Nanomedicine activation profile determines efficacy depending on tumor c-Myc expression

It is known that c-Myc is involved in cancer cell proliferation and angiogenesis and changes the cell cycle, suppresses normal cell differentiation, and promotes cancer metastasis. It is a typical proto-oncogene that regulates many genes related to growth factors and is known to be involved in developing of many cancers, such as chromosomal translocation in Burkitt lymphoma. Therefore, drug discovery research is being conducted worldwide as an anticancer drug targeting this transcription factor that can directly attack cancer stem cells. However, since embryonic lethality occurs in c-Myc knockout mice, c-Myc is considered as an essential gene for living cells, and selective delivery to cancer tissues is an important key to developing its inhibitors. Besides, c-Myc is also known as a factor necessary for the initial induction of iPS cells. In the future this inhibition can be expected to be applied as a technology that can also be used to suppress iPS cell-derived carcinogenesis.

In this study, JQ1H, which is a structural analogue of JQ1H, a typical indirect c-Myc inhibitor, was encapsulated inside functional nano-micelles, and their efficacy was evaluated. JQ1 binds to a bromodomain protein called BRD4, which is involved in the activation of RNA polymerase II regulating the expression of c-Myc, to inhibit this stream strongly. As a result, the activity of RNA polymerase is weakened and c-Myc expression is down-regulated. Although JQ1 was expected as a promising epigenome drug due to its strong gene expression inhibition, it has an extremely short half-life in vivo due to its fast kidney excretion and rapid clearance after administration. Additionally, JQ1 is almost insoluble in water. These properties of JQ1 became big issues to develop it as an effective drug. The polymeric nano-micelles developed so far at the Innovation Center of NanoMedicine (iCONM), for anticancer therapy, demonstrated (1) stabilization of encapsulated drugs, (2) suppression of kidney excretion, (3) EPR (selective drug delivery to cancer tissues) mediated tumor accumulation, and (4) drug release based on tumor acidosis. This time, we confirmed good antitumor activity in mice transplanted with tongue cancer, melanoma and pancreatic cancer using JQ1-equipped nano-micelles.

Fig. 1: Different drug release profile depending on the linker used for block-copolymers of nano-micellesFR-JQ1H/m with aliphatic aldehyde linker: Fast drug release in gradually elevated aciditySR-JQ1H/m with aromatic aldehyde linker: Slow drug release in gradually elevated acidityDrug release curve of FR-JQ1 and SR-JQdepending on the pH change of tumor tissues Credit: 2021 Innovation. Center of NanoMedicine

upper: tongue cancer, lower: pancreatic cancer. Credit: 2021 Innovation Center of NanoMedicine

Polymeric micelles were one of the first polymer self-assemblies reported as a nano-DDS, and are composed of distinct two domains, a drug-loading core and a hydrophilic shell. Amphiphilic block copolymers, containing a hydrophilic block and a hydrophobic block, are firstly revealed to construct those distinct domains in a micelle structure through spontaneous self-assemble as a result of hydrophobic interactions in aqueous. H. Cabral, K. Miyata, K. Osada, K. Kataoka, "Block copolymer micelles in nanomedicine applications" Chem. Rev. 2018, 118 6844-6892. (DOI: 10.1021/acs.chemrev.8b00199). Credit: 2021 Innovation Center of NanoMedicine