Highly efficient eradication of intracranial glioblastoma using Eg5 siRNA combined with HVJ envelope

Abstract

Hemagglutinating virus of Japan envelope (HVJ-E) vector with inactivated replication-defective Sendai virus was originally developed as a versatile drug delivery system. Recently, we have shown the direct tumor-killing activity of HVJ-E itself without therapeutic molecules in prostate cancer cells. Although human glioblastoma cells were also sensitive to HVJ-E treatment, complete eradication was not achieved using HVJ-E alone. Here, to develop more effective therapeutic strategy of glioblastoma, we enhanced the anti-tumor activity by incorporating Short interfering RNA (siRNA) of mitotic motor protein Eg5 into HVJ-E. Treatment with HVJ-E-containing Eg5 siRNA induced monopolar spindle formation and resulted in cell-cycle arrest and apoptosis. When HVJ-E-containing Eg5 siRNA was directly injected into an intradermal tumor xenograft, all mice became tumor-free. Similar results were observed in the intracranial tumor xenografts. The survival time of treated mice was significantly prolonged when HVJ-E was used. Histological examination showed that tumors remained in the brain after treatment with HVJ-E-containing negative control siRNA, but no tumors were detected after treatment with HVJ-E-containing Eg5 siRNA. This remarkable anti-tumor response was likely due to a synergistic effect of Eg5 siRNA and HVJ-E. Thus, this combination shows promise as an attractive novel therapy for glioblastoma.

Gene Therapy of Melanoma Using Inactivated Sendai Virus Envelope Vector (HVJ-E) with Intrinsic Anti-Tumor Activities

“…Therefore, Tween 80-treated HVJ-E can be equipped with both anti-tumor immunities and cancer-killing activities. Recently, we also demonstrated the augmentation of the anti-tumor activities of HVJ-E by incorporating siRNA against motor protein Eg5 in glioblastoma treatment (30). The ability of Eg5 siRNA to induce cell-cycle arrest compensated for HVJ-E in conducting apoptosis.…”

The combination of chemotherapy with HVJ-E containing Rad51 siRNA elicited diverse anti-tumor effects and synergistically suppressed melanoma

“…[11][12][13] Furthermore, HVJ-E itself induces diverse anti-tumor immunity, including dendritic cell maturation, NK cell activation, cytotoxic T lymphocyte (CTL) induction and regulatory T-cell suppression. [14][15][16] Therefore, therapeutic molecules, such as oligonucleotides, plasmids or siRNA, that are packaged into HVJ-E are expected to have increased anti-cancer activities. Here, we tested the dual synergy of the anti-tumor effects of DTIC treatment combined with Rad51 siRNA-encapsulated HVJ-E. Rad51 siRNA enhanced the cancer-killing activity of DTIC, and anti-tumor immune responses were enhanced by HVJ-E.…”

Delivery of RNAi therapeutics: work in progress

“…These ABD nanoparticles were used to mediate functional delivery of anti-CD40 siRNAs to dendritic cells in order to effect actual immunomodulation [66]. In contrast, viral envelopes from the flu virus or Sendai virus (Hemagglutinating Virus of Japan) have been formulated with siRNA in order to generate siRNA-ABD nanoparticles presenting fusogenic viral proteins in order to aid entry to target cell cytoplasms without endocytosis [67][68][69][70]. Finally, the first reports of ABD nanoparticles presenting carbohydate ligands have surfaced.…”