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Anticancer drugs delivered by a new drug delivery system reduce tumor size

Osaka University-led researchers enhance the efficacy of inhibitors in cancer stem cells therapy for hepatocellular cancer stem cells by technology to develop novel polymer conjugates

Osaka University

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IMAGE: Outline of the drug delivery system (DDS) created in this study. view more 

Credit: Osaka University

Cancer tissue cells are divided into two major groups: cancer cells and cancer stem cells (CSCs). CSCs are related to cancer progression and dissemination, so it's necessary to eradicate CSCs in order to cure cancer. However, because CSCs are resistant to chemotherapy and radiotherapy, cancer is refractory.

A research group from Osaka University, in collaboration with Tokyo Institute of Technology, had found that there were CD13 surface markers in hepatocellular carcinoma (HCC) stem cells. When CD13 inhibitor ubenimex is added to CSCs, HCC stem cells cause apoptosis (programmed cell death), becoming extinct. However, because CSCs only reside in part of tumor tissues, it's imperative to develop a method for delivering drugs in high concentration to target sites.

The researchers created a drug delivery system (DDS) using a poly(ethylene glycol)-poly(lysine) block copolymer-ubenimex conjugate (PEG-b-PLys(Ube)). The use of this DDS has enabled an increase in the concentration of ubenimex in target CSCs. In addition, combined use of standard anticancer drugs significantly decreased CSCs. (Figure 1) Their research results were published in Oncogene.

Lead author Masamitsu Konno says, "First, we developed a DDS to deliver highly concentrated ubenimex and then, another DDS in which 20 ubenimex molecules were bound with poly (ethylene glycol)-poly(lysine) block copolymer conjugates."

Using this method, they performed intraperitoneal administration and intravenous injection of ubenimex in mice, finding that the tumor size was significantly reduced. (Figure 2) This shows that it has become possible to deliver ubenimex to CSCs in high concentration.

Next, the combined administration of ubenimex and existing anticancer drugs (luorouracil (5-FU), cisplatin (CDDP), and doxorubicin (DXR)) was performed, enhancing apoptosis in vitro synergistically in CSCs in mice.

Corresponding author Hideshi Ishii says, "Our research results will promote the application of drugs whose medical effects on CSCs were verified but there were challenges in their delivery to target sites, which will promote repositioning, i.e., the drugs will be used to treat different diseases. Block copolymers used in the DDS in this study can be easily produced and exhibit strong effects, allowing them to be used for the application of other drugs as well."

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Osaka University was founded in 1931 as one of the seven imperial universities of Japan and now has expanded to one of Japan's leading comprehensive universities. The University has now embarked on open research revolution from a position as Japan's most innovative university and among the most innovative institutions in the world according to Reuters 2015 Top 100 Innovative Universities and the Nature Index Innovation 2017. The university's ability to innovate from the stage of fundamental research through the creation of useful technology with economic impact stems from its broad disciplinary spectrum.

Website: http://resou.osaka-u.ac.jp/en/top

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