Carborane confined nanoparticles for boron neutron capture therapy: Improved stability, blood circulation time and tumor accumulation
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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 °C, 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, 125I (RI: radioisotope)-labeled CL and NCL micelles were injected into tumor-bearing BALB/c mice via the tail vein. The 125I-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 125I-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 125I-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 125I concentrations (%ID/g) in blood and tumor. Thus, the boron concentration ratios of the CL micelles to the NCL micelles (CLICP/NCLICP) in blood (15.8) and tumor (3.8) were much higher than the 125I concentration ratios of CLRI/NCLRI 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. 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).
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