Pre-treatment of oncolytic reovirus improves tumor accumulation and intratumoral distribution of PEG-liposomes
Pre-treatment of oncolytic reovirus improves tumor accumulation and intratumoral distribution of PEG-liposomes
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DOI：
10.1016/j.jconrel.2022.12.050
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发表时间：
2023-01-03
影响因子：
10.8
通讯作者：
Sakurai，Fuminori
中科院分区：
文献类型：
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作者：
Eguchi，Maho;Hirata，Seiya;Sakurai，Fuminori
聚乙二醇化脂质体（PEG-liposomes，PEG-liposomes）是一种具有良好的肿瘤靶向性的药物载体，具有良好的肿瘤靶向性和增强的药物渗透性和滞留性（EPR）。然而，聚乙二醇脂质体的肿瘤靶向，特别是其在肿瘤内的递送，通常会受到肿瘤中物理屏障的干扰，包括肿瘤细胞本身、细胞外基质和间质压力。在该研究中，在施用PEG-脂质体之前，用溶瘤呼肠孤病毒静脉内注射携带B16黑色素瘤肿瘤的小鼠，以增强PEG-脂质体的肿瘤处置。接种呼肠孤病毒后3天，肿瘤组织中呼肠孤病毒sigma 3蛋白表达明显增强，凋亡相关基因表达增强，caspase 3激活，肿瘤组织中可见凋亡细胞。这些数据表明呼肠孤病毒在肿瘤中有效地复制并诱导肿瘤细胞凋亡。与PBS预处理组相比，通过呼肠孤病毒预给药，PEG-脂质体的肿瘤处置水平大约加倍。PEG脂质体在呼肠孤病毒预处理小鼠的肿瘤中广泛分布，而在PBS预处理组中，PEG脂质体主要在肿瘤中的血管周围或内部被发现。用呼肠孤病毒预处理还改善了PEG-脂质体在人胰腺BxPC-3肿瘤中的肿瘤积累。整个BxPC-3肿瘤的3D成像分析表明，用呼肠孤病毒预处理导致肿瘤内PEG-脂质体积累的增强。用呼肠孤病毒和紫杉醇负载的PEG-脂质体（PTX-PEG-脂质体）的组合治疗显著抑制B16肿瘤生长。这些结果为呼肠孤病毒与纳米给药系统（DDS）联合治疗的临床应用提供了重要信息。
PEGylated liposomes (PEG-liposomes) are a promising drug delivery vehicle for tumor targeting because of their efficient tumor disposition profilesviathe enhanced permeability and retention (EPR) effect. However, tumor targeting of PEG-liposomes, particularly their delivery inside the tumors, is often disturbed by physical barriers in the tumor, including tumor cells themselves, extracellular matrices, and interstitial pressures. In this study, B16 melanoma tumor-bearing mice were injected intravenously with oncolytic reovirus before administration of PEG-liposomes to enhance PEG-liposomes' tumor disposition. Three days after reovirus administration, significant expression of reovirus sigma 3 protein, elevation of apoptosis-related gene expression, and activation of caspase 3 in the tumors were found. Apoptotic cells were found inside the tumors. These data indicated 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 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. Pre-treatment with reovirus also improved the tumor accumulation of PEG-liposomes in human pancreatic BxPC-3 tumors. 3D imaging analysis of whole BxPC-3 tumors demonstrated that 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 B16 tumor growth. These results provide important information for clinical use of combination therapy of reovirus and nanoparticle-based drug delivery system (DDS).