NANO-SILICA PARTICLES CONTAINING BORON ISOTOPE AND SERVING AS BORON NEUTRON CAPTURE AGENT

Abstract

The present invention is the creation of stable boron isotope (.sup.10B) containing nanosilica particles composing of amino acids, amino-oligosaccharides, and oligopeptides appropriate to the improvement of drug delivery system (DDS) function of delivering more boron to tumors selectively to facilitate the efficacy of boron neutron capture therapy (BNCT).

Claims

1-6. (canceled)

7. A compound specialized in Drug Delivery System (DDS), for use in “boron-neutron capture therapy (BNCT)” the compound being synthesized such that an amino acid and an oligopeptide are bonded to boron isotope (.sup.10B) using a reactive functional group with which porous spherical nanosilica particles having a particle diameter of from 5 to 2000 nm are chemically modified.

8. A compound or drug specialized in DDS, for use in BNCT, obtained by causing transportable substrates of amino acid transporters that are highly expressed in cancer cells to chemically bond to the compound of claim 7 thereby synthesizing an amino acid boron isotope (.sup.10B).

9. A method for synthesizing nanosilica particles to which only phenylboronic acid (boron isotope (.sup.10B)) is chemically bonded, and a drug or compound utilizing the same for BNCT, provided that boron isotope (.sup.11B) is not contained.

10. A method for synthesizing oligosaccharide-constituting silica particles that comprise phenylboronic acid (boron isotope (.sup.10B)).

11. A compound or synthesis method, wherein the constituent oligopeptide relating to claim 7 is a cell membrane-permeable oligopeptide having a sequence of: TABLE-US-00001 Ser-Leu-Ile-Val-Met-Thr-Cys-Arg, Ser-Les-Pro-Thr-, Tyr-Tyr-Arg-Ala-Tyr, Ser-Trp-Lys-Pro-Leu-Arg, or Tyr-Ser-Lys-Cys-His.

12. The method for synthesizing boron isotope (.sup.10B) nanosilica particles compound, as claimed in claim 10, wherein the oligosaccharide comprises, as constituent amino-saccharides, glucosamine, mannosamine, galactosamine, and neuraminic acid.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0019] FIG. 1 shows a structural formula of a basic compound of the present invention, i.e., an aminophenylboronic acid isotope (.sup.10B)-connected nanosilica particles modified with succinic anhydride.

MODE FOR CARRYING OUT THE INVENTION

[0020] Porous spherical nanosilica particles used in the present invention as a drug delivery system (DDS) material have a particle diameter of from 5 nm to 2000 nm, preferably from 5 nm to 50 nm, but is not particularly limited.

[0021] The nanosilica particles can be administrated intravenously through a neovascularized coarse blood wall closer to the tumor tissue to accumulate into the tumor cells at high boron isotope (.sup.10B) concentration. Additionally, the nanosilica used in the present invention has a large surface area of 100-300 m.sup.2/g so as to be able to chemically bond oligosaccharides, substrate amino acids, and oligopeptides thereto at high concentrations. The typical examples are shown as follows.

EXAMPLE 1

[0022] Synthesis of a basic compound of the present invention, i.e., an aminophenylboronic acid (boron isotope (.sup.10B))-connected nanosilica particles modified with succinic anhydride (Compound 1) as shown in FIG. 1

[0023] For the synthesis of succinic anhydride-modified nanosilica particles, nanosilica SiO.sub.2 (10.0 g; particle size of 10 nm, but not limited to this particle size) was washed with acetone (100 mL), then washed with isopropanol (100 mL), and finally washed with deionized water, and dried in the microwave and then dried under nitrogen stream. To the resulted nanosilica particles, 2-[3-triethoxysilylpropyl] succinic anhydride (0.3-0.9 mol; its molar concentration is not particularly limited) dissolved in ethanol (100 mL) was added. The reaction mixture was heated at 120° C. for 1.5 hours. The resulted reaction mixture was washed with isopropanol (100-150 mL) and dried under vacuum to yield the desired succinic anhydride-modified nanosilica particles. Subsequently, the obtained succinic anhydride-modified nanosilica particles (2.0 g) was added to prepare an aqueous solution (10 ml) and then a boron isotope (.sup.10B)-containing 4-aminophenylboronic acid (2-200 mg; more preferably 40-120 mg) was added thereto. The reaction temperature was set at 0-60° C. (more preferably 20-30° C., but it is not particularly limited). Thus an aminophenylboronic acid (boron isotope (.sup.10B)-connected and succinic anhydride-modified nanosilica particles (as shown in FIG. 1) was obtained at 70-80 yield.

EXAMPLE 2

[0024] Synthesis of aminophenylboronic acid (boron isotope (.sup.10B))-connected oligosaccharide nanosilica particles

(Typical Example)

[0025] Oligoglucosamine (5-100 mmoL) was dissolved in 10 ml of water, and 1.0 g of the compound obtained in the example 1 was added thereto. The reaction was carried out at 5-40° C. for 0.5-120 min (the conditions of temperature and time are not particularly limited). The resulted mixture was filtered and then stirred for 5-120 min with the addition of 10 mL of HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) buffer solution. The mixture was filtered and then washed with ethanol, thereby obtaining the desired compound.

EXAMPLE 3

[0026] Synthesis of aminophenylboronic acid (boron isotope (.sup.10B))-connected oligopeptide nanosilica particles

(Typical Example)

[0027] An oligopeptide having a sequence of Ser-Trp-Lys-Pro-Leu-Arg (3-10 mg) was suspended in MES buffer (10 mL) and then stirred with the addition of 0.1 g of the compound obtained in the example 1 to carried out a reaction for 0.5-120 min (more preferably 1-30 min, but is not particularly limited) at 3-60° C. The reaction mixture was washed with an excess amount of water and then washed with an excess amount of acetone and finally dried under vacuum, thereby to obtain the aminophenylboronic acid (boron isotope (.sup.10B)-connected oligopeptide nanosilica particles.