Review
Development of gene drug delivery systems based on pharmacokinetic studies

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Abstract

A series of pharmacokinetic studies following systemic or local administration for the development of delivery systems for gene drugs, such as plasmid DNA and oligonucleotides, are reviewed. The pharmacokinetics of gene drugs after intravenous injection into mice was evaluated based on clearance concepts. Pharmacokinetic analysis revealed that the overall disposition characteristics of the gene drug itself were determined by the physicochemical properties of its polyanionic DNA. Based on these findings, liver cell-specific carrier systems via receptor-mediated endocytosis were successfully developed by optimizing physicochemical characteristics. On the other hand, the pharmacokinetics of gene drugs after intratumoral injection were assessed in a tissue-isolated tumor perfusion system. The relationship between the physicochemical properties of gene drug delivery systems and intratumoral pharmacokinetics was determined and the therapeutic effect was also discussed in relation to pharmacokinetics. Collectively, it was demonstrated that a rational design of gene drug delivery systems that can control their in vivo disposition is possible by means of pharmacokinetic studies at whole body, organ and cellular levels.

Introduction

The great progress in biotechnology, together with an increased understanding of the molecular mechanisms underlying the pathogenesis of a variety of diseases at the gene level, has resulted in dramatic changes in therapeutic modalities. The first generation of therapeutic recombinant proteins has already reached the market. Furthermore, recombinant plasmid DNA itself has been used like a ‘drug’ in the novel treatment approach of gene therapy, in which genes encoding therapeutic proteins are used to treat a patient. Broadly speaking, antisense therapy where oligonucleotides, relatively small fragments of synthetic DNA designed to hybridize specific mRNA sequences, are used to block gene expression relating to a disease, can also be classified as gene therapy. In vivo delivery of these gene drugs to patients via systemic or local administration like conventional drugs represents an ideal methodology for the treatment of a variety of inherited and acquired diseases. The therapeutic application of gene drugs requires non-invasive and cost-effective methods for gene therapy delivery, which should be safe for repetitive use and provide reproducible therapeutic effects.

To construct a strategy for developing efficient and safe in vivo gene drug delivery systems, a variety of aspects such as the design of the gene therapy itself (efficient tissue-specific promoter and enhancer for plasmids or altered chemistry for oligonucleotides), development of sophisticated carrier systems, pharmacokinetics at whole body, organ, cellular and subcellular levels need to be considered. In particular, a thorough understanding of the in vivo pharmacokinetic and disposition characteristics of gene drugs, their carrier systems and DNA/carrier complexes is important for assessing the availability of administered gene drugs at their target and non-target tissues (Takakura and Hashida, 1996, Takakura et al., 1996a, Mahato et al., 1997a, Mahato et al., 1997b). However, little systematic information is available on the pharmacokinetics of DNA after systemic and local administration.

In this paper, we will review a series of our recent investigations on the development of delivery systems for plasmid DNA and oligonucleotides based on pharmacokinetic studies. The pharmacokinetics of gene therapy delivery systems after systemic and local administration will also be discussed.

Section snippets

Development of gene drug delivery systems after systemic administration

Drug delivery systems can be defined as the methodology for manipulating drug disposition in the body in order to optimize the effect of the drug concerned. In order to construct a rational strategy for developing delivery systems that can control the in vivo disposition of gene drugs after systemic administration, we studied the in vivo stability and basic pharmacokinetic characteristics of model plasmid DNA and oligonucleotides prior to the development of carrier systems. In vivo whole

Development of gene drug delivery systems for local administration

Local administration methods, such as direct injection into the target site and intra-arterial infusion, are being tried for in vivo gene drug delivery. In particular, tumors are one of the most important targets for local injection of gene drug treatments. However, the intratumoral pharmakokinetics of gene drugs are poorly understood.

Conclusions

In this mini-review, we have described our pharmacokinetic studies after systemic and local administration in an attempt to develop gene drug delivery systems. It was demonstrated that a rational design of gene drug delivery systems that can control in vivo disposition of gene drugs, such as plasmid DNA and oligonucleotides, is possible by means of pharmacokinetic studies at whole body, organ and cellular levels. Manipulation of intracellular pharmacokinetics of gene drugs at the subcellular

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