Modified paramagnetic nanoparticles for targeted delivery of therapeutics and methods thereof

Patent metadata

Field	Value
Publication number	US-2016346389-A1
Application number	US-201415021333-A
Country	US
Kind code	A1
Filing date	Sep 12, 2014
Priority date	Sep 12, 2013
Publication date	Dec 1, 2016
Grant date	—

Abstract

Described herein is a method of making modified paramagnetic nanoparticles with improved therapeutic loading efficiency and enhanced circulation properties. The method comprises coating a paramagnetic nanoparticle (PMNP) with a hydrophobic coating comprising lipophilic drug and a polymer. Also described herein is a PMNP, and a composition comprising PMNP. In certain embodiment, the PMNP have improved permeability through the blood brain barrier. Also described herein is a method of using the PMNP for the treatment of diseases. In certain embodiments, the method of treatment is a combination therapy. Described herein are imaging of therapeutic delivery of PMNP and diagnostic methods using the PMNP. Also described herein is a diagnostic kit that comprises the PMNP. The invention provides compositions comprising a paramagnetic nanoparticle having an external coating comprising a small organic molecule, a polymer, a blood protein, oleic acid, a lipophilic pharmaceutical or an allosteric effector of hemoglobin, as well as methods of making thereof, and use thereof in treatment and imaging.

First claim

1 . A method of making modified PMNP comprising the steps of:
(i) adding fatty acid to PMNP core to form a mixture; (ii) Sonicating the mixture; (iii) Spinning the sonicated mixture and washing in deionized water; (iv) Drying and lyophilizing the washed mixture to form a powder; (v) mixing the lyophilized powder with a non-aqueous concentrated solution of a therapeutic agent to form a mixture; (vi) sonicating the mixture from step (v); (vii) spinning the sonicated mixture and washing in deionized water.

2 . A method of making a modified PMNP comprising the steps of:
(i) adding fatty acid to PMNP core to form a mixture; (ii) Sonicating the mixture; (iii) Spinning the sonicated mixture and washing in deionized water to form an aqueous suspension; (iv) mixing the aqueous suspension with a non-aqueous concentrated solution comprising a therapeutic agent; (v) sonicating the mixture from step (vi); (vi) removing the non-aqueous solvent.

3 . The method of claim 1 wherein the therapeutic agent is Adriamycin, taxol, curcumin, dasationib, melanin, allosteric effector, albumin, plasmid, siRNA or a combination thereof.

4 . A method of making a drug-loaded albumin-coated paramagnetic nanoparticle (alb-PMNP) comprising the steps of:
(i) mixing an ethanol in methanol solution comprising PMNP core with a methanol solution comprising a therapeutic agent to form a mixture; (ii) sonicating the mixture; (iii) adding an aqueous solution comprising albumin to the sonicated mixture.

5 . The method of claim 4 further comprising the step of:
(i) adding methoxy PEG-DSPE, fluorescence-labeled PEG-DSPE, or a derivatized PEG-DSP to the sonicated mixture in step (iii).

6 . The method of claim 5 wherein the PEG-DSPE comprises a reactive species including maleimide, amine, thiol or a combination thereof.

7 . The method of claim 6 wherein the reactive species is attached to a fluorophore, PET imaging agent, peptide, antibody, aptamer, contrasting agent or a combination thereof.

8 . The method of claim 7 wherein the peptide is CXCR4 antagonistic peptide.

9 . A method of making modified PMNP comprising the steps of:
(i) adding 3-mercaptopropyl-trimethoxysilane (3MPTS) or (N-(2-Aminoethoxyl)-11-Aminoundecyl trimethoxysilane) (APTS) to a solution containing PMNP core in deionized water to form a mixture; (ii) Sonicating the mixture in step (i); (iv) incubating the sonicated mixture at 4° C.; (v) washing the mixture in deionized water; and (vi) adding 4′-dithiodipyridine (4-PDS) to form a mixture.

10 . The method of claim 9 further comprising the step of:
(i) adding 2-imminothiolane & mal-PEG-5K to the mixture of step (vi).

11 . The method of claim 10 further comprising the step of:
(i) adding dithiothreitol (DTT) to the mixture of step (vi);
(ii) treating the mixture with buffer saturated with pure NO gas.

12 . The method of claim 1 wherein the PMNP core comprises substantially of Gd 2 O 3 or iron oxide.

13 . The method of claim 12 wherein the Gd 2 O 3 is doped with europium or other lanthanides.

14 . The method of claim 1 wherein the fatty acid is oleic acid.

15 . A method of delivering the modified PMNP to a target location in a subject comprising:
(i) administering to the subject an effective amount of the modified PMNP prepared by the method of claim 1 ; (ii) applying a magnetic field to the subject, such that the magnetic field is present at the target location at a strength sufficient to attract the modified PMNP.

16 . The method of claim 15 wherein the modified PMNP is administered systemically.

17 . The method of claim 15 wherein the location of the modified PMNP is monitored using MRI.

18 . The method of claim 15 wherein the modified PMNP comprises fluorophores.

19 . A method of treating cancer in a subject comprising: (i) administering to the subject an effective amount of the modified PMNP prepared by the method of claim 1 ; and (ii) applying a magnetic field to the subject at the location of the cancer, and wherein the magnetic field is at a strength sufficient to attract the modified PMNP to the cancer.

20 . The method of claim 19 wherein the therapeutic agent is a chemotherapeutic drug, small organic molecule, cytotoxic drug, or a combination thereof.

21 . The method of claim 19 wherein the cancer is pancreatic cancer, CNS cancer, bone cancer, hypoxic tumor.

22 . The method of claim 19 wherein the subject is treated with a second cancer therapy.

23 . A method of treating cancer in a subject comprising: (i) administering to the subject an effective amount of the modified PMNP prepared by the method of claim 4 ; and (ii) applying a magnetic field to the subject at the location of the cancer, and wherein the magnetic field is at a strength sufficient to attract the modified PMNP to the cancer.

24 . The method of claim 23 wherein the peptide binds to a cell-surface target.

25 . A method of treating sickle cell disease in a subject comprising administering to the subject an effective amount of the modified PMNP prepared by the method of claim 1 , wherein the therapeutic agent is an allosteric effector.

26 . A method of treating an inflammation in a subject comprising: (i) administering to the subject an effective amount of the modified PMNP prepared by the method of claim 1 ; and (ii) applying a magnetic field to the subject at the location of the inflammation, and wherein the magnetic field is at a strength sufficient to attract the modified PMNP to the predetermined location.

27 . The method of claim 26 wherein the inflammation is at a joint.

28 . A method of treating or reducing a reperfusion injury or ischemia in a subject comprising: (i) administering to the subject an effective amount of the modified PMNP prepared by the method of claim 1 ; and (ii) applying a magnetic field to the subject at the location of the reperfusion injury or ischemia, and wherein the magnetic field is at a strength sufficient to attract the modified PMNP to the reperfusion injury or ischemia.

29 . A method of imaging a predetermined location in a subject comprising:
(i) administering to the subject an effective amount of the modified PMNP prepared by the method of claim 1 ; (ii) applying a magnetic field to the subject predetermined location at a strength sufficient to attract the modified PMNP to the predetermined location; and (iii) collecting an imaging signal from the predetermined location using an imaging device so as to thereby image the predetermined location.

30 . A method of increasing oxygen levels in a target tissue in a subject having a disorder comprising: (i) administering to the subject an effective amount of the modified PMNP prepared by the method of claim 1 ; and (ii) applying a magnetic field to the subject at the predetermined location where an increased oxygen level is desired, and wherein the magnetic field is at a strength sufficient to attract the modified PMNP to the predetermined location.

31 . The method of claim 30 wherein the disorder is cancer, hypoxic tumor, sickle cell anemia, or local hypoxic conditions.

32 . A modified paramagnetic nanoparticle (PMNP) comprising a PMNP core, which core comprises a coating, said coating comprising oleic acid, a fatty acid, albumin, or a combination

Assignees

• Albert Einstein College Medicine Inc

Inventors

• Friedman Joel
• Mahantesh Navati

Classifications

• A61K9/5146

  obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides · CPC title

• A61K9/19

  lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)} · CPC title

• A61K31/12

  Ketones · CPC title

• A61K31/713

  Double-stranded nucleic acids or oligonucleotides · CPC title

• A61K9/5192

  Processes · CPC title