binding of the ligand to a specific plasma membrane-bound receptor protein generally initiates the formation of clathrin-coated pits and subsequently formation of a vesicle (the endosome) inside the cell. Viruses, drugs and delivery vectors can also be internalized by displaying the natural ligand or an analogue.

TRANSFECTION

Delivery of biomolecules, usually DNA or RNA, into mammalian cells in culture mediated by synthetic reagents such as polymers, polypeptides or lipids.

ENDOLYSOSOMES

Cytoplasmic vacuoles formed by inward budding of the cell membrane during endocytosis. The organelles, first known as endosomes, acidify and fuse with enzyme-carrying vesicles from the Golgi to become lysosomes.

IMPORTINS

Cytoplasmic proteins that bind nuclear localization signal peptides and, therefore, target proteins for transport across the nuclear membrane. Importins are recognized by the nuclear pore complex, a macromolecular assembly of more than 100 different proteins, and translocated (along with their cargo molecule) through the pore by an energy-dependent mechanism.

INCLUSION COMPLEXES

Bi-molecular complexes in which the 'host' forms a cavity into which the 'guest' molecule binds through non-covalent (van der Waals) interactions.

SUICIDE GENE

A gene that, once expressed in a target cell, causes death of the cell — for example, by initiating apoptosis or making the cell susceptible to the activity of a prodrug. One example of the latter is herpes simplex thymidine kinase, which activates drugs such as acyclovir and ganciclovir.

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Pack, D., Hoffman, A., Pun, S. et al. Design and development of polymers for gene delivery. Nat Rev Drug Discov 4, 581–593 (2005). https://doi.org/10.1038/nrd1775

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