Ryuta Saito

Gadolinium-loaded liposomes allow for real-time magnetic resonance imaging of convection-enhanced delivery in the primate brain

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.

Convection-enhanced delivery of Ls-TPT enables an effective, continuous, low-dose chemotherapy against malignant glioma xenograft model

Treatment of malignant gliomas represents one of the most formidable challenges in oncology. The combination of surgery, radiation, and chemotherapy yields median survivals of less than one year. Here we demonstrate the use of a minimally invasive surgical technique, convection-enhanced delivery (CED), for local administration of a novel nanoparticle liposome containing topotecan. CED of this liposomal topotecan (Ls-TPT) resulted in extended brain tissue retention (t1/2 = 1.5 days), whereas free topotecan was rapidly cleared (t1/2 = 0.1 days) after CED. The favorable pharmacokinetic profile of extended topotecan release for about seven days, along with biodistribution featuring perivascular accumulation of the nanoparticles, provided, in addition to the known topoisomerase I inhibition, an effective antiangiogenic therapy. In the rat intracranial U87MG tumor model, vascular targeting of Ls-TPT with CED was associated with reductions in laminin expression and vascular density compared to free topotecan or control treatments. A single CED treatment on day 7 showed that free topotecan conferred no survival benefit versus control. However, Ls-TPT produced a significant (P = 0.0002) survival benefit, with six of seven complete cures. Larger U87MG tumors, where CED of Ls-TPT on day 12 resulted in one of six cures, indicated the necessity to cover the entire tumor with the infused therapeutic agent. CED of Ls-TPT was also efficacious in the intracranial U251MG tumor model (P = 0.0005 versus control). We conclude that the combination of a novel nanoparticle Ls-TPT and CED administration was very effective in treating experimental brain tumors.

Tissue affinity of the infusate affects the distribution volume during convection-enhanced delivery into rodent brains: Implications for local drug delivery

Convection-enhanced delivery (CED) is a recently developed technique for local delivery of agents to a large volume of tissue in the central nervous system (CNS). We have previously reported that this technique can be applied to CNS delivery of nanoparticles including viruses and liposomes. In this paper, we describe the impact of key physical and chemical properties of infused molecules on the extent of CED-mediated delivery. For simple infusates, CED distribution was significantly increased if the infusate was more hydrophilic or had less tissue affinity. Encapsulation of tissue-affinitive molecules by neutral liposomes significantly increased their tissue distribution. The poorer brain distribution observed with cationic liposomes, due to their greater tissue affinity, was completely overcome by PEGylation, which provides steric stabilization and reduced surface charge. Finally, liposomal encapsulation of doxorubicin reduced its tissue affinity and substantially increased its distribution within brain tumor tissue. Taken together, the physical and chemical properties of drugs, small molecules and macromolecular carriers determine the tissue affinity of the infusate and strongly affect the distribution of locally applied agents. Thus, an increased and more predictable tissue distribution can be achieved by reducing the tissue affinity of the infusate using appropriately engineered liposomes or other nanoparticles.

Effects of the perivascular space on convection-enhanced delivery of liposomes in primate putamen

Convection-enhanced delivery has recently entered the clinic and represents a promising new therapeutic option in the field of neurodegenerative diseases and treatment of brain tumors. Understanding of the principles governing delivery and flow of macromolecules within the CNS is still poorly understood and requires more investigation of the microanatomy and fluid dynamics of the brain. Our previously established, reflux-free convection-enhanced delivery (CED) technique and real-time imaging MR method for monitoring CED delivery of liposomes in primate CNS allowed us to closely monitor infusions of putamen. Our findings indicate that CED in putamen is associated with perivascular transport of liposomes, throughout CNS arteries. The results may explain side effects seen in current clinical trials using CED. In addition, they clearly show the necessity for a monitoring technique for future direct delivery of therapeutic agents to the human central nervous system. Based on these findings, we believe that the physiological concept that the perivascular space serves as a conduit for distribution of endogenous molecules within the CNS also applies to interstitially infused agents.

Safety of real-time convection-enhanced delivery of liposomes to primate brain: a long-term retrospective.

Convection-enhanced delivery (CED) is gaining popularity in direct brain infusions. Our group has pioneered the use of liposomes loaded with the MRI contrast reagent as a means to track and quantitate CED in the primate brain through real-time MRI. When co-infused with therapeutic nanoparticles, these tracking liposomes provide us with unprecedented precision in the management of infusions into discrete brain regions. In order to translate real-time CED into clinical application, several important parameters must be defined. In this study, we have analyzed all our cumulative animal data to answer a number of questions as to whether real-time CED in primates depends on concentration of infusate, is reproducible, allows prediction of distribution in a given anatomic structure, and whether it has long term pathological consequences. Our retrospective analysis indicates that real-time CED is highly predictable; repeated procedures yielded identical results, and no long-term brain pathologies were found. We conclude that introduction of our technique to clinical application would enhance accuracy and patient safety when compared to current non-monitored delivery trials.

Convection-enhanced delivery of liposomal doxorubicin in intracranial brain tumor xenografts

We previously reported that convection-enhanced delivery (CED) of liposomes into brain tissue and intracranial brain tumor xenografts produced robust tissue distribution that can be detected by magnetic resonance imaging. Considering image-guided CED of therapeutic liposomes as a promising strategy for the treatment of brain tumors, we evaluated the efficacy of pegylated liposomal doxorubicin delivered by CED in an animal model. Distribution, toxicity, and efficacy of pegylated liposomal doxorubicin after CED were evaluated in a U251MG human glioblastoma intracranial xenograft model. CED of pegylated liposomal doxorubicin achieved good distribution in brain tumor tissue and surrounding normal brain tissue. Distribution was not affected by the particle concentration of pegylated liposomal doxorubicin, but tissue toxicity increased at higher concentrations. CED of pegylated liposomal doxorubicin, at a dose not toxic to normal rat brain (0.1xa0mg/ml doxorubicin), was significantly more efficacious than systemic administration of pegylated liposomal doxorubicin at the maximum tolerated dose. CED of pegylated liposomal doxorubicin resulted in improved survival compared to CED of free doxorubicin at the same dose. Outcomes of this study suggest that CED of liposomal drugs is a promising approach for the treatment of glioblastoma.

Preoperative Visualization of the Lenticulostriate Arteries Associated with Insulo-Opercular Gliomas Using 3-T Magnetic Resonance Imaging

Improving the extent of resection and reducing the risk of neurological complications are important goals in the treatment of insulo-opercular gliomas [1–5, 10–13]. Aggressive surgical resection of intrinsic insular gliomas is associated with high rates of gross total resection and low rates of permanent neurological deficits and requires meticulous surgical approach based on the regional insular anatomy [1–5, 8–13]. Interruption of the perforating lenticulostriate arteries (LSA) and long insular arteries that arise from the M2 [8] can damage the descending motor pathways [7] and cause postoperative hemiplegia [4]. Therefore, preservation of the perforating arteries is of utmost importance during surgical resection of insulo-opercular tumors [2, 4, 5, 8].