technique to be successful, it
must be ensured that the boron molecules remain within the cancer cells for a
specified period of time so that the nuclear fission reaction is strong enough
The present study,
published in Science Advances
, focuses on how to
keep the boron molecules within the cancer cells, without being exported out of
The study was led
by Professor Nobuhiro Nishiyama, Laboratory for Chemistry and Life Science,
Institute of Innovative Research, Tokyo Institute of Technology, Tokyo, Japan.
He is also the Principal Research Scientist and Laboratory Head at the
Innovation Center of NanoMedicine (iCONM), Kawasaki Institute of Industrial
Promotion, Kawasaki City, Japan.
Background of the Study
The uptake of boron
into cancer cells occurs through a chemical compound known as p
-boronophenylalanine (BPA), which has a boron
molecule incorporated within the structure of the amino acid phenylalanine. The
transport of BPA into the cancer cells is mediated by certain transporter
proteins, which are unique to cancer cells.
The most prevalent
of these cell membrane transporter proteins is called Large neutral Amino acid Transporter 1 (LAT1)
, which transports specific types of amino acids,
such as phenylalanine, across the cell membrane and into the cells. Therefore,
LAT1 very efficiently transports BPA into the cancer cells, thereby enabling
successful BNCT to be performed. Importantly, BPA is often regarded as the best
available drug for performing BNCT.
Drawback of BPA
Despite being a
superior drug, BPA has a drawback. When the level of BPA increases within the
cancer cells, it is transported out of the cells by an "antiport" mechanism,
which is so-called because it transports molecules in the
opposite ("anti") direction i.e., out of the cells.
As a result, BPA needs to be continuously infused into cancer patients for
30-60 minutes so that its level within the cancer cells remains adequate for
performing BNCT. However, if there is any human error during the infusion
process, the patient's health could be jeopardized.
How was the Drawback Overcome?
In order to
overcome the drawback, the researchers explored other possibilities for
retaining boron within the cancer cells for prolonged periods of time in order
to successfully perform BNCT.
Nishiyama indicates: "We
assumed that modulating the presence of BPA inside the cell will ensure that it
is not sent back out via the antiport mechanism."
The researchers eventually found a way around the problem. They
observed that when poly(vinyl alcohol) (PVA) was mixed with BPA, it formed a
PVA-BPA complex that could be transported within the cancer cells.
Importantly, the structure of phenylalanine in BPA was not disrupted
due to the formation of the PVA-BPA complex, thereby allowing LAT1 to recognize
the molecular complex easily. However, as the PVA-BPA complex was too large to
be transported through the narrow transmembrane channels, LAT1 facilitated the
transport of the complex through the formation of minute structures called
endosomes, which are produced by engulfment of the substance to be transported
within the cell. These endosomes are formed by the invagination and
pinching-off of the cell membrane during the process of engulfment and
internalization of a trapped biomolecule, which in this case was the PVA-BPA
The PVA-BPA complex remained protected within the endosome, thereby
preventing it from being transported out of the cancer cells by the antiport
mechanism. This ensured that the boron remained within the cancer cells long
enough for killing them by BNCT. Importantly, this method was tested in animal
models, which revealed that the anti-cancer effect of BNCT was significantly
The study clearly
revealed that the addition of PVA is a simple and effective way
to enhance the therapeutic potential of BPA.
concludes:"This technique is effortless
and offers a novel approach for drug delivery, focusing on the metabolic
elimination processes of drugs. We will advance research on the PVA-BPA complex
for clinical trials in cooperation with Stella Pharma Corporation, which has
conducted BPA clinical trials."
The study was
funded by the Japan Science and Technology Agency, Japan Agency for Medical
Research and Development, and Japan Society for the Promotion of Science.
- Poly(vinyl alcohol) Boosting Therapeutic Potential of p-boronophenylalanine in Neutron Capture Therapy by Modulating Metabolism - (https://advances.sciencemag.org/content/6/4/eaaz1722)