Poly(vinyl alcohol) boosting therapeutic potential of -boronophenylalanine in neutron capture therapy by modulating metabolism
Authors: Nobuhiro Nishiyama
Makoto Matsui
Minoru Suzuki
Kaito Kanamori
Keishiro Tomoda
Yukiya Inoue
Takahiro Nomoto
Hiroyasu Takemoto
Ying Yao
Journal: Science advances (2020)
Discipline: Multidisciplinary
Keywords: boron neutron capture therapy; p-boronophenylalanine; BPA; poly(vinyl alcohol); LAT1
Affiliations: Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, 4259 Nagatsutacho, Midori-ku, Yokohama, Kanagawa 226-8503, Japan., Division of Particle Radiation Oncology, Particle Radiation Oncology Research Center, Institute for Integrated Radiation and Nuclear Science, Kyoto University, 2-1010 Asashiro-nishi, Kumatori-cho, Sennan-gun, Osaka 590-0494, Japan., Innovation Center of Nanomedicine, Kawasaki Institute of Industrial Promotion, 3-25-14 Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa 210-0821, Japan.

Abstract:  In the current clinical boron neutron capture therapy (BNCT), p-boronophenylalanine (BPA) has been the most powerful drug owing to its ability to accumulate selectively within cancers through cancer-related amino acid transporters including LAT1. However, the therapeutic success of BPA has been sometimes compromised by its unfavorable efflux from cytosol due to their antiport mechanism. Here, we report that poly(vinyl alcohol) (PVA) can form complexes with BPA through reversible boronate esters in aqueous solution, and the complex termed PVA-BPA can be internalized into cancer cells through LAT1-mediated endocytosis, thereby enhancing cellular uptake and slowing the untoward efflux. In in vivo study, compared with clinically used fructose-BPA complexes, PVA-BPA exhibited efficient tumor accumulation and prolonged tumor retention with quick clearance from bloodstream and normal organs. Ultimately, PVA-BPA showed critically enhanced antitumor activity in BNCT. The facile technique proposed in this study offers an approach for drug delivery focusing on drug metabolism. 

Retracted: No

PubPeer comments:
 The authors developed a new methodology for delivery of boron-related drug. The first motivation of the research would solubilize the drug using PVA, but actually the authors set basic condition (pH ~9.5) for systemic administration to get homogeneous solution. This would be because PVA cannot solubilize the drug at physiological pH. In addition, the biodistribution of PVA was done using fluorescently labeled PVA. Herein, PVA was labeled with Cy5 via ester bond (which can be easily degraded at basic condition). Thus, most of the dye was released from PVA, leading to the difficulty of the biodistribution of PVA. The obtained result would show biodistribution of released Cy5. The size of the tumor volume was quite large (~4000mm3). Is it ethically okay in Japan? , 
 To Dr. Nigricornis, Generally, the size of tumor in mice should be smaller than 10% of the weight in Japan. The weight of mice is ~20g, and the size in the experiment was larger than the rule. , 
 This article includes weird points, as the two said above. The authors said that the polymer was well distributed in CT26 tumors relative to BxPC3 tumors. But, the result obviously showed that the polymer (red) was dispersed for BxPC3 tumors.  , 
 #2 No, there is no rule in Japan. ,