Poly(vinyl alcohol) boosting therapeutic potential of p-boronophenylalanine in neutron capture therapy by modulating metabolism

「スライムの化学」を利用した第5のがん治療法を開発 --液体のりの主成分でホウ素中性子捕捉療法の効果を劇的に向上--. 京都大学プレスリリース. 2020-01-24.How to keep boron inside cells during radiotherapy, a simple novel approach to cancer treatment. 京都大学プレスリリース. 2020-01-24.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

Artificial Control of Gene Silencing Activity Based on siRNA Conjugation with Polymeric Molecule Having Coil–Globule Transition Behavior

A new strategy for controlling gene silencing activity of siRNA in the cell was developed in the present study. siRNA was linearly conjugated with PNIPAAm, where coil–globule transition of the conjugated PNIPAAm allows thermoresponsive exposure of the vicinal siRNA molecule; a coil form of PNIPAAm (<i>T</i> < LCST) inhibits siRNA interaction with gene silencing-related proteins due to the steric hindrance effect, while a globule form of PNIPAAm (<i>T</i> > LCST) allows a ready access of siRNA to gene silencing pathway. As a result, at <i>T</i> > LCST, PNIPAAm-siRNA elicited effective association of siRNA with a gene silencing-related protein of Ago2, while siRNA recruitment into the gene silencing pathway was significantly suppressed at <i>T</i> < LCST. Ultimately, gene silencing efficacy of PNIPAAm-siRNA was close to unconjugated siRNA at <i>T</i> > LCST (∼80%), while it was dramatically decreased to ∼20% at <i>T</i> < LCST, suggesting that coil–globule transition of the conjugated polymer can control the bioactivity of the vicinal siRNA molecule