Systemic administration of a PEGylated adenovirus vector with a cancer-specific promoter is effective in a mouse model of metastasis

Abstract

Cancer gene therapy by adenovirus vectors (Advs) for metastatic cancer is limited because systemic administration of Adv produces low therapeutic effect and severe side effects. In this study, we generated a dual cancer-specific targeting vector system by using PEGylation and the telomere reverse transcriptase (TERT) promoter and attempted to treat experimental metastases through systemic administration of the vectors. We first optimized the molecular size of PEG and modification ratios used to create PEG-Ads. Systemic administration of PEG-Ad with 20-kDa PEG at a 45% modification ratio (PEG[20K/45%]-Ad) resulted in higher tumor-selective transgene expression than unmodified Adv. Next, we examined the effectiveness against metastases and side effects of a TERT promoterdriven PEG[20K/45%]-Ad containing the herpes simplex virus thymidine kinase (HSVtk) gene (PEG-Ad-TERT/ HSVtk). Systemic administration of PEG-Ad-TERT/HSVtk showed superior antitumor effects against metastases with negligible side effects. A cytomegalovirus (CMV) promoter-driven PEG[20K/45%]-Ad also produced antimetastatic effects, but these were accompanied by side effects. Combining PEG-Ad-TERT/HSVtk with etoposide or 5-fluorouracil enhanced the therapeutic effects with negligible side effects. These results suggest that modification with 20-kDa PEG at a 45% modification ratio is the optimal condition for PEGylation of Adv, and PEG-Ad-TERT/HSVtk is a prototype Adv for systemic cancer gene therapy against metastases.

Intravenous Administration of Polyethylene Glycol-Coated (PEGylated) Proteins and PEGylated Adenovirus Elicits an Anti-PEG Immunoglobulin M Response

“…13,14) Furthermore, although still in the preclinical stage, PEGylated adenoviruses (PEG-Ad) have been developed and have shown higher accumulation rates, stronger tumor-suppressive activity, and fewer hepatotoxic side effects than unmodified adenoviruses (Ad). 10,[15][16][17][18] In contrast to the preceding argument, we and others have reported that PEGylated liposomes lose the expected long circulating property when they are injected repeatedly in the same animal (the so-called accelerated blood clearance (ABC) phenomenon). 19,20) On the basis of our earlier results, 21,22) we proposed the following tentative mechanism for the cause of this phenomenon: anti-PEG IgM, which is produced in the spleen in response to the initial dose, selectively binds to the PEG of the second dose liposomes injected several days later Regular Article * To whom correspondence should be addressed.…”

“…[15][16][17][18] In addition, they showed that the PEGylation to Ad can avoid production of specific neutralizing Abs to Ad following intravenous administration. 17) However, in the present study, we observed that a single intravenous injection of PEG-Ad elicits anti-PEG IgM, although neutralizing anti-Ad Abs were not detected (Fig.…”

“…The modification ratio of each PEGylated adenovirus (PEG-Ad) was determined by SDS-PAGE analysis as described previously. 15,16) The ratios were approximately 30, 45 and 90%, and were dependent on the PEG amount required to elicit a reaction. The particle size of PEG-Ad was measured using a ZETASIZER 3000HS (Malvern, U.K.) and was approximately 100 nm, irrespective of the modification ratio and size of the PEG.…”

“…[15][16][17][18] We investigated whether PEG-Ad elicits an anti-PEG IgM response similar to PEG-proteins and PEGylated liposome as described above. All PEG-Ads used in this study obviously induced an anti-PEG IgM response at day 5 after a single intravenous injection (Fig.…”

Gene therapy for C-26 colon cancer using heparin-polyethyleneimine nanoparticle-mediated survivin T34A

“…[2][3][4] These features make survivin of interest in targeted cancer therapy. 5 Gene therapy holds promise for the treatment of various diseases for which there is little hope of finding a conventional cure. 6 Cancer is the leading cause of death in economically developed countries, 7 and is a major public health problem throughout the world.…”