ABSTRACT
AIM: The aim of this work is to evaluate combining targeting strategy and convection-enhanced delivery in brain tumor models by imaging quantum dot-immunoliposome hybrid nanoparticles. MATERIALS & METHODS: An EGF receptor-targeted, quantum dot-immunoliposome hybrid nanoparticle (QD-IL) was synthesized. In vitro uptake was measured by flow cytometry and intracellular localization was imaged by confocal microscopy. In the in vivo study, QD-ILs were delivered to intracranial xenografts via convection-enhanced delivery and fluorescence was monitored noninvasively in real-time. RESULTS: QD-ILs exhibited specific and efficient uptake in vitro and exhibited approximately 1.3- to 5.0-fold higher total fluorescence compared with nontargeted counterpart in intracranial brain tumor xenografts in vivo. CONCLUSION: QD-ILs serve as an effective imaging agent in vitro and in vivo, and the data suggest that ligand-directed liposomal nanoparticles in conjunction with convection-enhanced delivery may offer therapeutic benefits for glioblastoma treatment as a result of specific and efficient uptake by malignant cells.
Subject(s)
Brain Neoplasms/metabolism , Brain/pathology , Drug Delivery Systems , ErbB Receptors/metabolism , Glioblastoma/metabolism , Liposomes/metabolism , Quantum Dots/metabolism , Animals , Brain/metabolism , Brain Neoplasms/pathology , Cell Line, Tumor , Convection , Female , Glioblastoma/pathology , Humans , Liposomes/analysis , Mice , Mice, Inbred BALB C , Mice, Nude , Quantum Dots/analysisABSTRACT
The majority of newly diagnosed brain tumors are treated with surgery, radiation, and the chemotherapeutic temozolomide. Development of additional therapeutics to improve treatment outcomes is complicated by the blood-brain barrier (BBB), which acts to protect healthy tissue from chemical insults. The high pressure found within brain tumors adds a challenge to local delivery of therapy by limiting the distribution of bolus injections. Here we discuss various drug delivery strategies, including convection-enhanced delivery, intranasal delivery, and intrathecal delivery, as well as pharmacological strategies for improving therapeutic efficacy, such as blood-brain barrier disruption.
Subject(s)
Antineoplastic Agents/administration & dosage , Central Nervous System Neoplasms/drug therapy , Central Nervous System Neoplasms/surgery , Drug Delivery Systems/trends , Animals , Antineoplastic Agents/metabolism , Blood-Brain Barrier/drug effects , Blood-Brain Barrier/metabolism , Brain Neoplasms/drug therapy , Brain Neoplasms/metabolism , Brain Neoplasms/surgery , Central Nervous System Neoplasms/metabolism , Drug Delivery Systems/methods , HumansABSTRACT
Achieving effective treatment outcomes for patients with glioblastoma (GBM) has been impeded by many obstacles, including the pharmacokinetic limitations of antitumor agents, such as topotecan (TPT). Here, we demonstrate that intravenous administration of a novel nanoliposomal formulation of TPT (nLS-TPT) extends the survival of mice with intracranial GBM xenografts, relative to administration of free TPT, because of improved biodistribution and pharmacokinetics of the liposome-formulated drug. In 3 distinct orthotopic GBM models, 3 weeks of biweekly intravenous therapy with nLS-TPT was sufficient to delay tumor growth and significantly extend animal survival, compared with treatment with free TPT (P ≤ .03 for each tumor tested). Analysis of intracranial tumors showed increased activation of cleaved caspase-3 and increased DNA fragmentation, both indicators of apoptotic response to treatment with nLS-TPT. These results demonstrate that intravenous delivery of nLS-TPT is a promising strategy in the treatment of GBM and support clinical investigation of this therapeutic approach.