Development of orthogonal nanotherapeutics for colorectal cancer treatment

Abstract

The tumour suppressor p53 has an impressive ability to regulate multiple cellular events such as apoptosis and cell cycle. Strategies aimed at activating the wild-type p53 convene a great therapeutic potential. This led to the discovery of the small molecule inhibitors, MDM2 antagonists which prevent the p53-MDM2 interaction and leads to rapid stabilisation of p53 protein. However, treatment with MDM2 antagonists often leads to the induction of cell cycle arrest but not cell death.

During the course of these studies, it was shown that FLIPL is potently upregulated in response to the MDM2 antagonist RG7388 and identified as a potential barrier towards RG7388-induced cell death. Also, this thesis demonstrates that FLIPL depletion by the HDAC inhibitor Entinostat results in synergistic induction of cell death following combined RG388 and Entinostat treatment in p53 wild-type colorectal cancer model.

The combination of therapies that work by different modes of action is a standard regimen in the clinic for the treatment of many cancer. Although the combination regimen of RG7388 and Entinostat holds promising outcomes, the administration of such combination and maintaining their optimal synergistic ratio while in vivo can be challenging due to the dissimilar pharmacokinetic profiles that can hugely affect their therapeutic effects. Moreover, RG7388 and Entinostat suffer from severe systemic toxicities such as leukopenia and thrombocytopenia.

The emerging clinical success of nanomaterials over the last decades is offering a promising platform for the delivery of drug combinations to the tumour site while preserving the optimal synergistic ratio, allowing for selective delivery and protecting the healthy tissues from the associated toxicities. This thesis reports the development of a novel dual-loaded polymeric nanoparticle-based cancer therapeutics co-encapsulating Entinostat and RG7388 at their optimal synergistic molar ratio to induce synergistic cell death. n vivo studies demonstrated that the nano-encapsulation of RG7388 and Entinostat protected the mice from the associated haematological toxicities, particularly leukopenia.

Date of Award	Jul 2021
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	Al-Ahliyyah Amman University
Supervisor	Steven Bell (Supervisor) & Christopher Scott (Supervisor)