Long Circulating Nanoparticles for Sustained Release of Therapeutic Agents

Abstract

The present disclosure is directed in part to a biocompatible nanoparticle composition comprising a plurality of non-colloidal long circulating nanoparticles, each comprising a α-hydroxy polyester-co-polyether and a therapeutic agent, wherein such disclosed compositions provide a therapeutic effect for at least 12 hours.

1 . A biocompatible nanoparticle composition comprising a plurality of long circulating nanoparticles, each comprising a α-hydroxy polyester-co-polyether and a therapeutic agent, said composition providing an elevated plasma concentration of the therapeutic agent for at least 12 hours when the composition is administered to a patient, to provide an area under the plasma concentration time curve (AUC) that is increased by at least 100% over the AUC provided when the therapeutic agent is administered alone to a patient. 
     
     
         2 . The biocompatible nanoparticle composition of  claim 1 , that provides an actual peak plasma concentration (C max ) that is at least 10% higher as compared to a C max  of said therapeutic agent w(Original) hen administered alone. 
     
     
         3 . The biocompatible nanoparticle composition of  claim 1 , wherein the volume of distribution when administered to the patient is less than or equal to about 5 plasma volumes. 
     
     
         4 . The biocompatible nanoparticle composition of  claim 1 , wherein the composition decreases the volume of distribution (V z ) by at least 50% as compared to the V z  of the patient when the therapeutic agent is administered alone. 
     
     
         5 . The biocompatible nanoparticle composition of  claim 1 , wherein the composition provides an elevated plasma concentration of the therapeutic agent for at least 24 hours 
     
     
         6 . The biocompatible nanoparticle composition of  claim 5 , wherein the long circulating nanoparticles each further comprise a biocompatible polymer coupled to a targeting moiety. 
     
     
         7 . The biocompatible nanoparticle composition of  claim 6 , wherein the targeting moiety is selected from the group consisting of a protein, peptide, antibody, antibody fragment, saccharide, carbohydrate, small molecule, glycan, cytokine, chemokine, nucleotide, lectin, lipid, receptor, steroid, neurotransmitter, cell surface marker, cancer antigen, or glycoprotein antigen. 
     
     
         8 . The biocompatible nanoparticle composition of  claim 7 , wherein the targeting moiety binds to prostate membrane specific antigen (PMSA). 
     
     
         9 . The biocompatible nanoparticle of  claim 8 , wherein the biocompatible polymer is PLA-PEG. 
     
     
         10 . The biocompatible nanoparticle of  claim 8 , wherein the biocompatible polymer coupled to the targeting moiety is PLA-PEG-((S,S-2-{3-[1-carboxy-5-amino-pentyl]-ureido}-pentanedioic acid. 
     
     
         11 . The biocompatible nanoparticle composition of  claim 8 , wherein the long circulating nanoparticles comprise about 1 to about 4% by weight of the biocompatible polymer coupled to the targeting moiety. 
     
     
         12 . The biocompatible nanoparticle composition of  claim 8 , wherein the α-hydroxy polyester-co-polyether is polylactic acid-co-polyethylene glycol. 
     
     
         13 . The biocompatible nanoparticle composition of  claim 12 , wherein the α-hydroxy polyester-co-polyether comprises about 16 kDa polylactic acid and about 5 kDa polyethylene glycol. 
     
     
         14 . (canceled) 
     
     
         15 . The biocompatible nanoparticle composition of  claim 13 , wherein the peak plasma concentration (C max ) of said therapeutic agent at least 100% higher than the C max  of said therapeutic agent when administered alone. 
     
     
         16 .- 18 . (canceled) 
     
     
         19 . The biocompatible nanoparticle composition of  claim 1 , wherein the long circulating nanoparticles have about 40 to about 50 weight percent poly(lactic)acid, and about 40 to about 50 weight percent of α-hydroxy polyester-co-polyether. 
     
     
         20 .- 22 . (canceled) 
     
     
         23 . The biocompatible nanoparticle composition of  claim 1 , wherein the therapeutic agent is an anti-neoplastic agent. 
     
     
         24 . The biocompatible nanoparticle composition of  claim 1 , wherein the therapeutic agent is chosen from docetaxel, vincristine, methotrexate, paclitaxel, or sirolimus. 
     
     
         25 . The biocompatible nanoparticle composition of  claim 1 , further comprising an aqueous solution of a saccharide. 
     
     
         26 . A biocompatible nanoparticle composition comprising a plurality of long circulating nanoparticles, each comprising a biocompatible polymer and a therapeutic agent, said composition providing an elevated plasma concentration of the therapeutic agent for at least 12 hours when the composition is administered to a patient, and an area under the plasma concentration time curve (AUC) that is increased by at least 100% over the AUC provided when the therapeutic agent is administered alone to a patient. 
     
     
         27 . The biocompatible nanoparticle composition of  claim 1 , wherein the patient is a mammal. 
     
     
         28 . (canceled) 
     
     
         29 . A method of treating a solid tumor cancer, comprising administering the nanoparticle composition of  claim 1 , to a patient in need thereof. 
     
     
         30 . The method of  claim 29 , wherein at least 24 hours after administration, the solid tumor has significant concentration of therapeutic agent. 
     
     
         31 . A method of treating a solid tumor in a mammal in need thereof, comprising administering a nanoparticle composition comprising a plurality of nanoparticles each comprising a α-hydroxy polyester-co-polyether and a therapeutic agent, wherein the composition has an amount of therapeutic agent effective to inhibit the growth of said tumor. 
     
     
         32 . The method of  claim 31 , wherein a single dose of said composition provides extended elevated plasma concentrations of said therapeutic agent in the patient for a least one day. 
     
     
         33 . The method of  claim 32 , wherein the peak plasma concentration (C max ) of the therapeutic agent after administration of the composition to the mammal is at least 10% higher than the C max  of said therapeutic agent if administered in a non-nanoparticle formulation. 
     
     
         34 .- 35 . (canceled)