Boron neutron capture synovectomy: Treatment of rheumatoid arthritis based on the nuclear reaction

Abstract

A novel application of the 10 B(n,␣) 7 Li nuclear reaction for the treatment of rheumatoid arthritis is under investigation. Rheumatoid arthritis is characterized by a painful inflammation of the membrane ͑synovium͒ lining articular joints. Since the tissue targeted for treatment is the diseased synovial membrane and the goal is synovial ablation ͑''synovectomy''͒, the proposed treatment is called Boron Neutron Capture Synovectomy. Development of this therapeutic modality has been carried out in a number of areas, including the ex vivo and in vivo evaluation of 10 B in arthritic synovium, and the design and construction of a dedicated neutron beam assembly for joint irradiation. Ex vivo evaluation of boron uptake in human arthritic synovium using K 2 B 12 H 12 has demonstrated that 10 B concentrations of 550-2400 ppm are repeatedly obtained. Preliminary in vivo experiments in an arthritic rabbit model have shown that synovial boron concentrations of approximately 265-950 ppm are obtained at 15 min post intra-articular injection. With these uptake levels experimental evaluation of the efficacy of BNCS in the treatment of rheumatoid arthritis in an animal model can be carried out. Optimal neutron beams suitable for joint irradiation are shown to be lower in energy than those used for BNCT. An assembly comprising a graphite reflector surrounding a D 2 O moderator has been designed, constructed, and installed on the 4.1 MeV tandem electrostatic accelerator at MIT's Laboratory for Accelerator Beam Applications. Monte Carlo calculations predict a total therapy time of between 8.4 and 31 min for the human knee, depending on the charged particle reaction used; a particle beam current of 1 mA is assumed. Therapy times to treat a human finger joint range from 4 to 14 min for a 1 mA accelerator current. These treatment times are based on average 10 B in vivo uptake levels ͑observed experimentally in the rabbit knee͒ of 950 ppm and a 10 000 RBE-cGy treatment dose. It is concluded that Boron Neutron Capture Synovectomy, consisting of intra-articular injection of a 10 B-labeled compound followed by neutron irradiation of the joint, has considerable potential as a means of treating rheumatoid arthritis.

Final Technical Report

“…This has been confirmed by previous dissection studies involving several different compounds (Binello 1999). Therefore, in the simulation study described here, 10 B is assumed to exist only in the synovium and/or the synovial fluid.…”

“…Dissection studies showed that some compounds, such as boron metal particulate, coagulate in the synovial fluid and do not disperse to other regions within the joint even after 24 hours; some others, such as the K 2 B 12 H 12 , redistribute throughout the knee quickly and leave the joint within 60 minutes (Binello 1999). If the information regarding the compound redistribution time course could be determined using an in vivo 10 B mapping technique performed on a single living animal, it would allow rejection of some compounds at the screening phase, leaving only those with reasonable longevity and distribution characteristics for more costly and time-consuming dissection studies.…”

“…However, the residence time of K 2 B 12 H 12 in the joint is very short (Binello 1999), and animal experiments showed that this compound is also able to enter the articular cartilage, resulting in extensive cartilage damage upon neutron irradiation (Shortkroff et al 2003). Therefore, it is necessary to find a new compound for eventual use with RA patients.…”

“…Another alternative treatment modality, Boron Neutron Capture Synovectomy (BNCS), is currently under investigation (Yanch et al 1999). BNCS is a two-part procedure involving a direct injection of a non-radioactive, boronated compound into the affected joint followed by irradiation of the joint with low energy neutrons.…”

“…To date, the in vivo uptake behavior of a small number of alternative compounds has been investigated using the AIA model in the knee joints of the New Zealand white rabbit (Binello 1999).…”