Shao Xiaodong, Saito Ryuta, Sato Aya, Okuno Saori, Saigusa Daisuke, Saito Ritsumi, Uruno Akira, Osada Yoshinari, Kanamori Masayuki, Tominaga Teiji
Department of Neurosurgery, Tohoku University Graduate School of Medicine.
Department of Neurosurgery, Nagoya University Graduate School of Medicine.
Tohoku J Exp Med. 2023 Nov 11;261(3):187-194. doi: 10.1620/tjem.2023.J069. Epub 2023 Aug 25.
Convection-enhanced delivery (CED) delivers agents directly into tumors and the surrounding parenchyma. Although a promising concept, clinical applications are often hampered by insufficient treatment efficacy. Toward developing an effective CED-based strategy for delivering drugs with proven clinical efficacy, we performed a basic characterization study to explore the locally delivered characteristics of the water soluble nitrosourea nimustine hydrochloride (ACNU). First, ACNU distribution after CED in rodent brain was studied using mass spectrometry imaging. Clearance of C-labeled ACNU after CED in striatum was also studied. ACNU was robustly distributed in rodent brain similar to the distribution of the hydrophilic dye Evans blue after CED, and locally delivered ACNU was observed for over 24 h at the delivery site. Subsequently, to investigate the potential of ACNU to induce an immunostimulative microenvironment, Fas and transforming growth factor-β1 (TGF-β1) was assessed in vitro. We found that ACNU significantly inhibited TGF-β1 secretion and reduced Fas expression. Further, after CED of ACNU in 9L-derived intracranial tumors, the infiltration of CD4/CD8 lymphocytes in tumors was evaluated by immunofluorescence.CED of ACNU in xenografted intracranial tumors induced tumor infiltration of CD4/CD8 lymphocytes. ACNU has a robust distribution in rodent brain by CED, and delayed clearance of the drug was observed at the local infusion site. Further, local delivery of ACNU affects the tumor microenvironment and induces immune cell migration in tumor. These characteristics make ACNU a promising agent for CED.
对流增强递送（CED）可将药物直接递送至肿瘤及其周围实质组织。尽管这是一个很有前景的概念，但临床应用往往因治疗效果不佳而受到阻碍。为了开发一种基于CED的有效策略来递送具有已证实临床疗效的药物，我们进行了一项基础特性研究，以探索水溶性亚硝基脲盐酸尼莫司汀（ACNU）的局部递送特性。首先，使用质谱成像研究了CED后ACNU在啮齿动物脑中的分布。还研究了CED后纹状体中C标记的ACNU的清除情况。与CED后亲水性染料伊文思蓝的分布相似，ACNU在啮齿动物脑中分布广泛，并且在递送部位观察到局部递送的ACNU超过24小时。随后，为了研究ACNU诱导免疫刺激微环境的潜力，在体外评估了Fas和转化生长因子-β1（TGF-β1）。我们发现ACNU显著抑制TGF-β1分泌并降低Fas表达。此外，在9L衍生的颅内肿瘤中进行ACNU的CED后，通过免疫荧光评估肿瘤中CD4/CD8淋巴细胞的浸润情况。ACNU在异种移植颅内肿瘤中的CED诱导了CD4/CD8淋巴细胞向肿瘤浸润。通过CED，ACNU在啮齿动物脑中分布广泛，并且在局部输注部位观察到药物清除延迟。此外，ACNU的局部递送会影响肿瘤微环境并诱导免疫细胞向肿瘤迁移。这些特性使ACNU成为CED的一种有前景的药物。
