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Locoregional Delivery of Adenoviral Vectors

¹ Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands; ² Department of Nuclear Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands; and ³ Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands

Correspondence: For correspondence or reprints contact: Peter A.E. Sillevis Smitt, MD, PhD, Department of Neurology, Erasmus University Medical Center, Dr Molewaterplein 40, Room H664, 3015 GD, Rotterdam, The Netherlands. E-mail: p.sillevissmitt{at}erasmusmc.nl

The overall median survival of patients with a malignant glioma is <1 y. Because malignant gliomas rarely metastasize outside the skull, locoregional treatment strategies, such as gene therapy, are under investigation. Recently, convection-enhanced delivery (CED) has been presented as a method to improve delivery of large molecules. The goal of this study was to evaluate whether CED improves intratumoral delivery of adenoviral vectors and compare it with single injection (SI) and multiple injection (4x, MI). Methods: A replication-deficient adenoviral vector encoding the herpes simplex virus thymidine kinase (HSV-tk) and the human somatostatin receptor subtype 2 (sst₂) was administered into nude mice bearing subcutaneous U87 xenografts. Tumors were injected with 1.5 x 10⁹ plaque-forming units of Ad5.tk.sstr by CED, SI, or MI. Three days later, [^99mTc-N₄^0–1,Asp⁰,Tyr³]octreotate (^99mTc-Demotate 2) was injected intravenously to monitor the virus-induced sst₂ expression. -Camera imaging was performed for in vivo imaging, and the tumor uptake of ^99mTc-Demotate 2 was determined by -counter. Furthermore, the tumor was sectioned and ex vivo autoradiography was performed. After decay of radioactivity, adjacent sections were submitted to in vitro autoradiography with ¹²⁵I-DOTA-Tyr³-octreotate, which was used to calculate the transduced areas. Results: Transfected xenograft tissues showed high sst₂ expression and were clearly visualized with a -camera. Accumulation of radioactivity was 2-fold higher in the tumors that were injected with MI compared with CED and SI (P = 0.01). CED and SI resulted in equal uptake of radioactivity in the tumors. The measured areas of transduction in ex vivo and in vitro autoradiographs showed a high concordance (r² = 0.89, P < 0.0001). The maximum area of transfection was significantly larger after MI than after CED (P < 0.05) or SI (P = 0.05). Also, the measured volume of distribution was twice as high after administration of Ad5.tk.sstr by MI (56.6 mm³) compared with SI (25.3 mm³) or CED (26.4 mm³). Conclusion: CED does not increase adenoviral vector distribution in a glioma xenograft model compared with SI. Therefore, in the clinic MI is probably the most effective delivery method for the large adenoviral particle (70 nm) in malignant gliomas.

Key Words: [^99mTc-N₄^0–1,Asp⁰,Tyr³]octreotate • somatostatin receptor • adenovirus • glioma • convection-enhanced delivery

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