This project will address the integration of neuroimaging for planning convection-enhanced delivery (CED) of liposomal therapeutics. CED is a promising technology that involves the direct delivery of agents to the diseased tissue, bypassing the blood-brain barrier. Recent CED clinical studies have achieved variable success, possibly due to sub-optimal distribution of the agent within the tumor and/or tumor margin. We propose that by: (1) developing patient-specific CED methods for optimizing the volume of distribution (Vd) and (2) visualizing the distribution during CED to monitor Vd and the incidence of retrograde reflux of the agent along the cannula track. Advanced MR neuroimaging methods are now available for assessing tissue structure. The advent of nanotechnology-based MR contrast modalities also provides a means for monitoring CED infusion in real time. Thus, including MRI in the therapeutic planning and monitoring CED may improve Vd, thereby improving the effectiveness of the infused agent.
Specific Aim I : To predict the volume of distribution and spatial extent of infused gadolinium encapsulated in liposomes (GD-liposomes) using an MRI-based simulation algorithm. We will first evaluate and, if necessary, modify an existing MRI-based algorithm designed to simulate CED of aqueous solutions into peritumoral brain regions. The model will be tested for its ability to simulate liposomal infusions in both peritumoral and intratumoral regions. If the model fails to accurately simulate the Vd, we will seek to improve the algorithm by including other physiologic imaging data from techniques such as dynamic contrast-enhanced (DCE) imaging of vascular permeability.
Aim 2 : Optimize CED infusion parameters and assess toxicity and Vd of GD-liposomes in the mammalian brain. We will image the infusion ofGD- liposomes in multiple brain regions in normal dogs while varying the cannula size and infusion rate with the goal of achieving maximal Vd and minimal reflux. The maximum Vd for each anatomic region will also be determined.
Aim 3 : Assess the distribution of co-administering GD- and therapeutic (GD/Rx-) liposomes using CED in dogs with glioma. Using optimal CED parameters, GD/Rx-liposomes will be administered to clinical patient dogs with glioma. We will assess the distribution of the liposomes within the tumor and surrounding brain using real time MRI. CED is a promising technology that can locally administer high concentrations of therapeutic agents to a diseased region. In this project, we will incorporate advanced MR imaging methods into the planning and implementation of CED treatment with the goal of increasing the volume within the diseased tissue while minimizing systemic exposure.
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