Enhancing Boron Uptake in Brain Glioma by a Boron-Polymer/Microbubble Complex with Focused Ultrasound

Abstract

Boron neutron capture therapy (BNCT) is a promising radiotherapy for treating glioblastoma multiforme (GBM). However, the penetration of drugs (e.g., sodium borocaptate and BSH) for BNCT into brain tumors is limited by cerebral vesicular protective structures, the blood–brain barrier, and the blood–brain tumor barrier (BTB). Although BSH has been reported to be selectively taken up by tumors, it is rapidly excreted from the body and cannot achieve a high tumor-to-normal brain ratio (T/N ratio) and tumor-to-blood ratio (T/B ratio). Despite the development of large-molecular weight boron compounds, such as polymers and nanoparticles, to enhance the permeation and retention effect, their effects remain insufficient for clinical use. To improve the efficiency of boron delivery to the tumor site, we propose combinations of self-assembled boron-containing polyanion [polyethylene glycol-b-poly­((closo-dodecaboranyl)­thiomethylstyrene) (PEG-b-PMBSH)] nanoparticles (295 ± 2.3 nm in aqueous media) coupled with cationic microbubble (B-MB)-assisted focused ultrasound (FUS) treatment. Upon FUS sonication (frequency = 1 MHz, pressure = 0.3–0.7 MPa, duty cycle = 0.5%, sonication = 1 min), B-MBs can simultaneously achieve safe BTB opening and boron drug delivery into tumor tissue. Compared with the MBs of the PEG-b-PMBSH mixture group (B + MBs), B-MBs showed 3- and 2.3-fold improvements in the T/N (4.4 ± 1.4 vs 1.3 ± 0.1) and T/B ratios (1.4 ± 0.6 vs 0.1 ± 0.1), respectively, after 4 min of FUS sonication. The spatial distribution of PEG-b-PMBSH was also improved by the complex of PEG-b-PMBSH with MBs. The findings presented herein, in combination with the expanding clinical application of FUS, may improve BNCT and treatment of GBM.

Boron neutron capture therapy: Current status and future perspectives

“…The stable boron delivery agents with low and high molecular weight connected with a tumor-targeting component or moiety via a hydrolytically stable linkage (boron carriers) belong to this group of compounds ( Figure 2). In particular, these thirdgeneration boron compounds include boronated DNA intercalators [30], boronated amino acids [31], boronated lipopeptides [32], boronated peptides [33], boronated folate receptor [34], boronated epidermal growth factor (EGF) or epidermal growth factor receptor (EGFR) monoclonal antibodies (MAbs) [35], boron-containing immunoliposomes [36] and liposomes [37,38], BSH-loaded polymeric micelles [39], transferrin-polyethylene glycol liposomes [40], maleimide-functionalized closo-dodecaborate albumin conjugates [41], carboranyl nucleosides [42], boronated porphyrins [43], boron-containing nanoparticles [44] coupled with cationic microbubble-assisted focused ultrasound (MB+FUS) treatment [45], pentanuclear porphyrazine complexes [46], boronated cyclic peptides [47], and boron nitride nanotubes [48].…”

“…It has been shown that electroporation can significantly increase the absolute and relative tumor boron concentrations and assist in optimizing the qualitative micro distribution of boron, as well as the retention of boron in vitro and in vivo, for different tumor cells [49,50]. To increase the efficiency of boron delivery to the tumor, combination of large boronated compounds with FUS treatment has been proposed since FUS facilitates the transport of such compounds across the blood-brain barrier (BBB) into tumor [45].…”

Exosomes in Gliomas: Biogenesis, Isolation, and Preliminary Applications in Nanomedicine

“…As natural carrier systems, EVs present low immunogenicity, low toxicity, stability in the bloodstream, and efficient cell uptake due to their endogenous cellular tropism [ 13 ]. Their ability to mediate intercellular communication, especially in brain tumor progression, allows their use as a promising therapeutic and diagnostic tool [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ], including the challenging treatment of gliomas [ 22 , 23 , 24 , 25 , 26 , 27 ]. Gliomas are the most frequent intrinsic tumors of the central nervous system and, by following the 2016 World Health Organization (WHO) update, encompass two principal subgroups: “nondiffuse gliomas”, showing a more circumscribed growth pattern (WHO grade I), and diffusely infiltrating gliomas (WHO grade II–IV), arising from glial cells or glial precursors [ 28 ].…”

<p>Ultrasound Assisted a Peroxisome Proliferator-Activated Receptor (PPAR)γ Agonist-Loaded Nanoparticle-Microbubble Complex to Attenuate Renal Interstitial Fibrosis</p>

“…In addition, freeze-dried commercial SonoVue powder coated with a thin lipid monolayer membrane shell and containing sulfur hexafluoride-filled MBs was used, as the surface charge of SonoVue MBs is negative, 23 the cationic PLNPs-RSG were conjugated with the MBs to synthesize a novel PLNPs-RSG-MBs complex via electrostatic interactions ( Figure 1A) with a conjugation method similar to the protocol described in a previous study. 24 Furthermore, this complex was administered to a unilateral ureteral obstruction (UUO) rat model with the assistance of US exposure, and the purpose of this study was to investigate its antifibrotic effect on RIF ( Figure 1B).…”