Regular Article Gadolinium-loaded liposomes allow for real-time magnetic resonance imaging of convection-enhanced delivery in the primate brain Ryuta Saito a , Michal T. Krauze a , John R. Bringas a , Charles Noble b , Tracy R. McKnight c , Pamela Jackson c , Michael F. Wendland c , Christoph Mamot b , Daryl C. Drummond d , Dimitri B. Kirpotin d , Keelung Hong d , Mitchel S. Berger a , John W. Park b , Krystof S. Bankiewicz a, * a Department of Neurological Surgery, Brain Tumor Research Center, University of California, San Francisco, 1855 Folsom Street, Room 226, San Francisco, CA 94103, USA b Division of Hematology-Oncology, University of California, San Francisco, 1855 Folsom Street, Room 226, San Francisco, CA 94103, USA c Department of Radiology, University of California, San Francisco, 1855 Folsom Street, Room 226, San Francisco, CA 94103, USA d Hermes Biosciences, Inc., 65 Airport Blvd. Suite B, South San Francisco, CA 94080, USA Received 9 April 2005; revised 18 July 2005; accepted 23 August 2005 Available online 28 September 2005 Abstract Drug delivery to brain tumors has long posed a major challenge. Convection-enhanced delivery (CED) has been developed as a drug delivery strategy to overcome this difficulty. Ideally, direct visualization of the tissue distribution of drugs infused by CED would assure successful delivery of therapeutic agents to the brain tumor while minimizing exposure of the normal brain. We previously developed a magnetic resonance imaging (MRI)-based method to visualize the distribution of liposomal agents after CED in rodent brains. In the present study, CED of liposomes was further examined in the non-human primate brain (n = 6). Liposomes containing Gadoteridol, DiI-DS, and rhodamine were infused in corona radiata, putamen nucleus, and brain stem. Volume of distribution was analyzed for all delivery locations by histology and MR imaging. Real-time MRI monitoring of liposomes containing gadolinium allowed direct visualization of a robust distribution. MRI of liposomal gadolinium was highly accurate at determining tissue distribution, as confirmed by comparison with histological results from concomitant administration of fluorescent liposomes. Linear correlation for liposomal infusions between infusion volume and distribution volume was established in all targeted locations. We conclude that an integrated strategy combining liposome/nanoparticle technology, CED, and MRI may provide new opportunities for the treatment of brain tumors. Our ability to directly monitor and to control local delivery of liposomal drugs will most likely result in greater clinical efficacy when using CED in management of patients. D 2005 Elsevier Inc. All rights reserved. Keywords: Convection-enhanced delivery; MRI; Primate; Liposomes; CNS Introduction Despite recent advances in drug delivery techniques, effective drug delivery to the central nervous system (CNS) still remains a challenge. Several randomized trials of systemic chemotherapy for malignant glioma, performed over a period of almost 30 years, have provided disappointing results (Stewart, 2002). The blood–brain barrier (BBB), though compromised to some extent in tumor tissue, can limit the effective distribution of systemically administered agents. Although direct local injection methods bypass the BBB, the effect of the injected drug is limited by poor tissue penetration in the brain parenchyma as well as in tumor tissue. Several newer drug delivery systems, including drug polymers (Guerin et al., 2004), have shown promise, although the extent of tissue penetration and distribution of these therapeutic agents remains suboptimal. Several investigators (Bobo et al., 1994) have recently demonstrated the efficacy of convection-enhanced delivery (CED) as an alternative therapeutic strategy for treating focal CNS diseases such as brain tumors. This local infusion technique, utilizing bulk flow, enables the delivery of small 0014-4886/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.expneurol.2005.08.016 * Corresponding author. Fax: +1 415 514 2177. E-mail address: kbank@itsa.ucsf.edu (K.S. Bankiewicz). Experimental Neurology 196 (2005) 381 – 389 www.elsevier.com/locate/yexnr