# US 2014/0193489 A1 · Dopamine Nanocapsules and Uses Thereof

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- Number: US 2014/0193489 A1
- Document ID: US20140193489A1
- Status: Published application
- Kind: A1
- Application number: 14/149,704
- Filed: 2014-01-07
- Published: 2014-07-10
- Earliest claimed: 2013-01-07
- Assignees: Bar-Ilan University
- Applicants: Bar-Ilan University
- Inventors: Shai Rahimipour; Gil Yeroslavsky; Michal Richman
- Web page: https://patentgrep.com/patent/US20140193489A1

## CPC

- A61K 9/4816: {Wall or shell material}
- A01N 25/28: Microcapsules {or nanocapsules}
- A61K 47/6925: {the form being a microcapsule, nanocapsule, microbubble or nanobubble}
- A61K 9/5094: {Microcapsules containing magnetic carrier material, e.g. ferrite for drug targeting}
- A61K 9/5138: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A01N: PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF (preservation of food or foodstuff A23); BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES (preparations for medical, dental or toiletry purposes which kill or prevent the growth or proliferation of unwanted organisms A61K); PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS

## Abstract

The present invention provides a sonochemical irradiation-based method for the preparation of polydopamine (PDA) nanocapsules having reduced wall thickness and uniform size distribution, which may further comprise at least one payload; nanocapsules obtained by this method; and compositions thereof. Such compositions may be formulated for different purposes, e.g., as pharmaceutical compositions for various therapeutic or diagnostic purposes.

## Claims

### Claim 1

A method for the preparation of nanocapsules each comprising a shell obtained upon polymerization of a compound of the general formula I:
wherein
R1 is H, OH, —CH2OH, F or CN;
R2 is H, R4 or —CH2—R4;
R3 is H, NH2, OH, SH or COOH; and
R4 1S NH2, OH or SH,
provided that R2 and R3 are not both H,
said shell having a thickness of about 1 nm to about 20 nm, about 3 nm to about 15 nm, about 3 nm to about 10 nm, about 4 nm to about 6 nm, or about 5 nm, said method comprising:
(i) dissolving said compound in a basic aqueous solution;
(ii) overlaying said aqueous solution with a non-aqueous solvent, thus forming a biphasic system;
(iii) applying sonication to the aqueous-non-aqueous interface of said biphasic system thereby obtaining said nanocapsules; and
(iv) isolating said nanocapsules.

### Claim 2 (depends on 1)

The method of claim 1, wherein said nanocapsules each having a diameter of about 200 nm to about 1800 nm, about 300 nm to about 1000 nm, about 400 nm to about 800 nm, about 450 nm to about 650 nm, or about 500 to about 550 nm.

### Claim 3 (depends on 1)

The method of claim 1, wherein (i) R2 is H; and R3 is NH2, OH, SH or COOH; or (ii) R3 is H; R2 is CH2—R4; and R4 is NH2, SH or OH.

### Claim 4 (depends on 3)

The method of claim 3, wherein R1 and R2 are H, and R3 is NH2 (dopamine).

### Claim 5 (depends on 4)

The method of claim 4, wherein said nanocapsules have a 50% decomposition temperature (Td50) of about 670° C. and 5% decomposition temperature (Td5) of about 209° C.

### Claim 6 (depends on 1)

The method of claim 1, wherein:
(i) said nanocapsules further comprise at least one payload encapsulated by said shell, said method further comprising the step of dissolving or suspending said at least one payload in said non-aqueous solvent prior to sonication; or
(ii) said nanocapsules further comprise at least one payload coordinated to functional groups on the outer surface of said shell or embedded within said shell, said functional groups being selected from the group consisting of OH, COOH, SH, NH2, —N— or ═N—, said method further comprising the step of dissolving said at least one payload in said aqueous solution prior to sonication; or
(iii) said nanocapsules further comprise at least one payload linked to the outer surface of said nanocapsules, optionally via a linker, said method further comprising the step of linking said at least one payload to said nanocapsules, optionally via said linker.

### Claim 7 (depends on 6)

The method of claim 6, wherein said at least one payload each independently is a metal atom or an ion or oxide thereof, a diagnostic agent, a targeting agent, a therapeutic agent, or a catalyst.

### Claim 8 (depends on 7)

The method of claim 7, wherein said metal is a transition metal, lanthanide, actinide, or main group element metal.

### Claim 9 (depends on 8)

The method of claim 8, wherein said transition metal is Os, Ru, Fe, Pt, Pd, Ni, Ir, Rh, Co, Cu, Re, Tc, Mn, V, Nb, Ta, Hf, Zr, Cr, Mo, W, Ti, Sc, Ag, Au or Y; said lanthanide is La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb or Lu; said actinide is Ac, Th, Pa, U, Np, Pu, Am, Cm, Bk, Cf, Es, Fm, Md, No or Lr; and said main group element metal is Zn, Ga, Ge, Al, Cd, In, Sn, Sb, Hg, Tl or Pb.

### Claim 10 (depends on 7)

The method of claim 7, wherein said diagnostic agent is a dye, fluorophore, luminophore, heavy atom, quantum dot, radioactive isotope, or contrast agent; said targeting agent is a protein, peptide, amino-acid sequence, antibody or a fragment thereof, single-chain variable fragment of an antibody, nucleotide sequence, DNA sequence, RNA sequence, peptide nucleic acid sequence, carbohydrate, or steroid; and said therapeutic agent is an antibacterial agent or antibacterial enzyme, antiviral agent, antifungal agent, anticancer agent, photosensitizer, vitamin, or hormone.

### Claim 11 (depends on 10)

The method of claim 10, wherein said dye is 9-diethylamino-5-benzo[α]phenoxazinone (Nile-red dye); said fluorophore is 3-mercapto-2-(14-(7-nitrobenzo [c] [1,2,5 ]oxadiazol-4-ylamino)-5-oxo-3,9,12-trioxa-6-azatetradecanamido) propanamide; said anticancer agent is cisplatin or a derivative thereof, an anthracycline chemotherapeutic agent such as doxorubicin (adriamycin), daunorubicin, epirubicin, idarubicin and mitoxantrone, a mitotic inhibitor such as paclitaxel, a topoisomerase I inhibitor such as camptothecin, or a topoisomerase II inhibitor such as ellipticine.

### Claim 12 (depends on 7)

The method of claim 7, wherein one of said at least one payload are metal ions coordinated to functional groups on the outer surface of said shell, and another one of said at least one payload is coordinated to said metal ions, said method further comprising the step of coordinating said another one of said at least one payload to said metal ions after isolation of said nanocapsules.

### Claim 13 (depends on 1)

Nanocapsules obtained according to the method of claim 1.

### Claim 14 (depends on 13)

The nanocapsules of claim 13, each comprising a shell obtained upon polymerization of dopamine.

### Claim 15 (depends on 14)

The nanocapsules of claim 14, each further comprising at least one payload each independently (i) encapsulated by said shell; or (ii) coordinated to OH groups on the outer surface of said shell or to the N atom of the indole moiety; or (iii) embedded within said shell; or (iv) linked to the outer surface of said shell, optionally via a linker; or (v) any combination of (i) to (iv).

### Claim 16 (depends on 15)

The nanocapsules of claim 15, wherein metal ions are coordinated to OH groups on the outer surface of said shell or to the N atom of the indole moiety, or atoms or an oxide of said metal are embedded within said shell.

### Claim 17 (depends on 16)

The nanocapsules of claim 16, wherein Cu2+, Fe2+, Fe3+, Zn2+, Mg2+, Mn2+, Ag+1, Ni2+, Gd2+, Ce2+ or Ce4+ ions are coordinated to OH groups on the outer surface of said shell or to the N atom of the indole moiety, or Cu, Fe, Zn, Mg, Mn, Ag, Ni, Gd or Ce atoms or an oxide thereof are embedded within said shell.

### Claim 18 (depends on 15)

The nanocapsules of claim 15, wherein said at least one payload each independently is covalently linked to the outer surface of said shell, optionally via a linker.

### Claim 19 (depends on 18)

The nanocapsules of claim 18, wherein said at least one payload is covalently linked to OH groups or their oxidized form on the outer surface of said shell.

### Claim 20 (depends on 18)

The nanocapsules of claim 18, wherein said linker comprises an amino acid moiety, DNA, PNA, RNA, peptide moiety, carbohydrate, or polyethylene glycol moiety.

### Claim 21 (depends on 15)

The nanocapsules of claim 15, wherein said at least one payload each independently is non-covalently linked to the outer surface of said shell.

### Claim 22 (depends on 15)

The nanocapsules of claim 15, wherein:
(i) a dye such as Nile-red is encapsulated by said shell; or
(ii) a magnetite such as Fe3O4 or Fe2O3 is encapsulated by said shell; or
(iii) a fluorescent probe such as 3-mercapto-2-(14-(7-nitrobenzo[c] [1,2,5]oxadiazol-4-ylamino)-5-oxo-3,9,12-trioxa-6-azatetradecanamido) propanamide is covalently linked to the outer surface of the shell; or
(iv) cisplatin or a derivative thereof is covalently linked to the outer surface of said shell; or
(v) Ni ions are coordinated to OH groups on the outer surface of said shell or to the N atom of the indole moiety, and a His-tagged protein is coordinated to said Ni ions.

### Claim 23 (depends on 13)

A composition comprising nanocapsules according to claim 13.

### Claim 24 (depends on 23)

The composition of claim 23, comprising nanocapsules each comprising a shell obtained upon polymerization of dopamine.

### Claim 25 (depends on 24)

The composition of claim 24, further comprising a pharmaceutically acceptable carrier.

### Claim 26 (depends on 25)

The composition of claim 25, wherein:
(i) Cu2+, Fe2+, Mg2+or Ag+1 ions are coordinated to OH groups on the outer surface of said shell or to the N atom of the indole moiety, or Cu, Fe, Mg or Ag atoms are embedded within said shell, for treatment of bacterial infection; or
(ii) Gd2+ ions are coordinated to OH groups on the outer surface of said shell or to the N atom of the indole moiety, or Gd atoms are embedded within said shell, for diagnostic purposes such as visualization of organs and tissues or diagnosis of tumors; or
(iii) a magnetite such as Fe3O4 or Fe2O3 is encapsulated by said shell, for diagnostic purposes such as visualization of organs and tissues or diagnosis of tumors; or
(iv) an anticancer agent such as cisplatin or a derivative thereof is linked to the outer surface of said shell, optionally via a linker, for use in targeted chemotherapy; or
(v) a protein or peptide such as an antibody or a fragment thereof, an enzyme, or a targeting peptide or peptidomimetic is covalently linked to the outer surface of said shell, optionally via a linker; or
(vi) Ni ions are coordinated to OH groups on the outer surface of said shell or to the N atom of the indole moiety, and a His-tagged protein or peptide such as Herceptin®, an antibacterial enzyme such as lysostaphin and lysosyme, or a targeting peptide or peptidomimetic is coordinated to said Ni ions.

### Claim 27 (depends on 24)

The composition of claim 24, wherein:
(i) Cu2+, Fe2+, Mg2+ or Ag+1 ions are coordinated to OH groups on the outer surface of said shell or to the N atom of the indole moiety, or Cu, Fe, Mg or Ag atoms are embedded within said shell, for use as an antibacterial additive; or
(ii) Ni2+ ions are coordinated to OH groups on the outer surface of said shell or to the N atom of the indole moiety, and a His-tagged an antibacterial enzyme such as lysostaphin or lysozyme is coordinated to said Ni ions, for use as an antibacterial additive; or
(iii) Ni2+ ions are coordinated to OH groups on the outer surface of said shell or to the N atom of the indole moiety, or Ni atoms are embedded within said shell, for use in protein purification; or
(iv) a Ce oxide such as CeO or CeO2 is embedded within said shell, for use as a catalyst in reactions for water splitting or for conversion of CO or NO to CO2 and NO2, respectively.

### Claim 28 (depends on 14)

An anti-bacterial or anti-fouling structure comprising a substrate having a surface and nanocapsules according to claim 14 adhered to said surface, wherein
(i) Cu, or Ag ions are coordinated to OH groups on the outer surface of said shell or to the N atom of the indole moiety, or Cu or Ag atoms are embedded within said shell; or
(ii) lysostaphin or lysozyme is covalently linked to the outer surface of said shell, optionally via a linker; or
(iii) Ni ions are coordinated to OH groups on the outer surface of said shell or to the N atom of the indole moiety, and a His-tagged lysostaphin or lysozyme is coordinated to said Ni ions.

### Claim 29 (depends on 28)

The structure of claim 28, wherein said substrate includes a material selected from the group consisting of glass, a doped glass, indium tin oxide (ITO)-coated glass, silicon, a doped silicon, SiO2, SiH, silicon carbide mirror, quartz, a metal, metal oxide, a mixture of metal and metal oxide, group IV elements, mica, a polymer such as polyacrylamide and polystyrene, a plastic, a zeolite, a clay, wood, a rubber, a paper material, a fabric such as cotton, a polyolefin, a membrane, an optical fiber, a ceramic, a metalized ceramic, an alumina, an electrically-conductive material, a semiconductor, steel or a stainless steel; or said substrate is optically transparent to the UV and visible spectral ranges.

### Claim 30 (depends on 29)

The structure of claim 29, wherein said substrate is in the form of wafers, beads, microparticles, nanoparticles, quantum dots or nanotubes.