3. Boron Compounds Conjugated with Biomolecules

Author: Martin Kellert and Evamarie Hey-Hawkins

© Dr. Christoph Selg

The effect of BNCT depends on the selective and relatively large amount of 10B delivery to tumor cells while sparing adjacent normal cells. Recent promising approaches entail the use of boron-conjugated biomolecules, such as peptides, growth factors (EGF ), antibodies (monoclonal antibodies; mAbs ) and carrier proteins . Only some selected examples are described here.

         3.1. Boron-conjugated Growth Factors
         3.2. Boron-Conjugated Antibodies
         3.3. Boron-conjugated Proteins

3.1. Boron-conjugated Growth Factors

The majority of high-grade gliomas express the amplified epidermal growth factor receptor (EGFR) gene, and increased numbers of EGFRs are found on the cell surface. EGF-conjugated boronated starburst polyamidoamine dendrimer (EGF-BSD) that contains ∼960 boron atoms per EGF molecule was shown by electron spectroscopic imaging to initially bind to the cell surface membrane and followed by endocytosis , which resulted in the accumulation of boron in lysosomes .

Fig. 3.1 Schematic structure of a starburst dendrimer (SBD)

3.2. Boron-Conjugated Antibodies

The anti-EGF mAb cetuximab (IMC-C225) has also been utilized as a delivery agent for BNCT. The boronated starburst polyamidoamine dendrimer (BSD) was chemically linked to cetuximab and the bioconjugate (BD-C225) was specifically taken up by F98EGFR glioma cells in vitro compared with receptor-negative F98WT cells (41.8 vs. 9.1 μg/g). For in vivo biodistribution studies in F98WT or F98EGFR glioma rats, BD-C225 was given intracerebrally by either convection-enhanced delivery (CED) or direct i.t. injection. The amount of boron retained by F98EGFR gliomas 24 h after CED or i.t. injection was 77.2 and 50.8 μg/g, respectively, with normal boron values in brain and blood (<0.05 μg/g). When BNCT was carried out 24 h after CED of BD-C225, either alone or in combination with i.v. BPA, the corresponding mean survival times (MSTs) were 54.5 and 70.9 days, respectively, with one long-term survivor (more than 180 days). In contrast, the MSTs of irradiated and untreated controls were 30.3 and 26.3 days, respectively. These data show the therapeutic efficacy of molecular targeting of EGFR using a boronated mAb either alone or in combination with BPA.

3.3. Boron-conjugated Proteins

Serum albumin is the most abundant monomeric multi-domain protein in plasma and well-known as a drug carrier due to its extraordinary ligand-binding capacity. Serum albumin accumulates in malignant and inflamed tissues due to the enhanced permeability and retention (EPR) effect.
A maleimide-closo-dodecaborate conjugate (MID) (1) was found to bind not only to Cys34 but also to Lys residues in bovine serum albumin (BSA) under physiological conditions according to a western blot analysis using anti-BSH antibody. An S–S bond-containing MID (SSMID) (2) was synthesized for identification of albumin binding sites: Three Lys residues, Lys221, Lys413 and Lys431, were identified as MID modification sites in addition to Cys34 in BSA. The BSA-MID conjugates showed high and selective accumulation in tumor and significant tumor growth inhibition in colon-26 tumor-bearing mice subjected to thermal neutron irradiation even at a dose of 7.5 mg[B]/kg.

Fig. 3.3 Molecular structure of MID and SSMID

1. Basic Requirements of BNCT – BSH and BPA

2. Development of Small Boron-containing Molecules as BNCT Agents
         2.1. Amino Acid Derivatives
         2.2. Nucleic Acid Derivatives
         2.3. Boronated Porphyrins and Their Analogs
         2.4. Carbohydrates
         2.5. Peptides
         2.6. DNA- or Mitochondria-targeting Molecules

3. Boron Compounds Conjugated with Biomolecules
         3.1. Boron-conjugated Growth Factors
         3.2. Boron-Conjugated Antibodies
         3.3. Boron-conjugated Proteins

4. Boronated Polymers, Liposomes, and Other Nanoparticles as Boron-delivery Systems
         4.1. Boronated Polymers and Micelles
         4.2. Boronated Biopolymers
         4.3. Emulsions
         4.4. Liposomes
         4.5. Boronated Nanoparticles
         4.6. Boronated Nanotubes

5. Strategy for MRI-guided BNCT

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