Multifunctional micellar nanoparticle-based drug and targeting agent system

Abstract

Embodiments provide systems, methods, and compositions for nanoparticle-based drug delivery to target cells or tissues. A drug delivery system may include a nanoparticle with a targeting component and a therapeutic component. The nanoparticle may have a predetermined number or valence of targeting molecules for multivalent interaction with a target cell or tissue. Binding of the targeting molecules to the target cell may result in receptor-mediated uptake of the nanoparticle by the target cell. The therapeutic component may be subsequently released within an endocytic vesicle of the target cell. Nanoparticle-based drug delivery systems as described herein may provide improved efficacy and/or reduced toxicity.

1 . A nanoparticle comprising:
 a hydrophobic interior portion surrounded by an outer portion, the outer portion comprising a water-soluble polymer;   a therapeutic agent coupled to, and disposed at least partially within, the outer portion; and   a targeting agent coupled to, and disposed at least partially within, the outer portion   
       wherein the targeting agent is a low-affinity, high-specificity peptide ligand of a conjugate of Formula I: 
       
         
           
           
               
               
           
         
       
       wherein
   140  is a targeting agent configured to bind to a receptor of a target cell; 
   112  comprises a polyethylene glycol moiety; and 
   124  comprises a lipid having a polar moiety ( 110 ) and a non-polar moiety ( 108 ); 
 
       or a salt thereof. 
     
     
         2 . The nanoparticle of  claim 1 , wherein the nanoparticle is a micellar nanoparticle. 
     
     
         3 . The nanoparticle of  claim 1 , wherein the water-soluble polymer is coupled to a first lipid, the therapeutic agent is coupled to a second lipid, and the targeting agent is coupled to a third lipid, and the first, second, and third lipids are disposed within the interior portion of the nanoparticle. 
     
     
         4 . The nanoparticle of  claim 3 , wherein the water-soluble polymer is polyethylene glycol (PEG). 
     
     
         5 . The nanoparticle of  claim 1 , wherein the therapeutic agent comprises an antibiotic, an anti-cancer agent, or a combination thereof. 
     
     
         6 . The nanoparticle of  claim 1 , wherein the therapeutic agent comprises a nucleic acid, doxorubicin, bortezomib, carfilzomib, cisplatin, carboplatin, or a combination thereof. 
     
     
         7 . (canceled) 
     
     
         8 . (canceled) 
     
     
         9 . The nanoparticle of  claim 1 , wherein the targeting agent comprises VLA 4 -pep (SEQ ID NO: 1), CFLDFP (SEQ ID NO: 2), (X)CDPC (SEQ ID NO: 3), XC(Z)PC (SEQ ID NO: 4), XCA(Z)C (SEQ ID NO: 5), (X)CSPC (SEQ ID NO: 6), YC(X)C (SEQ ID NO: 7), or RC(X)PC (SEQ ID NO: 8) where X and Z are variable amino acids. 
     
     
         10 . The nanoparticle of  claim 1 , wherein the nanoparticle has a size of about 20 nm and includes about 10 to about 20, about 20 to about 40, or about 80 to about 100 molecules of said targeting agent. 
     
     
         11 . The nanoparticle of  claim 3 , wherein the water-soluble polymer comprises polyethylene glycol (PEG), and the therapeutic agent is coupled to the second lipid via a pH-sensitive bond. 
     
     
         12 . The nanoparticle of  claim 11 , wherein the targeting agent is configured to bind to a VLA-4 receptor of a target cell, the therapeutic agent comprises doxorubicin, and the pH-sensitive bond is configured to hydrolyze at the pH of an endocytic vesicle of the target cell. 
     
     
         13 . A method of delivering a therapeutic agent to a cell or tissue of interest in an individual, comprising administering the nanoparticle of  claim 1  to a patient in need thereof, wherein the targeting agent of said nanoparticle enhances accumulation of said therapeutic agent in the cell or tissue of interest. 
     
     
         14 . The method of  claim 13 , wherein the targeting agent binds to a receptor of the cell or tissue of interest, and the targeting agent enhances receptor-mediated endocytosis of the nanoparticle by the cell or tissue of interest. 
     
     
         15 . The method of  claim 13 , wherein the cell or tissue of interest is a cancerous cell or tissue, or bacterially infected tissue. 
     
     
         16 . The method of  claim 15 , wherein the cell of interest is a multiple myeloma cell, leukemia cell, or lymphoma cell. 
     
     
         17 . The method of  claim 15 , wherein the targeting agent comprises VLA 4 -pep (SEQ ID NO: 1), CFLDFP (SEQ ID NO: 2), (X)CDPC (SEQ ID NO: 3), XC(Z)PC (SEQ ID NO: 4), XCA(Z)C (SEQ ID NO: 5), (X)CSPC (SEQ ID NO: 6), YC(X)C (SEQ ID NO: 7), or RC(X)PC (SEQ ID NO: 8) where X and Z are variable amino acids, and the therapeutic agent comprises a nucleic acid, doxorubicin, bortezomib, carfilzomib, cisplatin, carboplatin, or a combination thereof. 
     
     
         18 . A pharmaceutical composition comprising the nanoparticle of  claim 1  and a pharmacologically acceptable excipient. 
     
     
         19 . The method of  claim 13  for the treatment of a cancer, or a bacterial infection. 
     
     
         20 . A method of constructing a nanoparticle-based drug delivery system, the method comprising:
 adding quantities of a first component, a second component, and a third component to a solvent in a predetermined molar ratio, wherein the first component comprises a targeting molecule coupled to a first lipid molecule, the second component comprises a therapeutic agent coupled to a second lipid molecule, and the third component comprises polyethylene glycol (PEG); and mixing said components in the solvent to form a plurality of nanoparticles that include said components in the predetermined molar ratio, wherein the nanoparticles have a hydrophobic interior portion surrounded by an outer portion, the first and second lipid molecules are disposed in the interior portion, and the PEG, the targeting molecule, and the therapeutic agent are disposed in the outer portion.   
     
     
         21 . The nanoparticle of  claim 1 , wherein the conjugate of Formula I is Formula II: 
       
         
           
           
               
               
           
         
       
       wherein
 Tx is targeting agent. 
 
     
     
         22 . The nanoparticle of  claim 1 , wherein the therapeutic agent comprises a pH-sensitive bond configured to hydrolyze at the pH of an endocytic vesicle of the target cell, and optionally the therapeutic agent is a conjugate of Formula III. 
       
         
           
           
               
               
           
         
       
       wherein
 Ty is therapeutic agent; 
 
       or a salt, or combination thereof.