Carborane confined nanoparticles for boron neutron capture therapy: Improved stability, blood circulation time and tumor accumulation

Abstract

Abstract-2 -Carborane confined nanoparticles based on the core cross-linked and boron-containing micelles (CL micelles) were prepared using the radical polymerization of poly(ethylene glycol)-block-poly(lactide) copolymer (PEG-b-PLA), which contained an acetal group at the PEG end and a methacryloyl group at the PLA end (acetal-PEG-b-PLA-MA), with polymerizable carborane (VB-carborane) as a cross-linker. No leakage of VB-carborane from the CL micelles was observed in PBS even in the presence of 10 % fetal bovine serum (FBS) at 37 ºC, whereas significant leakage (80 %) of VB-carborane was observed for the non-cross-linked (NCL) micelles under the same conditions. To clarify the biodistribution of both types of micelles, 125 I (RI: radioisotope)-labeled CL and NCL micelles were injected into tumor-bearing BALB/c mice via the tail vein. The 125 I-labeled CL micelles showed a remarkably prolonged blood circulation time (7.9 %ID/g) and high tumor accumulation (2.9 %ID/g) compared with the 125 I-labeled NCL micelles (blood: 3.1 %ID/g, tumor:1.8 %ID/g) at 24 h after injection. Moreover, the biodistribution of the VB-carborane (boron species) was also evaluated using ICP-MS at 24 h after intravenous injection of the CL and NCL micelles. The boron concentrations in blood and tumor after injection of the CL micelles (blood: 13.5 %ID/g, tumor: 5.4 %ID/g) were also significantly higher than the concentrations after the injection of the NCL micelles (blood: 1.8 %ID/g, tumor: 1.4 %ID/g). Note that the biodistribution of the boron species in the CL micelles was similar to that of the 125 I-labeled CL micelles, whereas the boron concentrations (%ID/g) in blood and tumor after injection of the NCL micelles were lower than those expected with the 125 I concentrations (%ID/g) in blood and tumor. Thus, the boron concentration ratios of the CL micelles to the NCL micelles (CL ICP /NCL ICP ) in blood (15.8) and tumor (3.8) were much higher than the 125 I concentration ratios of CL RI /NCL RI in blood (2.5) and tumor (1.6). These differences might be caused by the suppression of the leakage of the VB-carborane from the CL micelles in the blood stream due to the existence of the cross-linking bonds between the VB-carborane and the PLA core.-3 -Based on these results, the CL micelles composed of PEG-b-PLA copolymer cross-linked by carborane represent a promising approach to the creation of a novel boron carrier for boron neutron capture therapy (BNCT).

Nanomaterials for boron and gadolinium neutron capture therapy for cancer treatment

“…Other boron containing nanoparticles, derived from boron carbides [50,51], block-copolymers [52,53], boron powder [54] and borosilicates [55], have also been reported. Commercially available boron carbide has been successfully functionalized with lissamine and the transacting transcriptional activator peptide, the resulting nanocomposites ( < 100 nm) can be translocated into B16 F10 malignant melanoma cells in a high amount of 1 wt% [50].…”

“…6) [52,53]. Compared with particles obtained from self-assembly (noncross-linked) rather than copolymerization, the particles from copolymerization of 1,2-bis(4-vinylbenzyl)-closo-carboranes demonstrated the following advantages [52]: improved stability in the presence of serum proteins without notable leakage in 50 h period; extended blood circulation time and increased tumor accumulation of up to 5.4 % injection dose/g. Similar results are reported from the same group for particles produced from self-assembly and co polymerization of mono-4-vinylbenzyl-substituted closo-carborane [53].…”

Boron neutron capture therapy assisted by boron-conjugated nanoparticles

“…Based on these results, our materials design of the covalent conjugation of the boron cluster to the micelle core is shown to represent a step forward for BNCT. 59 However, the loading content of the carborane in the micelles is insufficient (ca. 1.0 wt%), most likely due to the low compatibility of the carborane with the micelle core.…”

“…Non-polymerized micelles (NPM ) were prepared by encapsulation of the VB-carborane into the acetal-PEG-b-PLA-MA micelles by means of the solvent evaporation method. 59 The PM were prepared by the thermal polymerization (60 1C for 24 h) after the encapsulation of both VB-carborane and azobisisobutyronitrile into the acetal-PEG-b-PLA-MA micelles by means of the solvent evaporation method. The average diameter (67.3 nm, m 2 /G 2 ¼ 0.113) of the PM was similar to that of the NPM (60.2 nm, m 2 /G 2 ¼ 0.119), suggesting that the core polymerization process does not influence the size distribution of the micelles.…”

Pharmacokinetics of core-polymerized, boron-conjugated micelles designed for boron neutron capture therapy for cancer

“…Therefore, we attempted to prepare polymeric micelles by conjugating the boron compounds through covalent bonds, since release of the incorporated drugs from nanoparticles is not required for BNCT. Recently, we reported the development of a new class of boron delivery systems based on core cross-linked and boron-conjugated micelles prepared by radical polymerization of poly(ethylene glycol)-block-poly(lactide) copolymer (PEG-b-PLA), which bears an acetal group at the PEG end and a methacryloyl group at the biodegradable PLA end (acetal-PEG-b-PLA-MA) and a polymerizable carborane bearing two vinylbenzyl groups (1,2-bis(4-vinylbenzyl)-closo-carborane) as the cross-linker [16]. Indeed, the obtained core cross-linked and boron-conjugated micelles showed no leakage of boron compounds from the micelles under physiological conditions even in the presence of fetal bovine serum (FBS) at 37 ºC, while significant leakage (80%) of boron compounds was observed from the non-cross-linked micelles, which incorporate the boron compounds by physical entrapment.…”