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Liposomal encapsulation of the anti-leukemic small molecule UNC0642 for increased tolerability

University of British Columbia

Acute Myeloid Leukemia (AML) is the most poorly treated subtype of leukemia, suffering from dated chemotherapeutic regimens and poor long-term survival rates. New therapies are needed for this aggressive disorder. Epigenetic inhibitors targeting G9a/GLP, crucial histone methyltransferases for AML progression, are a promising avenue for treatment. Unfortunately, one of the most potent small molecule inhibitors of these enzymes, UNC0642, suffers from dose-limiting toxicities. It was hypothesized that encapsulation of UNC0642 in liposomal nanoparticles would help attenuate these toxicities, better control drug release and biodistribution of the small molecule, and ultimately enable the therapeutic use of UNC0642. The work presented here demonstrates that UNC0642 can be successfully loaded within liposomal systems composed of DSPC/Cholesterol or POPC/Cholesterol to a maximum drug:lipid ratio of 0.2. These particles show stable drug release patterns, which may be due to precipitation of the drug within the nanoparticle interior as observed using cryo-TEM. Furthermore, the particles exhibit a dose-dependent uptake into HoxA9/Meis1 AML cells in vitro and an anti-proliferative effect that is 10-times lower than the free drug in cell culture. When injected in a single dose tolerability study using healthy C57Bl/6 mice, liposomal encapsulation is shown to completely abolish the acute toxicity associated with free UNC0642 injection. Even at doses 8-times higher than the maximum tolerated dose of the free small molecule, minimal toxicity is observed for liposomal UNC0642. In addition, no major signs of chronic toxicity are observed when the encapsulated drug is injected in a multiple-dose regimen (2 injections/week for 4 weeks), as determined by detailed clinical scoring of animal health, body weight, and blood chemistry. These reductions in acute and chronic toxicity are attributed to the nanoparticle carriers’ ability to alter the biodistribution of the drug and prevent exposure of the nervous system to UNC0642. The data presented in this thesis form the basis of a promising and novel therapeutic strategy for treatment of AML through epigenetic inhibition. These systems are well suited for pre-clinical studies in animal models of disease and offer an easily modifiable nanoparticle carrier for tuning biodistribution and drug release to better treat this aggressive form of leukemia.

Text

2020-07-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/66639

Biochemistry and Molecular Biology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/