Aptamer bioconjugate drug delivery device

Abstract

A delivery device for an active agent comprises nanoparticles based on a biopolymer such as starch. The delivery device may also be in the form of an aptamer-biopolymer-active agent conjugate wherein the aptamer targets the device for the treatment of specific disorders. The nanoparticles may be made by applying a high shear force in the presence of a crosslinker. The particles may be predominantly in the range of 50-150 nm and form a colloidal dispersion of crosslinked hydrogel particles in water. The biopolymer may be functionalized. The aptamer may be conjugated directly to the cross-linked biopolymers. The active agent may be a drug useful for the treatment of cancer. The delivery device survives for a period of time in the body sufficient to allow for the sustained release of a drug and for the transportation and uptake of the conjugate into targeted cells. However, the biopolymer is biocompatible and resorbable.

We claim: 
     
         1 . A medicament comprising,
 a) a mass of crosslinked starch polymers;   b) a chemotherapeutic active agent conjugated with the mass of crosslinked starch polymers; and,   c) a targeting ligand attached to the mass of crosslinked starch polymers, wherein the targeting ligand extends beyond the mass of crosslinked starch polymers by less than 10 mm.   
     
     
         2 . The medicament of  claim 1  wherein the mass of crosslinked starch polymers has a size in the range of 50-150 nm when measured by any of SEM, NTA or DLS. 
     
     
         3 . The medicament of  claim 1  wherein the mass of crosslinked starch polymers is formed by a process in which native starch granules are plasticized using heat and/or shear and mixed with a crosslinking agent. 
     
     
         4 . The medicament of  claim 1  dispersed in an aqueous medium. 
     
     
         5 . The medicament of  claim 1  wherein the chemotherapeutic active agent is doxorubicin ((7S,9S)-7-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione), cyclophosphamide ((RS)—N,N-bis(2-chloroethyl)-1,3,2-oxazaphosphinan-2-amine 2-oxide) or carmustine (N, N′-bis(2-chloroethyl)-N-nitroso-urea). 
     
     
         6 . The medicament of  claim 1  having a zeta potential that is more negative than negative 10 mV. 
     
     
         7 . The medicament of  claim 1  wherein the ligand comprises an aptamer. 
     
     
         8 . The medicament of  claim 1  wherein the aptamer is selected from a T-cell leukemia cell line. 
     
     
         9 . The medicament of  claim 1  wherein the chemotherapeutic active agent is adsorbed or absorbed to the mass of crosslinked starch polymers. 
     
     
         10 . The medicament of  claim 1  wherein the starch polymers comprise carboxyl functional groups. 
     
     
         11 . The medicament of  claim 1  wherein the chemotherapeutic active agent is doxorubicin. 
     
     
         12 . The medicament of  claim 1  wherein the starch polymers are thermoplastic starch polymers. 
     
     
         13 . The medicament of  claim 1  wherein the starch polymers are waxy corn starch polymers. 
     
     
         14 . The medicament of  claim 1  wherein the mass of crosslinked starch polymer chains extend into a shell effective to provide steric stabilization of the medicament. 
     
     
         15 . The medicament of  claim 1  wherein the mass of crosslinked starch polymer chains are crossliked with glyoxal. 
     
     
         16 . The medicament of  claim 3  wherein the glyoxal is mixed with the starch during mechanical treatment of the starch. 
     
     
         17 . A method of treating cancer comprising a step of administering a medicament according to  claim 1  intravenously into a patient. 
     
     
         18 . A method of making a medicament comprising steps of,
 producing a thermoplastic melt phase of starch;   producing nanoparticles from the thermoplastic melt phase of starch; and,   conjugating an active agent to the starch nanoparticles.   
     
     
         19 . The method of  claim 18  comprising crosslinking the starch. 
     
     
         20 . The method of  claim 18  comprising attaching a targeting ligand to the starch nanoparticles.