Convection-Enhanced Drug Delivery: Increase efficacy and MRI monitoring
Inventors
Prof. Zvi Ram, Head of Neurology Department, Tel Aviv Medical Center
Dr. Yael Mardor, Chief Scientist, The Advanced Technology Center,
Sheba Medical Center
Background, highlights & our innovation:
Convection-enhanced drug delivery (CED) is an emerging tool for drug delivery into solid
tissue that in preliminary studies has shown great promise in patients with recurrent GBM.
Based on our clinical experience, as well as others, we believe CED has the potential of
becoming an effective treatment modality for brain tumors, and perhaps for other nonneoplastic disorders of the nervous system. Several multi-center phase II/phase III trials
using CED are ongoing where up to several hundred patients will be treated in each study.
Still, the main pitfalls of this treatment methodology are the difficulty in forming efficient
convection (thus obtaining efficient drug distribution in the brain) and monitoring its extent
and effect on the normal and pathological tissue. Our data indicate that convection does not
always form and once it does, the spread of the convective wave varies in rate and shape
among patients and among drugs used for CED.
We have previously reported (Mardor et al, Cancer Res, 2001), the application of diffusionweighted MRI (DWMRI) for monitoring CED using Taxol as the therapeutic agent. A full
summary of that study has been published by our group and described a high response rate of
the treated patients (Lidar et al, JNS, 2004).
In addition to the clinical CED trial using Taxol, we have been involved and are currently
participating in several phase II and phase III CED trials with other drugs. The different
response rates obtained for different drugs in the preliminary clinical experience published
thus far, as well as our own personal experience, has triggered us to initiate an animal trial
described in a paper which has recently been published (Mardor et al, Cancer Res 2005;
Perlstein et al, NeuroOncology 2008). In these papers we describe the application of MRI for
immediate assessment of convection efficiency/extent and for early assessment of cytotoxic
tissue response in a rat brain model. The results of this animal study helped us understand
that the effects observed in the MRI of the clinical Taxol study were non-specific cytotoxic
tissue response to the convected drug. The latter imaging techniques were used to develop
methodologies to enhance the extent of convection. By establishing the correlation between
CED extent and infusates viscosity we have shown that low viscosity infusates tend to
backflow (without penetrating the tissue), while high viscosity infusates tend to form
efficient convection. These results may explain the different response rates of the different
drugs studied clinically and provide means by which poor convective compounds may be
modified to enhance their convective power. In addition, we have demonstrated the
application of these methodologies for efficient CED of nano-particles.
Therefore, the results of the animal trial suggest that CED formation and extent may be
monitored in real time by MRI and may be significantly improved by simple changes of the
infusate parameters, thus increasing treatment effects.
We have studied the feasibility of applying our methodologies to several additional drugs, two of
which were performed in collaboration with international pharma companies. Currently in
preparation for clinical trials.
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05/02/2016