The clinical application of chemotherapy to brain tumors has been severely limited because antitumor agents are typically unable to penetrate an intact blood-brain barrier (BBB). Although doxorubicin (DOX) has been named as a strong candidate for chemotherapy of the central nervous system (CNS), the BBB often prevents cytotoxic levels from being achieved. In this study, we demonstrate a noninvasive method for the targeted delivery of DOX through the BBB, such that drug levels shown to be therapeutic in human tumors are achieved in the normal rat brain. Using MRI-guided focused ultrasound with preformed microbubbles (Optison) to locally disrupt the BBB and systemic administration of DOX, we achieved DOX concentrations of 886 6 327 ng/g tissue in the brain with minimal tissue effects. Tissue DOX concentrations of up to 5,366 6 659 ng/g tissue were achieved with higher Optison doses, but with more significant tissue damage. In contrast, DOX accumulation in nontargeted contralateral brain tissue remained significantly lower for all paired samples (p < 0.001). These results suggest that targeted delivery by focused ultrasound may render DOX chemotherapy a viable treatment option against CNS tumors, despite previous accessibility limitations. In addition, MRI signal enhancement in the sonicated region correlated strongly with tissue DOX concentration (r 5 0.87), suggesting that contrast-enhanced MRI could perhaps indicate drug penetration during image-guided interventions. Our technique using MRIguided focused ultrasound to achieve therapeutic levels of DOX in the brain offers a large step forward in the use of chemotherapy to treat patients with CNS malignancies. ' 2007 Wiley-Liss, Inc.
The blood-brain barrier (BBB) inhibits the entry of the majority of chemotherapeutic agents into the brain. Previous studies have illustrated the feasibility of drug delivery across the BBB using focused ultrasound (FUS) and microbubbles. Here, we investigated the effect of FUS-enhanced delivery of doxorubicin on survival in rats with and 9L gliosarcoma cells inoculated in the brain. Each rat received either: (1) no treatment (control; N=11), (2) FUS only (N=9), (3) i.v. liposomal doxorubicin (DOX only; N=17), or (4) FUS with concurrent i.v. injections of liposomal doxorubicin (FUS+DOX; N=20). Post-treatment MRI showed that FUS+DOX reduced tumor growth compared to DOX only. Further, we observed a modest but significant increase in median survival time after a single treatment FUS+DOX treatment (p=0.0007), whereas neither DOX nor FUS had any significant impact on survival on its own. These results suggest that combined ultrasound-mediated BBB disruption may significantly increase the antineoplastic efficacy of liposomal doxorubicin in the brain.
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