Evaluating the Usefulness of a Novel  10 B-Carrier Conjugated With Cyclic RGD Peptide in Boron Neutron Capture Therapy

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Abstract

Background

To evaluate the usefulness of a novel ¹⁰B-carrier conjugated with an integrin-binding cyclic RGD peptide (GPU-201) in boron neutron capture therapy (BNCT).

Methods

GPU-201 was synthesized from integrin-binding Arg-Gly-Asp (RGD) consensus sequence of matrix proteins and a ¹⁰B cluster 1, 2-dicarba- closo-dodecaborane- ¹⁰B. Mercaptododecaborate- ¹⁰B (BSH) dissolved in physiological saline and BSH and GPU-201 dissolved with cyclodextrin (CD) as a solubilizing and dispersing agent were intraperitoneally administered to SCC VII tumor-bearing mice. Then, the ¹⁰B concentrations in the tumors and normal tissues were measured by γ-ray spectrometry. Meanwhile, tumor-bearing mice were continuously given 5-bromo-2’-deoxyuridine (BrdU) to label all proliferating (P) cells in the tumors, then treated with GPU-201, BSH-CD, or BSH. Immediately after reactor neutron beam or γ-ray irradiation, during which intratumor ¹⁰B concentrations were kept at levels similar to each other, cells from some tumors were isolated and incubated with a cytokinesis blocker. The responses of the Q and total (= P + Q) cell populations were assessed based on the frequency of micronuclei using immunofluorescence staining for BrdU.

Results

The ¹⁰B from BSH was washed away rapidly in all these tissues and the retention of ¹⁰B from BSH-CD and GPU-201 was similar except in blood where the ¹⁰B concentration from GPU-201 was higher for longer. GPU-201 showed a significantly stronger radio-sensitizing effect under neutron beam irradiation on both total and Q cell populations than any other ¹⁰B-carrier.

Conclusion

A novel ¹⁰B-carrier conjugated with an integrin-binding RGD peptide (GPU-201) that sensitized tumor cells more markedly than conventional ¹⁰B-carriers may be a promising candidate for use in BNCT. However, its toxicity needs to be tested further.

Related collections

Most cited references 14

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Boron neutron capture therapy of cancer: current status and future prospects.

Carolina Vicente, Jeffrey A Coderre, Rolf Barth … (2005)

Boron neutron capture therapy (BNCT) is based on the nuclear reaction that occurs when boron-10 is irradiated with low-energy thermal neutrons to yield high linear energy transfer alpha particles and recoiling lithium-7 nuclei. Clinical interest in BNCT has focused primarily on the treatment of high-grade gliomas and either cutaneous primaries or cerebral metastases of melanoma, most recently, head and neck and liver cancer. Neutron sources for BNCT currently are limited to nuclear reactors and these are available in the United States, Japan, several European countries, and Argentina. Accelerators also can be used to produce epithermal neutrons and these are being developed in several countries, but none are currently being used for BNCT. Two boron drugs have been used clinically, sodium borocaptate (Na(2)B(12)H(11)SH) and a dihydroxyboryl derivative of phenylalanine called boronophenylalanine. The major challenge in the development of boron delivery agents has been the requirement for selective tumor targeting to achieve boron concentrations ( approximately 20 microg/g tumor) sufficient to deliver therapeutic doses of radiation to the tumor with minimal normal tissue toxicity. Over the past 20 years, other classes of boron-containing compounds have been designed and synthesized that include boron-containing amino acids, biochemical precursors of nucleic acids, DNA-binding molecules, and porphyrin derivatives. High molecular weight delivery agents include monoclonal antibodies and their fragments, which can recognize a tumor-associated epitope, such as epidermal growth factor, and liposomes. However, it is unlikely that any single agent will target all or even most of the tumor cells, and most likely, combinations of agents will be required and their delivery will have to be optimized. Current or recently completed clinical trials have been carried out in Japan, Europe, and the United States. The vast majority of patients have had high-grade gliomas. Treatment has consisted first of "debulking" surgery to remove as much of the tumor as possible, followed by BNCT at varying times after surgery. Sodium borocaptate and boronophenylalanine administered i.v. have been used as the boron delivery agents. The best survival data from these studies are at least comparable with those obtained by current standard therapy for glioblastoma multiforme, and the safety of the procedure has been established. Critical issues that must be addressed include the need for more selective and effective boron delivery agents, the development of methods to provide semiquantitative estimates of tumor boron content before treatment, improvements in clinical implementation of BNCT, and a need for randomized clinical trials with an unequivocal demonstration of therapeutic efficacy. If these issues are adequately addressed, then BNCT could move forward as a treatment modality.

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The radiation biology of boron neutron capture therapy.

Richard Morris, Jeffrey A Coderre (1998)

Boron neutron capture therapy (BNCT) is a targeted radiation therapy that significantly increases the therapeutic ratio relative to conventional radiotherapeutic modalities. BNCT is a binary approach: A boron-10 (10B)-labeled compound is administered that delivers high concentrations of 10B to the target tumor relative to surrounding normal tissues. This is followed by irradiation with thermal neutrons or epithermal neutrons which become thermalized at depth in tissues. The short range (5-9 microm) of the alpha and 7Li particles released from the 10B(n,alpha)7Li neutron capture reaction make the microdistribution of 10B of critical importance in therapy. The radiation field in tissues during BNCT consists of a mixture of components with differing LET characteristics. Studies have been carried out in both normal and neoplastic tissues to characterize the relative biological effectiveness of each radiation component. The distribution patterns and radiobiological characteristics of the two 10B delivery agents in current clinical use, the amino acid p-boronophenylalanine (BPA) and the sulfhydryl borane (BSH), have been evaluated in a range of normal tissues and tumor types. Considered overall, BSH-mediated BNCT elicits proportionately less damage to normal tissue than does BNCT mediated with BPA. However, BPA exhibits superior in vivo tumor targeting and has proven much more effective in the treatment of brain tumors in rats. In terms of fractionation effects, boron neutron capture irradiation modalities are comparable with other high-LET radiation modalities such as fast-neutron therapy. There was no appreciable advantage in increasing the number of daily fractions of thermal neutrons beyond two with regard to sparing of normal tissue in the rat spinal cord model. The experimental studies described in this review constitute the radiobiological basis for the new BNCT clinical trials for glioblastoma at Brookhaven National Laboratory, at the Massachusetts Institute of Technology, and at the High Flux Reactor, Petten, The Netherlands. The radiobiology of experimental and clinical BNCT is discussed in detail.

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Hypoxia-inducible factor regulates alphavbeta3 integrin cell surface expression.

Charles E. Robertson, V Weaver, Karen Cowden Dahl … (2005)

Hypoxia-inducible factor (HIF)-deficient placentas exhibit a number of defects, including changes in cell fate adoption, lack of fetal angiogenesis, hypocellularity, and poor invasion into maternal tissue. HIF is a heterodimeric transcription factor consisting of alpha and beta aryl hydrocarbon receptor nuclear translocator or ARNT) subunits. We used undifferentiated trophoblast stem (TS) cells to characterize HIF-dependent adhesion, migration, and invasion. Arnt(-/-) and Hifalpha(-/-) TS cells exhibit reduced adhesion and migration toward vitronectin compared with wild-type cells. Furthermore, this defect is associated with decreased cell surface expression of integrin alphavbeta3 and significantly decreased expression of this integrin in focal adhesions. Because of the importance of adhesion and migration in tumor progression (in addition to placental development), we examined the affect of culturing B16F0 melanoma cells in 1.5% oxygen (O(2)). Culturing B16F0 melanoma cells at 1.5% O(2) resulted in increased alphavbeta3 integrin surface expression and increased adhesion to and migration toward vitronectin. Together, these data suggest that HIF and O(2) tension influence placental invasion and tumor migration by increasing cell surface expression of alphavbeta3 integrin.

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Author and article information

Journal

Journal ID (nlm-ta): World J Oncol

Journal ID (iso-abbrev): World J Oncol

Journal ID (publisher-id): Elmer Press

Title: World Journal of Oncology

Publisher: Elmer Press

ISSN (Print): 1920-4531

ISSN (Electronic): 1920-454X

Publication date (Print): June 2012

Publication date (Electronic): 05 July 2012

Volume: 3

Issue: 3

Pages: 103-112

Affiliations

[a ]Particle Radiation Oncology Research Center, Research Reactor Institute, Kyoto University, 2-1010, Asashiro-nichi, Kumatori-cho, Sennan-gun, Osaka 590-0494, Japan

[b ]Laboratory of Medicinal and Pharmaceutical Chemistry, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan

[c ]Radiation Medical Physics, Research Reactor Institute, Kyoto University, 2-1010, Asashiro-nichi, Kumatori-cho, Sennan-gun, Osaka 590-0494, Japan

Author notes

[d ]Corresponding author: Shin-ichiro Masunaga. Email: smasuna@ 123456rri.kyoto-u.ac.jp

Article

DOI: 10.4021/wjon477w

PMC ID: 5649788

SO-VID: 11b46ebb-77c9-4fd6-8984-2e2906758354

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.