No abstract

This tacrolimus population PK model will be a valuable tool in developing rational guidelines and provides a basis for individualized therapy after kidney transplantation in clinical settings of Korea.

Oncolytic virotherapy is a promising alternative to conventional treatment, yet systemic delivery of these viruses to tumors remains a major challenge. In this regard, mesenchymal stem cells (MSC) with well-established tumor-homing property could serve as a promising systemic delivery tool. We showed that MSCs could be effectively infected by hepatocellular carcinoma (HCC)-targeted oncolytic adenovirus (HCC-oAd) through modification of the virus' fiber domain and that the virus replicated efficiently in the cell carrier. HCCtargeting oAd loaded in MSCs (HCC-oAd/MSC) effectively lysed HCC cells in vitro under both normoxic and hypoxic conditions as a result of the hypoxia responsiveness of HCC-oAd. Importantly, systemically administered HCC-oAd/MSC, which were initially infected with a low viral dose, homed to HCC tumors and resulted in a high level of virion accumulation in the tumors, ultimately leading to potent tumor growth inhibition. Furthermore, viral dose reduction and tumor localization of HCC-oAd/MSC prevented the induction of hepatotoxicity by attenuating HCC-oAd hepatic accumulation. Taken together, these results demonstrate that MSCmediated systemic delivery of oAd is a promising strategy for achieving synergistic antitumor efficacy with improved safety profiles. Significance: Mesenchymal stem cells enable delivery of an oncolytic adenovirus specifically to the tumor without posing any risk associated with systemic administration of naked virions to the host.

Oncolytic adenovirus (Ad) is a promising candidate for cancer gene therapy. However, as a monotherapy, it has shown insufficient therapeutic efficacy in clinical trials. In this work, we demonstrate that gold nanorod (GNR)-mediated mild hyperthermia enhances the cellular uptake and consequent gene expression of oncolytic Ad to head and neck tumor cells. We examined the combination of oncolytic Ad expressing vascular endothelial growth factor promoter-targeted artificial transcriptional repressor zinc-finger protein and GNR-mediated mild hyperthermia to improve antitumor effects. The in vitro mechanisms of increased transduction in the presence and absence of hyperthermia were explored followed by evaluation of efficacy of this combination strategy in an animal model. Exposure to optimized hyperthermia conditions improved endocytosis of oncolytic Ad, transgene expression, viral replication, and subsequent cytolysis of head and neck cancer cells. GNR-mediated plasmonic photothermal therapy resulted in precise control of tumor temperature and induction of mild hyperthermia. A combination of oncolytic Ad and GNRs resulted in potent tumor growth inhibition of head and neck tumors.