Recent advances in the targeting of systemically administered non-viral gene delivery systems

ABSTRACT

Introduction: Systemically administered non-viral gene delivery systems face multiple biological barriers that decrease their efficiency. These systems are rapidly cleared from the circulation and sufficient concentrations do not accumulate in diseased tissues. A number of targeting strategies can be used to provide for sufficient accumulation in the desired tissues to achieve a therapeutic effect.

Areas covered: We discuss recent advances in the targeting of non-viral gene delivery systems to different tissues after systemic administration. We compare passive and active targeting applied for tumor delivery and propose some strategies that can be used to overcome the drawbacks of each case. We also discuss targeting the liver and lungs as two particularly important organs in gene therapy.

Expert opinion: There is currently no optimum non-viral gene delivery system for targeting genes to specific tissues. The dose delivered to tumor tissues using passive targeting is low and shows a high patient variation. Although active targeting can enhance binding to specific cells, only a few reports are available to support its value in vivo. The design of smart nanocarriers for promoting active targeting is urgently needed and targeting the endothelium is a promising strategy for gene delivery to tumors as well as other organs.

KEYWORDS:

• Delivery
• target
• passive
• active
• endothelium
• nanoparticles

Article highlights

• The key for successful gene therapy after systemic administration is to improve the accumulation of the therapeutic gene in targeted tissues as well as to enhance the efficiency of expression of these genes in selected cells.

• The enhanced permeability and retention (EPR) effect is the main mechanism for tumor delivery in passive targeting.

• The EPR effect has been shown to be highly heterogeneous among patients and even among lesions in the same patient, indicating the importance of personalization of gene delivery in cancer.

• Active targeting using ligands that bind to specific cell surface components increases internalization by cells, which is particularly useful for carriers containing nucleic acids.

• Different strategies are used to improve passive and active targeting of gene delivery systems to specific tissues.

• The gene delivery system must be efficiently internalized in target cells and must release the encapsulated nucleic acids into the cytosol in sufficient concentrations.

• Improving the efficiency of gene expression requires the use of novel biomaterials that enhance cellular uptake, endosomal escape, and the release of genes from their carriers.

This box summarizes key points contained in the article.

Acknowledgments

The authors wish to thank Milton S. Feather for editing the English in this manuscript.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript is supported by the Special Education and Research Expenses of the Ministry of Education, Culture, Sports, Science and Technology of Japan.