Abstract
The uptake of (10)boron by tumor cells plays an important role for cell damage in boron neutron capture therapy (BNCT). CD133 is frequently expressed in the membrane of glioma stem cells (GSCs), resistant to radiotherapy and chemotherapy, and represents a potential therapeutic target. To increase (10)boron uptake in GSCs, we created a polyamido amine dendrimer, conjugated CD133 monoclonal antibodies, encapsulating mercaptoundecahydrododecaborate (BSH) in void spaces, and monitored the uptake of the bioconjugate nanoparticles by GSCs in vitro and in vivo. Fluorescence microscopy showed the specific uptake of the bioconjugate nanoparticles by CD133-positive GSCs. Treatment with the biconjugate nanoparticles resulted in a significant lethal effect after neutron radiation due to efficient and CD133-independent cellular targeting and uptake in CD133-expressing GSCs. A significantly longer survival occurred in combination with the biconjugate nanoparticles and BSH compared with BSH alone in human intracranial GBM models employing CD133-positive GSCs xenografts. Our data demonstrated that this bioconjugate nanoparticle targets human CD133-positive GSCs and is a potential boron agent in BNCT.
Highlights
Boron neutron capture therapy (BNCT) is a high-dose tumor-selective radiotherapy, which utilizes non-radioactive isotope (10)boron (10B) to capture thermal neutrons with high probability leading to nuclear reaction of 10B(n,α)7Li
One mAb-CD133 molecule was conjugated to each molecule of polyamido amine (PAMAM) dendrimers, which was determined by SDS-PAGE, ultraviolet-visible spectra and Ellman assay
The PAMAM dendrimers incorporated with CD133 antibody carry drugs, comprising BSH as a clinical boron neutron capture therapy (BNCT) agent encapsulated in PD-CD133 for high uptake by tumor cells
Summary
Boron neutron capture therapy (BNCT) is a high-dose tumor-selective radiotherapy, which utilizes non-radioactive isotope (10)boron (10B) to capture thermal neutrons with high probability leading to nuclear reaction of 10B(n,α)7Li. Treating tumors with high linear-energy-transfer (LET) alpha and 7Li particles is effective biologically. As the range of these particles in tissue is limited to 10–14 μm, the use of short-range radiation ensures that adjacent normal tissues are spared from radiation-induced damage [1]. High LET radiation kills anoxic and quiescent cells, as well as oxygenated and proliferative cells [2, 3]. Successful BNCT requires selective targeting and delivery of adequate 10B to all tumor cells (~ 20 μg/g weight or ~109 atoms/cell). Previous studies confirmed 10B uptake by proliferative cells targeted for killing with thermal neutrons [4,5,6]
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