Biodegradable and clinically-compatible nanoparticles as drug delivery carriers

Abstract

The present invention relates to the composition of a nanoparticle based on a magnesium salt, and methods of drug delivery using the nanoparticle. A preferred embodiment uses magnesium phosphate, with or without a shell to deliver aiRNA and/or siRNA. The nanoparticles of the present invention are also effective when administered orally.

1 - 72 . (canceled) 
     
     
         73 . A nanoparticle comprising:
 a core comprising an inorganic magnesium salt, and a medically useful agent comprising a nucleic acid, wherein the core is encapsulated by a shell, and   wherein the shell comprises a protein or peptide.   
     
     
         74 . The nanoparticle of  claim 73 , wherein the inorganic magnesium salt is magnesium phosphate. 
     
     
         75 . The nanoparticle of  claim 73 , wherein the core consists substantially of magnesium phosphate and one or more medically useful agents. 
     
     
         76 . The nanoparticle of  claim 73 , wherein the core further comprises calcium phosphate. 
     
     
         77 . The nanoparticle of  claim 73 , wherein the nucleic acid is chemically modified. 
     
     
         78 . The nanoparticle of  claim 73 , wherein the nucleic acid is selected from the group consisting of an antisense DNA, an RNA, a DNA-RNA hybrid, a PNA and an aptamer. 
     
     
         79 . The nanoparticle of  claim 78 , wherein the RNA is selected from the group consisting of:
 (i) an asymmetric interfering RNA (aiRNA);   (ii) a small interfering RNA (siRNA); and   (iii) a mixture of aiRNA and siRNA.   
     
     
         80 . The nanoparticle of  claim 79 , wherein the aiRNA or siRNA is a modified aiRNA or modified siRNA. 
     
     
         81 . The nanoparticle of  claim 79 , wherein said aiRNA or siRNA targets at least an RNA that either encodes a protein or regulates a part of a biological pathway implicated in a mammalian disease. 
     
     
         82 . The nanoparticle of  claim 73 , wherein the medically useful agent further comprises a protein or peptide, or a small molecule. 
     
     
         83 . The nanoparticle of  claim 82 , wherein said protein or peptide is an antibody or a fragment thereof. 
     
     
         84 . The nanoparticle of  claim 73 , wherein the core further comprises an additive selected from the group consisting of a protein or peptide, an amino acid, a carbohydrate, and a small molecule. 
     
     
         85 . The nanoparticle of  claim 84 , wherein the protein or peptide is selected from the group consisting of protamine, histone, albumin, albumin derivative, polyarginine and polylysine. 
     
     
         86 . The nanoparticle of  claim 73 , wherein the shell further comprises an ingredient selected from the group consisting of a protein or peptide, a surfactant, a lipid, a ligand, an amino acid, a carbohydrate, a nucleic acid, a small molecule, a biocompatible polymer and a combination thereof. 
     
     
         87 . The nanoparticle of  claim 86 , wherein said surfactant is selected from 1,3-dichloropropan-2-yl carbamate (CAS Registry Number: 61791-12-6), 2-[2-[3,4-bis(2-hydroxyethoxy)oxolan-2-yl]-2-(2-hydroxyethoxy)ethoxy]ethyl dodecanoate (CAS Registry Number:9005-64-5), 2-[2-[3,4-bis(2-hydroxyethoxy)oxolan-2-yl]-2-(2-hydroxyethoxy)ethoxy]ethyl (E)-octadec-9-enoate (CAS Registry Number:9005-65-6), 2-hydroxyethyl 12-hydroxyoctadecanoate (CAS Registry Number: 61909-81-7), 2-[4-(2,4,4-trimethylpentan-2-yl) phenoxy]ethanol (CAS Registry Number: 9002-93-1) and 2-[1,3-bis(2-hydroxyethoxy)propan-2-yloxy]ethanol (CAS Registry Number: 62563-68-2). 
     
     
         88 . The nanoparticle of  claim 86 , wherein said ingredient is selected from the group consisting of a surfactant, a targeting ligand, a cell-penetrating peptide, cyclodextrin, RGD tripeptide, cholesterol, a phospholipid, polyethylene glycol (PEG) and a combination thereof. 
     
     
         89 . The nanoparticle of  claim 88 , wherein said cell-penetrating peptide is polyarginine or polylysine. 
     
     
         90 . The nanoparticle of  claim 86 , wherein said ingredient is selected from the group consisting of:
 (i) a protein or peptide, and a surfactant;   (ii) a protein or peptide, and RGD tripeptide; and   (iii) a protein or peptide, a surfactant and cyclodextrin.   
     
     
         91 . The nanoparticle of  claim 73 , wherein said shell comprises an ingredient selected from the group consisting of:
 (I) histone;   (II) protamine;   (III) albumin or a derivative thereof;   (IV) at least one of polyarginine and polylysine;   (V) histone and RGD tripeptide;   (VI) histone and one of the surfactants selected from the group consisting of: 1,3-dichloropropan-2-yl carbamate (CAS Registry Number: 61791-12-6), 2-[2-[3,4-bis(2-hydroxyethoxy)oxolan-2-yl]-2-(2-hydroxyethoxy)ethoxy]ethyl dodecanoate (CAS Registry Number:9005-64-5), 2-[2-[3,4-bis(2-hydroxyethoxy)oxolan-2-yl]-2-(2-hydroxyethoxy)ethoxy]ethyl (E)-octadec-9-enoate (CAS Registry Number:9005-65-6), and 2-[4-(2,4,4-trimethylpentan-2-yl) phenoxy]ethanol (CAS Registry Number: 9002-93-1);   (VII) protamine and 1,3-dichloropropan-2-yl carbamate (CAS Registry Number: 61791-12-6);   (VIII) protamine, 1,3-dichloropropan-2-yl carbamate (CAS Registry Number: 61791-12-6), and hydroxypropyl beta cyclodextrin; and   (IX) protamine and two of the surfactants selected from the group consisting of: 1,3-dichloropropan-2-yl carbamate (CAS Registry Number: 61791-12-6), 2-[2-[3,4-bis(2-hydroxyethoxy)oxolan-2-yl]-2-(2-hydroxyethoxy)ethoxy]ethyl dodecanoate (CAS Registry Number:9005-64-5), 2-[2-[3,4-bis(2-hydroxyethoxy)oxolan-2-yl]-2-(2-hydroxyethoxy)ethoxy]ethyl (E)-octadec-9-enoate (CAS Registry Number:9005-65-6), 2-hydroxyethyl 12-hydroxyoctadecanoate (CAS Registry Number: 61909-81-7), and 2-[4-(2,4,4-trimethylpentan-2-yl) phenoxy]ethanol (CAS Registry Number: 9002-93-1).   
     
     
         92 . The nanoparticle of  claim 73 , wherein said nanoparticle is more soluble in a solution with a pH value between 6.0 and 7.0 than in one with a pH of 7.0 or more. 
     
     
         93 . The nanoparticle of  claim 92 , wherein said nanoparticle is even more soluble in a solution with an acidic pH value equal to or less than 6.0 than in one with a pH of 7.0 or more. 
     
     
         94 . The nanoparticle of  claim 73 , wherein said nanoparticle is characterized with a surface charge between −30 mV and +50 mV. 
     
     
         95 . The nanoparticle of  claim 94 , wherein said nanoparticle is characterized with a surface charge between −10 mV and +20 mV. 
     
     
         96 . A pharmaceutical composition comprising a plurality of nanoparticles of  claim 73 , and a pharmaceutically acceptable excipient, carrier, or diluent. 
     
     
         97 . The pharmaceutical composition of  claim 96  for use in the treatment of a disease in a mammalian subject. 
     
     
         98 . The pharmaceutical composition of  claim 97 , formulated for oral administration.