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Nicholas J. Szerlip, Stuart Walbridge, Linda Yang, Paul F. Morrison, Jeffrey W. Degen, S. Taylor Jarrell, Joshua Kouri, P. Benjamin Kerr, Robert Kotin, Edward H. Oldfield, and Russell R. Lonser

Object

Despite recent evidence showing that convection-enhanced delivery (CED) of viruses and virus-sized particles to the central nervous system (CNS) is possible, little is known about the factors influencing distribution of these vectors with convection. To better define the delivery of viruses and virus-sized particles in the CNS, and to determine optimal parameters for infusion, the authors coinfused adeno-associated virus ([AAV], 24-nm diameter) and/or feru-moxtran-10 (24 nm) by using CED during real-time magnetic resonance (MR) imaging.

Methods

Sixteen rats underwent intrastriatal convective coinfusion with 4 μl of 35S-AAV capsids (0.5–1.0 × 1014 viral particles/ml) and increasing concentrations (0.1, 0.5, 1, and 5 mg/ml) of a similar sized iron oxide MR imaging agent (ferumoxtran-10). Five nonhuman primates underwent either convective coinfusion of 35S-AAV capsids and 1 mg/ml ferumoxtran-10 (striatum, one animal) or infusion of 1 mg/ml ferumoxtran-10 alone (striatum in two animals; frontal white matter in two). Clinical effects, MR imaging studies, quantitative autoradiography, and histological data were analyzed.

Results

Real-time, T2-weighted MR imaging of ferumoxtran-10 during infusion revealed a clearly defined hypo-intense region of perfusion. Quantitative autoradiography confirmed that MR imaging of ferumoxtran-10 at a concentration of 1 mg/ml accurately tracked viral capsid distribution in the rat and primate brain (the mean difference in volume of distribution [Vd] was 7 and 15% in rats and primates, respectively). The Vd increased linearly with increasing volume of infusion (Vi) (R2 = 0.98). The mean Vd/Vi ratio was 4.1 ± 0.2 (mean ± standard error of the mean) in gray and 2.3 ± 0.1 in white matter (p < 0.01). The distribution of infusate was homogeneous. Postinfusion MR imaging revealed leakback along the cannula track at infusion rates greater than 1.5 μl/minute in primate gray and white matter. No animal had clinical or histological evidence of toxicity.

Conclusions

The CED method can be used to deliver AAV capsids and similar sized particles to the CNS safely and effectively over clinically relevant volumes. Moreover, real-time MR imaging of ferumoxtran-10 during infusion reveals that AAV capsids and similar sized particles have different convective delivery properties than smaller proteins and other compounds.

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Jeffrey W. Degen, Stuart Walbridge, Alexander O. Vortmeyer, Edward H. Oldfield, and Russell R. Lonser

Object. Convection-enhanced delivery (CED) can be used safely to perfuse regions of the central nervous system (CNS) with therapeutic agents in a manner that bypasses the blood—brain barrier (BBB). These features make CED a potentially ideal method for the distribution of potent chemotherapeutic agents with certain pharmacokinetic properties to tumors of the CNS. To determine the safety and efficacy of the CED of two chemotherapeutic agents (with properties ideal for this method of delivery) into the CNS, the authors perfused naive rats and those harboring 9L gliomas with carboplatin or gemcitabine.

Methods. Dose-escalation toxicity studies were performed by perfusing the striatum (10 µl, 24 rats) and brainstem (10 µl, 16 rats) of naive rats with carboplatin (0.1, 1, and 10 mg/ml) or gemcitabine (0.4, 4, and 40 mg/ml) via CED. Efficacy trials involved the intracranial implantation of 9L tumor cells in 20 Fischer 344 rats. The tumor and surrounding regions were perfused with 40 µl of saline (control group, four rats), 1 mg/ml of carboplatin (four rats), or 4 mg/ml of gemcitabine (four rats) 7 days after implantation. Eight rats harboring the 9L glioma were treated with the systemic administration of 60 mg/kg of carboplatin (four rats) or 150 mg/kg of gemcitabine (four rats) 7 days postimplantation. Clinical, gross, and histological analyses were used to determine toxicity and efficacy.

Toxicity occurred in rats that had received only the highest dose of the CED of carboplatin or gemcitabine. Among rats with 9L gliomas, all control and systemically treated animals died within 26 days of tumor implantation. Long-term survival (120 days) and eradication of the tumor occurred in both CED-treated groups (75% of rats in the carboplatin group and 50% of rats in the gemcitabine group). Furthermore, animals harboring the 9L glioma and treated with intratumoral CED of carboplatin or gemcitabine survived significantly longer than controls treated with intratumoral saline (p < 0.01) or systemic chemotherapy (p < 0.01).

Conclusions. The perfusion of sensitive regions of the rat brain can be accomplished without toxicity by using therapeutic concentrations of carboplatin or gemcitabine. In addition, CED of carboplatin or gemcitabine to tumors in this glioma model is safe and has potent antitumor effects. These findings indicate that similar treatment paradigms may be useful in the treatment of glial neoplasms in humans.