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bioRxiv · 10.1101/2020.05.29.123125

Polymer-assisted intratumoral delivery of ethanol: Preclinical investigation of safety and efficacy in a murine breast cancer model

Nief, C.·Morhard, R.·Chelales, E.·Adrianzen Alvarez, D.·Bourla, I.·Lam, C. T.·Crouch, B.·Sag, A. A.·Mueller, J. L.·Katz, D.·Dewhirst, M. W.·Everitt, J. I.·Ramanujam, N.
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Abstract

Focal tumor ablation with ethanol could provide benefits in low-resource settings because of its low overall cost, minimal imaging technology requirements, and acceptable clinical outcomes. Unfortunately, ethanol ablation is not commonly utilized because of a lack of predictability of the ablation zone, caused by inefficient retention of ethanol at the injection site. To create a predictable zone of ablation, we have developed a polymer-assisted ablation method using ethyl cellulose (EC) mixed with ethanol. EC is ethanol-soluble and water-insoluble, allowing for EC-ethanol to be injected as a liquid and precipitate into a solid, occluding the leakage of ethanol upon contact with tissue. The aims of this study were to compare the 1) safety, 2) release kinetics, 3) spatial distribution, 4) necrotic volume, and 5) overall survival of EC-ethanol to conventional ethanol ablation in a murine breast tumor model. Non-target tissue damage was monitored through localized adverse events recording, ethanol release kinetics with Raman spectroscopy, injectate distribution with in vivo imaging, target-tissue necrosis with NADH-diaphorase staining, and overall survival by proxy of tumor growth. EC-ethanol exhibited decreased localized adverse events, a slowing of the release rate of ethanol, more compact injection zones, 5-fold increase in target-tissue necrosis, and longer overall survival rates compared to the same volume of pure ethanol. A single 150 {micro}L dose of 6% EC-ethanol achieved a similar survival probability rates to six daily 50 {micro}L doses of pure ethanol used to simulate a slow-release of ethanol over 6 days. Taken together, these results demonstrate that EC-ethanol is safer and more effective than ethanol alone for ablating tumors. Graphical AbstractThe inclusion of ethylcellulose limits extra-tumoral leakage of ethanol and increases the target-tissue ablation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=102 SRC="FIGDIR/small/123125v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@172afb5org.highwire.dtl.DTLVardef@6d96deorg.highwire.dtl.DTLVardef@cbdf9borg.highwire.dtl.DTLVardef@c56187_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Nief, C., Morhard, R., Chelales, E., Adrianzen Alvarez, D., Bourla, I., Lam, C. T., Crouch, B., Sag, A. A., Mueller, J. L., Katz, D., Dewhirst, M. W., Everitt, J. I., Ramanujam, N.. 2020-05-29. Polymer-assisted intratumoral delivery of ethanol: Preclinical investigation of safety and efficacy in a murine breast cancer model. https://doi.org/10.1101/2020.05.29.123125

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