# Nanoencapsulation of MDM2 Inhibitor RG7388 and Class-I HDAC Inhibitor Entinostat Enhances their Therapeutic Potential Through Synergistic Antitumor Effects and Reduction of Systemic Toxicity

## TL;DR

Nanoencapsulating two cancer drugs improves their effectiveness and reduces harmful side effects in colorectal cancer treatment.

## Contribution

The study shows that combining and nanoencapsulating RG7388 and Entinostat enhances antitumor effects while reducing toxicity.

## Key findings

- Nanoencapsulation of RG7388 and Entinostat increases cell death in colorectal cancer cells.
- Nanoencapsulation reduces drug-induced leukopenia in murine blood leukocytes.
- The drug combination shows synergistic effects regardless of delivery format.

## Abstract

Inhibitors
of the p53–MDM2 interaction such as RG7388 have
been developed to exploit latent tumor suppressive properties in p53
in 50% of tumors in which p53 is wild-type. However, these agents
for the most part activate cell cycle arrest rather than death, and
high doses in patients elicit on-target dose-limiting neutropenia.
Recent work from our group indicates that combination of p53–MDM2
inhibitors with the class-I HDAC inhibitor Entinostat (which itself
has dose-limiting toxicity issues) has the potential to significantly
augment cell death in p53 wild-type colorectal cancer cells. We investigated
whether coencapsulation of RG7388 and Entinostat within polymeric
nanoparticles (NPs) could overcome efficacy and toxicity limitations
of this drug combination. Combinations of RG7388 and Entinostat across
a range of different molar ratios resulted in synergistic increases
in cell death when delivered in both free drug and nanoencapsulated
formats in all colorectal cell lines tested. Importantly, we also
explored the in vivo impact of the drug combination
on murine blood leukocytes, showing that the leukopenia induced by
the free drugs could be significantly mitigated by nanoencapsulation.
Taken together, this study demonstrates that formulating these agents
within a single nanoparticle delivery platform may provide clinical
utility beyond use as nonencapsulated agents.