The effectiveness of polymeric nano-micelles depends on the sensitivity level of c-Myc

NanoMedicine Innovation Center (Director General: Professor Kazunori Kataoka, Location: Kawasaki in Japan, Abbreviation: iCONM) reported in ACS Nano (Impact Factor: 14.588 in 2019) together with the group of Professor Yu Matsumoto of Otorhinolaryngology and Head and Neck Surgery (Professor Tatsuya Yamasoba) and the group of Professor Horacio Cabral of the Department of Bio- engineering (Professor Ryo Miyake) at the University of Tokyo that the efficacy of polymeric nano-micelles with different drug action profile depends on the sensitivity level of c-Myc, one of the major proto-oncogene.

C-Myc is known to be involved in cancer cell proliferation and angiogenesis and alter the cell cycle, inhibit normal cell differentiation, and promote cancer metastasis. It is a common proto-oncogene that regulates many genes associated with growth factors and is known to be involved in the development of many cancers, such as chromosomal mutations in Burkitt lymphoma.

Therefore, the discovery of drugs worldwide is being studied as an anticancer drug that targets this transcription factor that can directly attack cancer stem cells. However, because embryonic lethality occurs in c-Myc knockout mice, c-Myc is considered an essential gene for living cells, and selective delivery to cancerous tumors is a key means of the development of the defenders. In addition, c-Myc has also been cited as a necessary factor for the initial entry of iPS cells.

In the future it can be expected that this inhibition will be implemented as a technology that can also be used to suppress carcinogenesis derived from iPS cells.

In this study, JQ1H, which is a structural analogue of JQ1H, a common indirect c-Myc inhibitor, was captured within active nano-micelles, and their efficacy was evaluated. JQ1 binds to a bromodomic protein called BRD4, which is involved in the activation of RNA polymerase II regulating c-Myc expression, to strongly inhibit this flow.

As a result, RNA polymerase activity is weakened and c-Myc expression is down-regulated. Although JQ1 was expected to be a promising epigenome drug due to its strong inhibition of gene expression, its half-life is very short in vivo due to the speed of the kidneys and the rapid clearance after administration. Moreover, JQ1 is almost water-soluble. These characteristics of JQ1 became major issues for its development as an effective drug.

The polymeric nano-micelles so far at the NanoMedicine Innovation Center (iCONM), for anticancer therapy, demonstrated (1) stabilization of encapsulated drugs, (2) removal of renal extraction, (3) EPR (selective drug delivery) to cancer cigarettes) centralized tumor accumulation, and (4) drug release based on tumor acidosis. This time, we demonstrated good antitumor activity in mice transplanted with tongue cancer, melanoma and pancreatic cancer using nano-micelles with JQ1 mechanism.

Nano-micelles containing JQ1H are leached into the tumor material from blood vessels after systemic administration due to the so-called EPR effect. Tumor cigarettes are rich in lactic acid due to its enhanced glycolysis and are more acidic than normal products. In this work, two types of nano-micelle were prepared; one in which JQ1H hydrophobic was bound to an amphiphilic block polymer composed of a hydrophilic polyethylene glycol block and a hydrophobic poly-amino acid block using a 3-aminopropionaldehyde (aliphatic aldehyde) binder and the other micelle in which JQ1H was bound polymer through p-aminomethylbenzaldehyde (aromatic aldehyde) binding.

An amphiphilic block polymer was synthesized and used as a raw material for nano-micelles. When it was automatically collected in water to a micellar structure and given to cancer-carrying mice, the antitumor activity seen in Figs. 2 achieve. When the aldehyde binding is aliphatic or when it is an aromatic aldehyde, the release pattern of the drug differs significantly depending on acidity. The latter releases the drug rapidly, and the latter slowly releases the drug.

Therefore, the former nano-treatment was named FR-JQ1H / m and the latter was named SR-JQ1H / m. The antitumor activity of these nano-micelles varies considerably according to the c-Myc sensitivity level. While FR-JQ1H / m is more effective for tumors with high c-Myc sensitivity, SR-JQ1H / m is more effective for tumors with low c-Myc sensitivity.

In the future, we believe that the selection of nano-micelles according to the sensitivity level of biomarkers will be an important step towards personal treatment and in-house hospitals.


NanoMedicine Innovation Center

Magazine Reference:

Shibasaki, H., et al. (2021) Efficacy of pH-Sensitive Nanomedicines in Tumors with Different C-MYC Expressions Dependent on the Intratumoral Activation Profile. ACS Nano.