Dual responsive brain targeted nanoparticles and their applications

Patent metadata

Field	Value
Publication number	US-2016346208-A1
Application number	US-201615164994-A
Country	US
Kind code	A1
Filing date	May 26, 2016
Priority date	May 28, 2015
Publication date	Dec 1, 2016
Grant date	—

Abstract

The preparation of dual functionalized nanoparticles is generally provided along with their application. The dual functionalized nanoparticles provide dual targeting and can effectively pass the blood brain barrier and target brain tissue. The dual targeted and dual responsive nanoparticles are functionalized to include at least two different ligands that are capable of transport across the blood brain barrier. The nanoparticles can be prepared from polymeric materials that can be biocompatible, provide long circulation life in a body, and be successfully ligated to both functionalities by use of acid-sensitive and/or redox potential-sensitive bonds for delivery across the blood brain barrier and delivery of a payload to brain tissue.

First claim

What is claimed:

1 . A nanoparticle comprising a biocompatible hydrophilic polymer, the nanoparticle further comprising a first ligand and a second ligand conjugated to the nanoparticle, the first and second ligands being separately conjugated to the nanoparticle via acid-sensitive and/or redox potential-sensitive bonds, the first and second ligands each independently comprising a blood brain barrier transporter.

2 . The nanoparticle of claim 1 , the biocompatible hydrophilic polymer comprising a pyridine-2-thiol monomer component copolymerized with a polymeric component.

3 . The nanoparticle of claim 2 , wherein the pyridine-2-thiol monomer comprises one or more of (pyridine-2-thiol)ethyl acrylate, (pyridine-2-thiol) ethyl methacrylate, N-(2-(pyridin-2-yldisulfanyl)ethyl) acrylamide, N-(2-(pyridin-2-yldisulfanyl)ethyl)methacrylamide, or ethyl (2-(pyridin-2-yldisulfanyl)ethyl) carbonate.

4 . The nanoparticle of claim 1 , wherein the acid-sensitive bonds and/or redox potential-sensitive bonds comprise ester bonds, hydrazone bonds, cis-aconityl bonds, or disulfide bonds.

5 . The nanoparticle of claim 1 , wherein the acid-sensitive bonds will degrade in an environment of about pH 6.8 or less.

6 . The nanoparticle of claim 1 , wherein the redox potential-sensitive bonds will degrade in an environment having a redox potential equal to that of an environment comprising a glutathione concentration of about 0.1 mM or higher.

7 . The nanoparticle of claim 1 , wherein the first and second ligands include scopine, glutathione, transferrin, melanotransferrin, adenosine, insulin, low-density lipoprotein, leptin, thiamine, rabies virus glycoprotein, TAT peptide, encephalin, angiopep-2, diphteria toxin, or tetanus toxin.

8 . The nanoparticle of claim 1 , further comprising a biologically active agent.

9 . The nanoparticle of claim 8 , wherein the biologically active agent is a central nervous system disease treatment agent.

10 . The nanoparticle of claim 8 , wherein the biologically active agent includes one or more of n-acetyl cysteine, pyrrolidine dithiocarbamate, disulfiram, diethyldithiocarbamate, tangeritin, resveratrol, indometacin, paclitaxel, doxorubicin, temozolomide, curcum in, carboplatin, carmustine, cisplatin, cyclophosphamide, etoposide, irinotecan, lomustine, methotrexate, procarbazine, vincristine, or sulindac.

11 . The nanoparticle of claim 1 , wherein the biocompatible hydrophilic polymer comprises one or more of polyethylene glycol, poly(N-isopropylacrylamide), poly(N-(2-hydroxypropyl)methacrylamide), poly(acrylic acid), poly(DL-lactic acid-co-glycolic acid), or poly(L-histidine).

12 . A method of forming a nanoparticle comprising:
conjugating a biocompatible hydrophilic polymer with a first ligand via an acid-sensitive and/or redox potential sensitive bond, the first ligand comprising a blood brain barrier transporter; and conjugating the biocompatible hydrophilic polymer with a second ligand via an acid-sensitive and/or redox potential-sensitive bond, the second ligand comprising a blood brain barrier transporter; and forming a nanoparticle including the biocompatible hydrophilic polymer.

13 . The method of claim 12 , wherein the biocompatible hydrophilic polymer comprises one or more of polyethylene glycol, poly(N-isopropylacrylamide), poly(N-(2-hydroxypropyl)methacrylamide), poly(acrylic acid), poly(DL-lactic acid-co-glycolic acid), or poly(L-histidine).

14 . The method of claim 13 , further comprising copolymerizing the biocompatible hydrophilic polymer with a pyridine-2-thiol containing monomer.

15 . The method of claim 14 , wherein the pyridine-2-thiol monomer comprises one or more of (pyridine-2-thiol)ethyl acrylate, (pyridine-2-thiol) ethyl methacrylate, N-(2-(pyridin-2-yldisulfanyl)ethyl) acrylamide, N-(2-(pyridin-2-yldisulfanyl)ethyl)methacrylamide, or ethyl (2-(pyridin-2-yldisulfanyl)ethyl) carbonate.

16 . The method of claim 12 , further comprising loading the nanoparticle with a biologically active agent.

17 . The method of claim 16 , wherein the biologically active agent comprises one or more of n-acetyl cysteine, pyrrolidine dithiocarbamate, disulfiram, diethyldithiocarbamate, tangeritin, resveratrol, indometacin, paclitaxel, doxorubicin, temozolomide, curcum in, carboplatin, carmustine, cisplatin, cyclophosphamide, etoposide, irinotecan, lomustine, methotrexate, procarbazine, vincristine, and sulindac.

18 . The method of claim 12 , wherein the acid-sensitive and/or redox potential-sensitive bonds comprise ester bonds, hydrazone bonds, cis-aconityl bonds, or disulfide bonds.

19 . The method of claim 12 , wherein the first and second ligands include scopine, glutathione, transferrin, melanotransferrin, adenosine, insulin, low-density lipoprotein, leptin, thiamine, rabies virus glycoprotein, TAT peptide, encephalin, angiopep-2, diphteria toxin, or tetanus toxin.

20 . A method for delivering a biologically active agent across the blood brain barrier of a subject, the method comprising providing to the subject a nanoparticle comprising a biocompatible hydrophilic polymer, the nanoparticle further comprising a first ligand and a second ligand conjugated to the nanoparticle, the first and second ligands being separately conjugated to the nanoparticle via acid-sensitive and/or redox potential-sensitive bonds, the first and second ligands each independently comprising a blood brain barrier transporter, wherein the biologically active agent is loaded within or on the nanoparticle.

21 . The method of claim 20 , wherein the biologically active agent comprises one or more of n-acetyl cysteine, pyrrolidine dithiocarbamate, disulfiram, diethyldithiocarbamate, tangeritin, resveratrol, indometacin, paclitaxel, doxorubicin, temozolomide, curcum in, carboplatin, carmustine, cisplatin, cyclophosphamide, etoposide, irinotecan, lomustine, methotrexate, procarbazine, vincristine, and sulindac.

22 . The method of claim 20 , wherein the first and second ligands include scopine, glutathione, transferrin, melanotransferrin, adenosine, insulin, low-density lipoprotein, leptin, thiamine, rabies virus glycoprotein, TAT peptide, encephalin, angiopep-2, diphteria toxin, or tetanus toxin.

23 . The method of claim 20 , wherein the subject is suffering from Alzheimer's disease, Parkinson's disease, traumatic brain injury, stroke, Down syndrome, amyotrophic lateral sclerosis, HIV encephalitis, epilepsy, Huntington's disease, multiple sclerosis, focal cerebral ischemia, addiction, obsessive-compulsive disorder, trichotillomania, schizophrenia, bipolar disorder, brain tumor, spinal cord injury or tumor, or autism.

Assignees

• Univ South Carolina

Inventors

• Xu Peisheng
• Markoutsa Eleni

Classifications

• A61K31/197

  the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid (carnitine A61K31/205) · CPC title

• A61K9/146 Primary

  with organic macromolecular compounds · CPC title

• A61K31/198 Primary

  Alpha-amino acids, e.g. alanine or edetic acid [EDTA] (betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00) · CPC title

• A61K47/6935

  the polymer being obtained otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol · CPC title

• A61K47/6933

  the polymer being obtained by reactions only involving carbon to carbon, e.g. poly(meth)acrylate, polystyrene, polyvinylpyrrolidone or polyvinylalcohol · CPC title