The Kawasaki Institute of Industrial Promotion Innovation Center of NanoMedicine (iCONM), collaborating with the University of Tokyo Graduate School of Medicine lecturer Yu Matsumoto and the University of Tokyo School of Engineering, has announced the development of functional nanocapsules (nanomicelles) that offer a choice of drug delivery pattern according to the amount of the potentially cancer-causing gene (oncogene) c-Myc that is present. Succeeding in converting epigenetic therapeutic JQ-1 to a micelle, the team developed both fast-release and slow-release versions that react to the pH microenvironment around the tumor. Tests on mice found that the fast-release micelle was highly effective on cancers with high levels of c-Myc present, while the slow-release micelle was highly effective on cancers with low levels of c-Myc present. It is expected that being able to select the micelle according to the cancer will boost the effectiveness of treatment. The findings were published in the international scientific journal ACS Nano.
C-Myc is one of the best-known genes that regulate the expression of many genes involved in cell proliferation. It is a target for cancer drug development worldwide as a transcription factor. At the same time, this transcription factor is likely to be indispensable to normal cells too, making it essential that the drug is delivered selectively to the cancer tissue, something that has not been achieved before. Previously, the research group has developed targeted drug delivery systems by nanomicelles with the drug spontaneously self-assembling into a macromollecular structure.
In this study, the research group has successfully micellized the c-Myc epigenetic inhibitor JQ-1. JQ-1 was developed in 2010 as a cancer treatment for suppressing c-Myc by inhibiting BRD4. However, it has been challenging due to its rapid renal excretion from the body due to poor water solubility.
Therefore, the research group tested the effect of micellizing JQ-1 so that it could accumulate in selected tumor cells. For the micelle, an aliphatic compound linker and an aromatic compound linker were used to bond to the JQ-1 derivative. From this, the two types of micelle were produced by self-assembly. Comparing the characteristics of the two micelles, the team found that their drug release speed varied according to pH level. Within the tumor cells, the micelle using the aliphatic compound linker released the drug quickly (FR micelle), while the micelle using the aromatic compound linker released the drug gradually (SR micelle). The micelles measured 38 nm and 39 nm, respectively, but otherwise they were identical.
In testing on diverse tumors to establish whether the anti-tumor effects of the JQ-1 derivative were equal to JQ-1, it was found that the more c-Myc was present, the more effective it was. It worked very well against cancers of the tongue and thymus in humans, and against melanoma and brain tumors in mice. On the other hand, straight JQ-1 worked better than the micelle on tongue cancer cells in humans. Moreover, in an investigation of comparing the impact of administration of the JQ-1 derivative and the micelle on c-Myc presence, both dose- and time-dependent testing revealed suppression of c-Myc in tongue cancer cells.
Next, human tongue cancer with overexpressed c-Myc was transplanted into immunocompromised mice. Each mouse was injected with either JQ-1, JQ-1 derivative, the FR micelle or the SR micelle, then their tumor proliferation and survival rates were tested. Unlike in the cellular tests, the most effective at blocking tumor growth was the FR micelle. The same effect was found in non-immunocompromised mice with malignant melanoma and overexpressed c-Myc.
Conducting the same experiment on mice transplanted with human pancreatic cancer with underexpressed c-Myc, the team found that the SR micelle was most effective in limiting tumor proliferation.
Looking at the two types of micelle drug kinetics, both exhibited better retentivity in blood and intratumoral accumulation than straight JQ-1. The FR micelle left the bloodstream and the tumor more quickly, but it released the JQ-1 derivative in an early burst. The SR micelle released the JQ-1 derivative gradually, building up in the tumor over a long period.
The cytotoxicity of the micelles is also being investigated.
Being able to select the right micelle based on analysis of c-Myc in the cancer is likely to open the door to more effective treatment.
This article has been translated by JST with permission from The Science News Ltd.(https://sci-news.co.jp/). Unauthorized reproduction of the article and photographs is prohibited.