Fig 2. NEO212 acts as a prodrug of TMZ and has a superior tumor uptake profile.

Based on GC/MS analyses, NEO212, once taken up by tumor cells, appears to break down into intact TMZ and perillyl alcohol. The same analyses show that at equivalent dosages a larger amount of TMZ is released from NEO212 inside GB cells compared to the amount of TMZ taken up by cells after the cells were incubated with equimolar concentrations of either NEO212 or TMZ (Panel A). Brain biodistribution data with NEO212 and TMZ indicate that NEO212 has a higher availability into the brain than TMZ after oral administration of the drugs presumably due to a better penetration of NEO212 through the blood-brain barrier (Panel B). NEO212 also shows a favorable differential uptake (i.e. higher uptake by the diseased brain) when administered orally to brain tumor bearing vs. non-tumor bearing mice (Panel C). For the in vivo studies, the drugs were measured in tissue homogenates by HPLC methods.