Stimuli-responsive nanoparticles for biomedical applications

Abstract

Stimuli-responsive NPs with excellent stability, high loading efficiency, encapsulation of multiple agents, targeting to certain cells, tissues or organs of the body, can be used as delivery tools. These NPs contain a hydrophobic inner core and hydrophilic outer shell, which endows them with high stability and the ability to load therapeutic agents with high encapsulation efficiency. The NPs are preferably formed from amphiphilic stimulus-responsive polymers or a mixture of amphiphilic and hydrophobic polymers or compounds, at least one type of which is stimuli-responsive. These NPs can be made so that their cargo is released primarily within target certain cells, tissues or organs of the body, upon exposure to endogenous or exogenous stimuli. The rate of release can be controlled so that it may be a burst, sustained, delayed, or a combination thereof. The NPs have utility as research tools or for clinical applications including diagnostics, therapeutics, or combination of both.

1 . Stimuli responsive amphiphilic polymers which self-assemble to form nanoparticles, wherein the stimuli are selected from the group consisting of pH, temperature, light, redox change, over-expressed enzymes, hypoxia, sound, magnetic force, electrical energy, and combinations thereof. 
     
     
         2 . The polymers of  claim 1  wherein the hydrophobic portion of the amphiphilic polymers changes shape and/or degrades upon exposure to the stimuli. 
     
     
         3 . The polymers of  claim 1  wherein the polymers responsive to pH are selected from the group consisting of poly (2-(diisopropylamino) ethylmethacrylate (PDPA), poly(2-(hexamethyleneimino) ethyl methacrylate (PHMEMA), conjugates and derives thereof thereof. 
     
     
         4 . The polymers of  claim 3  wherein the polymer derivatives are selected from the group consisting of methoxyl-polyethylene glycol-b-poly (2-(diisopropylamino) ethylmethacrylate) (Meo-PEG-b-PDPA), methoxyl-polyethylene glycol-b-poly (2-(diisopropylamino) ethylmethacrylate-co-glycidyl methacrylate) (Meo-PEG-b-P(DPA-co-GMA)), methoxyl-polyethylene glycol-b-poly (2-(diisopropylamino) ethylmethacrylate-co-glycidyl methacrylate-tetraethylenepentamine) (Meo-PEG-b-P(DPA-co-GMA-TEPA)), methoxyl-polyethylene glycol-b-poly (2-(diisopropylamino) ethylmethacrylate-co-glycidyl methacrylate-tetraethylenepentamine-C14) (Meo-PEG-b-P(DPA-co-GMA-TEPA-C14)), methoxyl-polyethylene glycol-b-poly (2-(diisopropylamino) ethylmethacrylate-co-glycidyl methacrylate-oligoarginine) (Meo-PEG-b-P(DPA-co-GMA-Rn)), methoxyl-polyethylene glycol-b-poly(2-(hexamethyleneimino) ethyl methacrylate) (Meo-PEG-b-PHMEMA), and poly (2-(hexamethyleneimino) ethyl methacrylate-co-2-aminoethyl methacrylate) Meo-PEG-b-P(HMEMA-co-AMA). 
     
     
         5 . The polymers of  claim 1  which are responsive to light selected from the group consisting of methoxyl-polyethylene glycol-b-poly (2-(2-oxo-2-phenylacetoxy) ethyl methacrylate) (Meo-PEG-b-POPEMA) and mixtures thereof. 
     
     
         6 . The polymers of  claim 1  which are redox responsive selected from the group consisting of L-cystine-based poly(disulfide) (PDSA) polymers. 
     
     
         7 . Nanoparticles formed by emulsion with a non-aqueous solvent, solvent extraction, or nanoprecipitation from polymers in combination with stimuli responsive polymers, wherein the stimuli are selected from the group consisting of pH, temperature, light, redox change, over-expressed enzymes, hypoxia, sound, magnetic force, electrical energy, and combinations thereof. 
     
     
         8 . The nanoparticles of  claim 7  wherein the polymers comprise a first amphiphilic polymer containing a polymer represented by Formula I:
   (X) m —(Y) n    Formula I
 
 wherein 
 m and n are independently integers between one and 1000, inclusive, 
 X is a hydrophobic polymer and Y is a hydrophilic polymer, and 
 at least one of X, Y, or both, is stimuli-responsive. 
 
     
     
         9 . The nanoparticles of  claim 8  comprising a mixture of polymers represented by Formula I and a second polymer containing a polymer represented by Formula II:
   (Q) c -(R) d    Formula II
 
 Wherein 
 c and d are independently integers between zero and 1000, inclusive, with the proviso that the sum (c+d) is greater than one, and 
 Q and R are independently hydrophilic or hydrophobic polymers. 
 
     
     
         10 . The nanoparticles of  claim 7  wherein the polymer represented by Formula I, Formula II, or both, contains a ligand. 
     
     
         11 . The nanoparticles of  claim 10 , wherein the ligand is a targeting ligand, an adhesion ligand, a cell-penetrating ligand, or an endosomal-penetrating ligand. 
     
     
         12 . The nanoparticles of  claim 10 , wherein the ligand is selected from the group consisting of a disulfide-based cyclic arginine-glycine-aspartic acid (RGD) peptide (iRGD), a tumor targeting moiety S,S-2-[3-[5-amino-1-carboxypentyl]-ureido]-pentanedioic acid (ACUPA), and oligoarginine, and combinations thereof. 
     
     
         13 . The nanoparticles of  claim 7  further comprising a stimuli-responsive hydrophobic polymer 
     
     
         14 . The nanoparticles of  claim 7  wherein the hydrophilic portion of the amphiphilic polymers is a polyalkylene oxide, or derivative thereof. 
     
     
         15 . The nanoparticles of  claim 7  wherein the polymers comprising polymer responsive to pH selected from the group consisting of poly (2-(diisopropylamino) ethylmethacrylate (PDPA), poly(2-(hexamethyleneimino) ethyl methacrylate (PHMEMA), conjugates and derives thereof thereof, conjugates and derives thereof. 
     
     
         16 . The nanoparticles of  claim 5  wherein the polymers comprising polymer responsive to pH selected from the group consisting of methoxyl-polyethylene glycol-b-poly (2-(diisopropylamino) ethylmethacrylate) (Meo-PEG-b-PDPA), methoxyl-polyethylene glycol-b-poly (2-(diisopropylamino) ethylmethacrylate-co-glycidyl methacrylate) (Meo-PEG-b-P(DPA-co-GMA)), methoxyl-polyethylene glycol-b-poly (2-(diisopropylamino) ethylmethacrylate-co-glycidyl methacrylate-tetraethylenepentamine) (Meo-PEG-b-P(DPA-co-GMA-TEPA)), methoxyl-polyethylene glycol-b-poly (2-(diisopropylamino) ethylmethacrylate-co-glycidyl methacrylate-tetraethylenepentamine-C14) (Meo-PEG-b-P(DPA-co-GMA-TEPA-C14)), methoxyl-polyethylene glycol-b-poly (2-(diisopropylamino) ethylmethacrylate-co-glycidyl methacrylate-oligoarginine) (Meo-PEG-b-P(DPA-co-GMA-Rn)), methoxyl-polyethylene glycol-b-poly(2-(hexamethyleneimino) ethyl methacrylate) (Meo-PEG-b-PHMEMA), and poly (2-(hexamethyleneimino) ethyl methacrylate-co-2-aminoethyl methacrylate) Meo-PEG-b-P(HMEMA-co-AMA), conjugates and derives thereof. 
     
     
         17 . The nanoparticles of  claim 7  comprising therapeutic, prophylactic, or diagnostic agents selected from the group consisting of proteins or peptides, nucleic acids, lipids, sugars or polysaccharides, small molecules, or combinations thereof. 
     
     
         18 . The nanoparticles of  claim 17  comprising between about 1% and about 70% weight/weight, between about 5% and about 50% weight/weight, or between about 10% and about 30% weight/weight of a therapeutic agent, a prophylactic agent, a diagnostic agent, or combinations thereof. 
     
     
         19 . The nanoparticles of  claim 17  release agent primarily within target certain cells, tissues or organs of the body, upon exposure to endogenous or exogenous stimuli. 
     
     
         20 . The nanoparticles of  claim 17  where the agent is released as a burst, sustained, delayed, or a combination thereof. 
     
     
         21 . The nanoparticles of  claim 17  wherein the agent is small interference RNA (siRNA), RNA interference (RNAi), miRNA, or other regulatory nucleic acid molecules. 
     
     
         22 . The nanoparticles of  claim 17  wherein the agent is a chemotherapeutic, or antiinfective for treatment of a disorder characterized by a stimuli effecting release or which can be exposed to a stimuli. 
     
     
         23 . The nanoparticles of  claim 22  releasing a chemotherapeutic, or antiinfective at a site of low pH caused by cancer or an infection. 
     
     
         24 . The nanoparticles of  claim 7  wherein the polymers comprise polymer selected from the group consisting of methoxyl-polyethylene glycol-b-poly (2-(diisopropylamino) ethylmethacrylate-co-glycidyl methacrylate) (Meo-PEG-b-P(DPA-co-GMA-TEPA-C14), Meo-PEG-b-P(DPA-co-GMA-TEPA-Cy5.5), iRGD-PEG-b-PDPA, and mixtures thereof. 
     
     
         25 . The nanoparticles of  claim 7  wherein membrane-penetrating oligoarginine grafts, and/or an S,S-2-[3-[5-amino-1-carboxypentyl]-ureido]-pentanedioic acid (ACUPA) terminus are bound to the polymer. 
     
     
         26 . The nanoparticles of  claim 5  comprising a mixture of Meo-PEG-b-P(DPA-co-GMA-Rn), and ACUPA-PEG-b-PDPA. 
     
     
         27 . The nanoparticles of  claim 26  comprising a mixture of Meo-PEG-b-P(DPA-co-GMA-Rn) (90 mol %) and ACUPA-PEG-b-PDPA (10 mol %). 
     
     
         28 . The nanoparticles of  claim 7  wherein the stimulus is pH. 
     
     
         29 . The nanoparticles of  claim 7  wherein the stimulus is temperature. 
     
     
         30 . The nanoparticles of  claim 7  wherein the stimuli is a change in redox, light, sound, oxygen concentration, or electrical energy. 
     
     
         31 . A method of making the nanoparticles of  claim 7  comprising adding polymer and optionally agent to an emulsion of an aqueous and a non-aqueous solvent to form stimuli responsive nanoparticles. 
     
     
         32 . A method of delivering therapeutic, prophylactic, and/or diagnostic agents comprising administering the nanoparticles of  claim 17  and exposing the nanoparticles thereafter to the stimulus causing release of agent to be delivered.