Theranostic Nanoprobes for Overcoming Cancer Multidrug Resistance and Methods

Patent metadata

Field	Value
Publication number	US-2016243254-A1
Application number	US-201615047902-A
Country	US
Kind code	A1
Filing date	Feb 19, 2016
Priority date	Feb 19, 2015
Publication date	Aug 25, 2016
Grant date	—

Abstract

Theranostic nanoprobes are provided for overcoming cancer multidrug resistance, and methods for treating biological tissue, including cancerous tissue. The theranostic nanoprobes may include gold nanoparticles functionalized with DNA-hairpin. The DNA-hairpin may be configured to hybridize to a complementary target, which may silence or lessen the multidrug resistance of cancer cells. The theranostic nanoprobes may be configured to release a chemotherapeutic agent upon hybridization of the DNA-hairpin to a target molecule.

First claim

We claim:

1 . A theranostic nanoprobe comprising:
a gold nanoparticle functionalized with
at least one DNA-hairpin labeled with a fluorophore, and
at least one anchor labeled with a quencher; and
a chemotherapeutic agent intercalated in the at least one DNA-hairpin; wherein the at least one DNA-hairpin is configured to hybridize to a complementary target in a cancer cell.

2 . The theranostic nanoprobe of claim 1 , wherein the gold nanoparticle is further functionalized with a spacer comprising PEG.

3 . The theranostic nanoprobe of claim 2 , wherein the spacer comprising PEG is derived from α-Mercapto-ω-carboxy PEG.

4 . The theranostic nanoprobe of claim 2 , wherein from about 20% to about 40% of the surface area of the gold nanoparticle is functionalized with the spacer comprising PEG.

5 . The theranostic nanoprobe of claim 1 , wherein the average diameter of the gold nanoparticle is from about 10 to about 16 nm.

6 . The theranostic nanoprobe of claim 1 , wherein the DNA-hairpin is a thio-DNA-hairpin.

7 . The theranostic nanoprobe of claim 1 , wherein the anchor is a thio-DNA oligonucleotide.

8 . The theranostic nanoprobe of claim 1 , wherein the ratio of DNA-hairpin:gold nanoparticle is from about 20:1 to about 40:1.

9 . The theranostic nanoprobe of claim 1 , wherein the fluorophore is a near-infrared dye.

10 . The theranostic nanoprobe of claim 9 , wherein the near-infrared dye comprises Quasar® 705 dye.

11 . The theranostic nanoprobe of claim 1 , wherein the quencher is Black Hole® Quencher 2.

12 . The theranostic nanoprobe of claim 1 , wherein the complementary target is MRP1 mRNA.

13 . The theranostic nanoprobe of claim 1 , wherein the chemotherapeutic agent is selected from 5-fluorouracil, cisplatin, doxorubicin, rebeccamycin, epirubicin, mitoxantrone, tomaymycin, anthramycin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin, gemcitabine, vincristine, or a combination thereof.

14 . The theranostic nanoprobe of claim 1 , wherein the gold nanoparticle at least partially quenches the emission of the chemotherapeutic agent.

15 . The theranostic nanoprobe of claim 1 , further comprising a hydrogel in which the gold nanoparticle is embedded.

16 . The theranostic nanoprobe of claim 15 , wherein the hydrogel comprises a dendrimer and a polymer.

17 . The theranostic nanoprobe of claim 16 , wherein the dendrimer is a G5 PAMAM-derived dendrimer having primary amines on about 25% of the dendrimer's surface groups.

18 . The theranostic nanoprobe of claim 16 , wherein the polymer is dextran with a molecular weight of about 10 kDa and about 50% of its hydroxyl groups converted to aldehydes.

19 . A method for treating a biological tissue, the method comprising:
providing a hydrogel comprising an embedded theranostic nanoprobe; and contacting the biological tissue with the hydrogel; wherein the embedded theranostic nanoprobe comprises
a gold nanoparticle functionalized with
at least one DNA-hairpin labeled with a fluorophore, and
at least one anchor labeled with a quencher; and

a chemotherapeutic agent intercalated in the at least one DNA-hairpin;
wherein the at least one DNA-hairpin is configured to hybridize to a complementary target in a cancer cell.

20 . The method of claim 19 , wherein the biological tissue comprises a tumor.

21 . The method of claim 19 , wherein contacting the biological tissue with the hydrogel comprises applying the hydrogel on a surface of the biological tissue.

22 . The method of claim 19 , wherein contacting the biological tissue with the hydrogel comprises injecting the hydrogel into the biological tissue.

23 . A method for treating a biological tissue, the method comprising:
providing a first solution comprising a polymer component, wherein the polymer component comprises a polymer having three or more aldehyde groups; providing a second solution comprising a dendrimer component, wherein the dendrimer component comprises a dendrimer having at least 2 branches with one or more surface groups; wherein at least one of the first solution and the second solution comprises a theranostic nanoprobe; and combining the first and second solutions together to produce a hydrogel and contacting one or more biological tissues with the hydrogel; wherein the embedded theranostic nanoprobe comprises
a gold nanoparticle functionalized with
at least one DNA-hairpin labeled with a fluorophore, and
at least one anchor labeled with a quencher; and

a chemotherapeutic agent intercalated in the at least one DNA-hairpin;
wherein the at least one DNA-hairpin is configured to hybridize to a complementary target in a cancer cell.

24 . The method of claim 23 , wherein the biological tissue comprises a tumor.

25 . The method of claim 23 , wherein contacting the biological tissue with the hydrogel comprises applying the hydrogel on a surface of the biological tissue.

26 . The method of claim 23 , wherein contacting the biological tissue with the hydrogel comprises injecting the hydrogel into the biological tissue.

27 . A hydrogel composition comprising:
a plurality of theranostic nanoprobes, each of which comprises
a gold nanoparticle functionalized with
at least one DNA-hairpin labeled with a fluorophore, and
at least one anchor labeled with a quencher; and

a chemotherapeutic agent intercalated in the at least one DNA-hairpin,
wherein the at least one DNA-hairpin is configured to hybridize to a complementary target in a cancer cell; and
a biocompatible hydrogel in which the plurality of theranostic nanoprobes are dispersed.

28 . A kit comprising:
a first solution comprising a polymer component, wherein the polymer component comprises a polymer having three or more aldehyde groups; a second solution comprising a dendrimer component, wherein the dendrimer component comprises a dendrimer having at least 2 branches with one or more surface groups; and a theranostic nanoprobe dispersed in either the first solution, the second solution, or both, wherein the theranostic nanoprobe comprises
a gold nanoparticle functionalized with
at least one DNA-hairpin labeled with a fluorophore, and
at least one anchor labeled with a quencher; and

a chemotherapeutic agent intercalated in the at least one DNA-hairpin;
wherein the at least one DNA-hairpin is configured to hybridize to a complementary target in a cancer cell.

29 . A theranostic nanoprobe comprising:
a gold nanoparticle functionalized with at least one DNA-hairpin; and a chemotherapeutic agent intercalated in the at least one DNA-hairpin; wherein the at least one DNA-hairpin is configured to hybridize to a complementary target in a cancer cell.

30 . The theranostic nanoprobe of claim 29 , wherein the complementary target is MRP1 mRNA.

31 . The theranostic nanoprobe of claim 29 , further comprising a hydrogel in which the gold nanoparticle is embedded.

32 . The theranostic nanoprobe of claim 31 , wherein the hydrogel comprises a G5 PAMAM-derived dendrimer having primary amines on about 25% of its surface groups.

33 . The theranostic nanoprobe of claim 31 , wherein the hydrogel comprises dextran with a molecular weight of about 10 kDa and about 50% of its hydroxyl groups c

Assignees

• Massachusetts Inst Technology

Inventors

• Artzi Natalie
• Conde João
• Oliva Nuria

Classifications

• A61K49/0093

  Nanoparticle, nanocapsule, nanobubble, nanosphere, nanobead, i.e. having a size or diameter smaller than 1 micrometer, e.g. polymeric nanoparticle · CPC title

• A61K49/0021

  the fluorescent group being a small organic molecule · CPC title

• A61K47/48092

  Human Necessities · mapped topic

• A61K47/48884 Primary

  Human Necessities · mapped topic

• A61K47/34

  Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers (A61K47/10 takes precedence) · CPC title