The use of gene transduction by viral vectors in human gene therapy is currently attracting a great deal of attention. In cancer therapy, gene therapy is expected to play a key role in next-generation treatments, as well as in complementing conventional treatment modalities, such as surgery, chemotherapy, and radiotherapy.1,2) Adenovirus vectors (Adv) have been very useful in clinical gene therapy because of their ability to propagate to a high titer and efficiently transduce cells and tissues regardless of the mitotic status of the cells. 3,4) Intratumoral injection of Adv has demonstrated therapeutic efficacy against primary tumors in several clinical trials. 5,6) However, the clinical application of Adv has been limited by several problems. The systemic administration of Adv can lead to the acute accumulation of Adv and transgene expression in the liver, which may cause marked hepatotoxicity and activate the acquired immune response.
4,7)Since systemic administration is required to treat distant metastases, it is currently difficult to use Adv to treat metastatic tumors, which are the major cause of mortality from cancer. Furthermore, because neutralizing antibodies (Abs) to Adv are highly prevalent in the human population, administration of high doses of Adv, which are needed to obtain sufficient therapeutic effects, causes negative side-effects. 8,9) In addition, neutralizing anti-Adv Abs are produced after administration of Adv in animal models.10,11) These preexisting or Adv-induced Abs can adversely affect the therapeutic effect of the Adv by attenuating the level of transgene expression.Covalent conjugation of polyethleneglycol (PEG) to the Adv surface, by a process called "PEGylation," is the one of the promising strategies to overcome these limitations. 4,12,13) Because of the steric hindrance of the PEG molecule, PEGylation can prolong the plasma half-life of molecules, prevent hepatic uptake, and alter the tissue distribution of the conjugates compared with the native form.14,15) The extended circulating lifetime in the blood induces the "enhanced permeability and retention" (EPR) effect, which is due to the leaky nature of tumor blood vessels. This effect results in increased delivery of the conjugates to tumor tissue. 16) We have examined the in vitro and in vivo characteristics of PEGylated Adv (PEG-Ad) manufactured using PEG of various molecular weights, and with various PEG modification rates. 17,18) With optimized modification conditions, PEG-Ad showed higher accumulation rates and transgene expression in tumors than unmodified Adv after systemic administration, due to the EPR effect.17,18) Furthermore, we showed that PEG-Ad encoding a therapeutic gene produced both stronger tumor-suppressive activity and fewer hepatotoxic side effects than unmodified Adv, suggesting that systemic administration of PEG-Ad has great potential for systemic cancer gene therapy. 17,18) In addition, we and others have reported that PEG-Ad can evade pre-existing neutralizing anti-Adv Abs, thereby making repeated vec...
