Nanoencapsulation of MDM2 Inhibitor RG7388 and Class-I HDAC Inhibitor Entinostat Enhances their Therapeutic Potential
Anas Abed1,2, Michelle K Greene1, Alhareth A Alsa'd2,3
1The Patrick G Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7AE, United Kingdom.
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.
Insights
Combining RG7388 and Entinostat drugs in nanoparticles enhances cancer cell death and reduces toxicity. This nanoparticle formulation may offer improved clinical utility for p53 wild-type colorectal cancers.
Area of Science:
- Oncology
- Nanomedicine
- Pharmacology
Background:
- p53-MDM2 inhibitors like RG7388 target wild-type p53 in cancer but primarily induce cell cycle arrest and cause neutropenia.
- Class-I HDAC inhibitors like Entinostat also have dose-limiting toxicities.
- Combining these agents shows potential for increased cancer cell death.
Purpose of the Study:
- To investigate coencapsulation of RG7388 and Entinostat in polymeric nanoparticles (NPs).
- To overcome efficacy and toxicity limitations of the combined drug therapy.
- To evaluate the synergistic effect on colorectal cancer cell death and in vivo toxicity.
Main Methods:
- Coencapsulation of RG7388 and Entinostat in polymeric nanoparticles at various molar ratios.
- Assessment of synergistic cell death in colorectal cancer cell lines.
- Evaluation of in vivo impact on murine blood leukocytes.
Main Results:
- Synergistic increases in cancer cell death were observed with both free and nanoencapsulated drug combinations.
- Nanoencapsulation significantly mitigated drug-induced leukopenia in vivo.
- All tested colorectal cancer cell lines showed enhanced cell death.
Conclusions:
- Coencapsulation of RG7388 and Entinostat in a single nanoparticle platform enhances synergistic cancer cell death.
- Nanoparticle formulation may overcome toxicity issues associated with individual drugs.
- This approach shows potential clinical utility for treating p53 wild-type colorectal cancers.
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