Potential of BPA functionalized poly(vinylalcohol)-shelled perfluorobutane nanodroplets towards enhanced boron neutron capture therapy and in-situ dosimetry

Abstract

p-boronophenylalanine (BPA) is so far the most promising drug in clinical boron neutron capture therapy (BNCT) due to its safety and selective targeting of numerous cancer cells through amino acid transporters, such as LAT1. However, the therapeutic effectiveness of BPA is limited to its low water solubility and poor accumulation in tumor tissues caused by antiport mechanism. Herein, we take advantage of BPA ability to form boronate ester complexes with diols and we report on the coupling of BPA to phase-change ultrasound contrast agents, namely superheated decafluorobutane nanodroplets (NDs) stabilized by a crosslinked shell of poly(vinyl-alcohol) (PVA). The NDs will serve, from one side, to boost the targeting of the cancer cells by enhancing the cellular uptake of BPA through LAT1-mediated endocytosis and by slowing the untoward efflux. From the other side, the high linear energy transfer (LET) particles emitted as a result of nuclear reaction between 10-boron and thermal neutrons will induce the liquid-to-gas transition of the NDs core converting them into echogenic microbubbles detectable by ultrasound imaging (US). The evaluation of US contrast enhancement will allow for in-situ radiation dosimetry. This study demonstrates the effective functionalization of BPA to the NDs and their interactions with the cells and reports on the early-stage in vitro proof-of-concept of neutron-induced NDs-BPA vaporization. The suggested facile technique offers in perspective an innovative approach for both drug delivery and real-time radiation dosimetry with US imaging.