Pillar 2 - Breast Cancer, page-117

Please, keep in mind that I am not a biochemist and if there are any reading this shaking their heads, feel free to contribute.

The City of Hope packaged bisantrene with mPEG-b-PLA micelles or B-cyclodextrin for their in vivo experiments. Although the administration method was intravenous (in the vein) or intraperitoneal (in the space between your skin and intestines/stomach) injection. You can see on the figure below that when combined with either micelles or B-cyclodextrin, Bisantrene occupies the middle of the structure, which keeps it safe.





Using cyclodextrins as an example, they have been found to improve the efficacy of oral drug delivery among other delivery methods. Drug bioavailability is referring to the amount of drug that is absorbed and reaches the blood stream to exert an effect. For example, bisantrene in its free state has poor bioavailability because the pH of the intestines prevents it from being absorbed and making it to the blood stream. It is basically like having a smart, savy packaging system that protects a drug from the hidden nasties along a route of oral absorption and helps with the drug being absorbed at a specific site.



What I have been mulling over for a little while now is how much more effective bisantrene was in vivo (animal) experiments when it was packaged into the micelles or B-cyclodextrins. Looking at the figure below and comparing the left (free CS1) and right (micelle packaged CS1), you can clearly see that the percentage of suvival was about 80% at day 55 when CS1 was packaged with micelles compared to 0% survival without packaging.



The paper below was published about 6 years ago, although at the time states that combining chemotherapeutics (that have poor aqueous solubility) with cyclodextrins can result in better efficacy. I have included a screenshot of the table below which shows the outcome of comining a chemotherapeutic with an advanced delivery system. What I take away from this is that there is a lot of data supporting the combination of advanced delivery systems and chemotherapeutics.







Now, I do not know if this could translate into improved efficacy in humans, but I am curious! I wouldn't be surprised if we saw some advanced packaging delivery system for Bisantrene, though. This may be why RAC management are considering a Phase I dose escalation study, but of course, this is speculation. Since historic dosing of Bisantrene was done around 250 mg/m2, which far exceeds the dose required to inhibit FTO, this may have saturated the body and overcome poor bioavailability observed in the City of Hope paper. Thus, to provide low dose bisantrene with high bioavailability may require combining it with an advanced delivery technology.