Local Delivery of Nimustine Hydrochloride against Brain Tumors: Basic Characterization Study

Local Delivery of Nimustine Hydrochloride against Brain Tumors: Basic Characterization Study

Xiaodong Shao,¹ Ryuta Saito,^1,2 Aya Sato,¹ Saori Okuno,¹ Daisuke Saigusa,^3,4,5 Ritsumi Saito,^4,5 Akira Uruno,^4,5 Yoshinari Osada,¹ Masayuki Kanamori¹ and Teiji Tominaga¹

¹Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
²Department of Neurosurgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
³Faculty of Pharma-Science, Teikyo University, Tokyo, Japan
⁴Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
⁵Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Miyagi, Japan

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 ¹⁴C-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.

Key words —— convection-enhanced delivery; glioma; immunostimulation; nimustine hydrochloride; pharmacokinetics

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Tohoku J. Exp. Med., 2023 November, 261(3), 187-194.

Correspondence: Ryuta Saito, Department of Neurosurgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan.

e-mail: ryuta@med.nagoya-u.ac.jp