Life science
Medical & healthcare, Drug development, Cancer treatment

Improvement of tumor targeting efficiency of nanoparticles
in combination with oncolytic reovirus
Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences
Associate Professor Fuminori Sakurai
https://researchmap.jp/read0165081/?lang=en

Life science

Abstract
PEGylated liposomes (PEG-liposomes) are a promising drugdelivery vehicle for tumor targeting because of their efficient tumor
disposition profiles. However, tumor targeting of PEG-liposomes
is often disturbed by physical barriers in the tumor, including
tumor cells themselves and extracellular matrices. In this study,
tumor-bearing mice were injected intravenously with oncolytic reovirus before administration of PEG-liposomes to enhance PEG-liposomes’ tumor disposition. Reovirus mediated significant expression of reovirus sigma 3 protein, elevation of apoptosis-related
gene expression, and activation of caspase 3 in the tumors, indicating that reovirus efficiently replicated in the tumors and induced
apoptosis of tumor cells. The tumor disposition levels of PEG-liposomes were approximately doubled by reovirus pre-administration,compared with a PBS-pretreated group. PEG-liposomes werewidely distributed in the tumors of reovirus-pretreated mice, whereas in the PBS-pretreated group, PEG-liposomes were found mainly
around or inside the blood vessels in the tumors. Furthermore, pretreatment with reovirus led to the enhancement of PEG-liposome
accumulation inside the tumors. Combination treatment with reovirus and paclitaxel-loaded PEG-liposomes (PTX-PEG-liposomes)
significantly suppressed the tumor growth. These results provide
important information for clinical use of combination therapy of reovirus and nanoparticle-based drug delivery system (DDS).

▍ Background & Results
PEGylated liposomes (PEG-liposomes) are a promising drugdelivery nanoparticle for tumor targeting because of their efficienttumor disposition profiles via the enhanced permeability and retention (EPR) effect. However, tumor targeting of PEG-liposomes,
particularly their delivery inside the tumors, is often disturbed byphysical barriers in the tumor, including tumor cells themselves,
extracellular matrices, and interstitial pressures. In this study,
tumor-bearing mice were injected intravenously with oncolytic reovirus, which mediates efficient cell lysis activity in not only tumor
cells but also cancer-associated fibroblasts, before administrationof PEG-liposomes to enhance PEG-liposomes’ tumor disposition.
Reovirus mediated significant expression of reovirus sigma 3 protein, elevation of apoptosis-related gene expression, and activation of caspase 3 in the tumors, indicating that virus infection andapoptosis were induced inside the tumors. The tumor dispositionlevels of PEG-liposomes were approximately doubled by reovirus
pre-administration, compared with a PBS-pretreated group. PEG-liposomes were widely distributed in the tumors of reovirus-pretreated mice, whereas in the PBS-pretreated group, PEG-liposomes
were found mainly around or inside the blood vessels in the tumors.
Furthermore, pretreatment with reovirus led to the enhancement ofPEG-liposome accumulation inside the tumors. Combination treatment with reovirus and paclitaxel-loaded PEG-liposomes significantly suppressed the tumor growth.

agents have been developed, and further improvement in therapeutic efficacy can be expected when used in combination withnovel tumor-targeted DDS technologies in the future.

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Figure1. Outline of this study.
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Pretreatment with PBS Pretreatment with reovirus

Figure 2. Tumor
accumulation of ofPEGylated
liposomesliposomes
Figure 2. Tumor
accumulation
PEGylated
Red; PEGylated
liposome, Green;endothelial cells cells
Red；PEGylated
liposome,Green；endothelial▍ Significance of the research and Future perspective
Oncolytic viruses, including reovirus, are expected to enhanceeach other’s antitumor effects when used in combination with tumor-targeted DDS agents. Various types of tumor-targeted DDS
P a t e n t
Tr e a t i s e

Eguchi, Maho; Mizuguchi, Hiroyuki; Sakurai, Fuminori. Pre-treatment of oncolytic reovirus improves tumor accumulation and intratumoral distribution ofPEG-liposomes. Journal of Controlled Release (2023) 354, 35-44. doi: 10.1016/j.jconrel.2022.12.050

URL
K e y w o r d reovirus, tumor targeting, EPR effect, PEGylated liposome, drug delivery system