Hepatocellular carcinoma (HCC) is the
second leading cause of cancer-associated death worldwide. These regrettably
poor prognoses are due to the difficulty in treating this cancer using
conventional chemotherapeutic drugs such as doxorubicin, epirubicin, cisplatin,
5-fluorouracil, etoposide or combinations therein. This may be attributed to
that the conventional medicines are not able to reach in a sufficient
concentration in the liver tumor cells at levels that are not harmful to the
rest of the body. Considering the large percentage of patients that are deemed
ineligible to undergo conventional curative interventions, it is highly
important to develop alternative drug treatment options that are able to target
the tumor tissues, without inducing toxicity in other parts of the body. Now a team of scientists, led by Prof.
Taeghwan Hyeon at the Institute for Basic Science (IBS)/Seoul National
University and Prof. Kam Man Hui at the National Cancer Center Singapore, has
screened a library containing hundreds of natural products against a panel of
HCC cells to search a better drug candidate. The screen uncovered a compound
named triptolide, a traditional Chinese medicine isolated from the thunder god
vine (Tripterygium wilfordii (Latin) or lei gong teng (Chinese)) which was
found to be far more potent than current therapies. Studies from other
researchers corroborate our findings as triptolide has also found to be very
effective against several other malignant cancers including; pancreatic,
neuroblastoma and cholangiocarcinoma. However this excitement was tempered when
the drug was administered to mice as the increased potency was coupled with
increased toxicity as well. Maximizing potency,
mitigating toxicity Prof. Hyeon et al. endeavoured to
alleviate the toxic burden by increasing the specific delivery of the drug to
the tumor using a nanoformulation. The designed formulation was a pH-sensitive
nanogel coated with the nucleotide precursor, folate. The researchers began by
esterfying the polymer pluronic F127 with folate to make the coating material.
They then polymerized β-benzyl-L-aspartate N-carboxy anhydride to make the core
material pH-sensitive due to repulsive forces upon protonation under acidic
conditions. “The combination of the two polymers forms a core/shell structured
nanoparticle in water,” explains Prof. Hyeon. “We loaded triptolide into the
hydrophobic core to produce a kind of drug-nanogel.” A tumor model of folate-overexpressing
HCC was then used to examine the effect of the nanogel formulation versus the
free drug. As expected, the nanogel triptolide showed increased tumor
accumulation and uptake into the tumor cells where the decreasing pH
efficiently triggered release of the entrapped triptolide. The result was as
hypothesized: In experiments on mice with HCC, the team found that its coated
triptolide accumulated in the inflamed tumour tissues. Once there, the
folate-targeted ligand enhances the HCC cells to take up the anticancer drug.
Since the fluid inside tumour cells is more acidic (with a pH of around 6.8)
compared to normal tissue (which has a pH of about 7.4), the drop in pH causes
the coating to fall apart, and release the pure form of the triptolide, which
then destroys the tumor cells, showing greater efficacy against the tumor and decrease
the overall toxicity. The mechanism of
action of Nf-Trip-FR+ represents an auspicious therapeutic approach While these initial proof-of-concept
studies have been promising, many drugs fail to become an IND (Investigational
New Drug); fewer still effectively replicate their results in human trials.
However, a felicitous discovery occurred while the researchers were examining
the mechanism of triptolide's activity. Researchers at the National Cancer
Center Singapore ran a profile on the effects triptolide had on protein
expression in a variety of HCC cells. From this they learned triptolide
primarily reduced the levels of two proteins, AURKA and CKS2, although the
mechanism is still not known. The researchers then cross-checked these proteins
against a clinical database of HCC patients and found an increased expression
of these proteins correlates with the aggressiveness of the cancer. Thus it is
hoped the negative effect triptolide has on these proteins could prove
beneficial in terms of clinical outcomes when this drug finally becomes
accepted for clinical studies in cancer patients. The present work is detailed in ACS
Nano.
Notes for editors -
References
Daishun Ling, Hongping Xia, Wooram Park, Michael
J. Hackett, Changyeong Song, Kun Na, Kam Man Hui, and Taeghwan Hyeon.
pH-Sensitive Nanoformulated Triptolide as a Targeted Therapeutic Strategy for
Hepatocellular Carcinoma. ACS Nano 2014, 3, 12-29, doi: 10.1021/nn502074x
(http://www.pnas.org/content/111/32/11828.full)
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Institute for Basic Science (IBS) was founded in November 2011 by
the Korean government. IBS supports basic research within the entire range of
natural sciences including physics, biology, chemistry, mathematics, earth science,
and astronomy.
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To speak with Prof.
Taeghwan Hyeon, please contact: Ms. Soyeon Yoon, IBS Center for Nanoparticle
Research (+82-2-880-7409; syyoon@snu.ac.kr)
or Mr. Han Bin Oh, IBS Public Relations Team (+82-42-878-8182; ohanvin@ibs.re.kr)
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