Lung targeting dual drug delivery system

Abstract

The American Cancer Society estimated that in 2009, 1,479,350 new cancer cases would be diagnosed in the United States of which 219,440 would be lung and bronchus related. The standard treatments for NSCLC include surgery, chemotherapy, radiation, laser and photodynamic therapy, all with various success rates depending on the stage of the cancer. National Cancer Institute assesses, however, that results of standard treatment are generally poor with only a 15 percent 5-year survival rate for combined cancer stages. Challenges facing the current chemotherapy drugs include excessive toxicity to healthy tissues and limited ability to prevent metastases. A dual drug delivery system described herein selectively targets the lung to deliver anti-cancer drugs and inhibit the formation of metastases.

What is claimed is: 
     
         1 . A delivery system comprising a gel microparticle, a plurality of nanoparticles associated with the gel microparticle, and one or more drugs associated with at least one of the nanoparticles. 
     
     
         2 . The delivery system of  claim 1  further comprising at least one of one or more targeting agents associated with at least one of the nanoparticles or one or more chemopotentiator associate with at least one of the nanoparticles. 
     
     
         3 . The delivery system of  claim 1 , wherein the plurality of nanoparticles are linked to the gel microparticle. 
     
     
         4 . The delivery system of  claim 1 , wherein the gel microparticles have a size of 1-60 μm. 
     
     
         5 . The delivery system of  claim 1 , wherein the gel microparticles have a size selected from the group consisting of 6-10 μm and 50-60 μm. 
     
     
         6 . The delivery system of  claim 1 , wherein the shear modulus of the gel microparticle is from 4 Pa to 200,000 Pa. 
     
     
         7 . The delivery system  claim 1 , wherein the gel microparticle includes polymers formed from at least one of functionalized poly(2-hydroxyethyl methacrylate) polymers, functionalized polyphosphate polymers, functionalized PEG polymers or copolymers, functionalized dextran polymers, functionalized polyvinyl pyrrolidone polymers or co-polymers or functionalized polyacrylic acid polymers or copolymers. 
     
     
         8 . The delivery system of  claim 1 , wherein the gel microparticles include at least one of functionalized PEG polymers have a molecular weight from 200 to 200,000 g/mole, functionalized dextran polymers have a molecular weight from 200 to 100,000 g/mole, functionalized polyvinyl pryollidone polymers or copolymers have a molecular weight from 200 to 100,000 g/mole or polymers formed from PLA-PEG-PLA macromers. 
     
     
         9 . The delivery system  claim 1 , wherein the one or more drugs includes a substance selected from the group consisting of an asthma therapeutic agent, a chronic obstructive pulmonary disease therapeutic agent, a tuberculosis therapeutic agent, a cancer therapeutic agent, a non-small cell lung cancer therapeutic agent, signal transduction inhibitors, cytotoxic agents, cell cycle inhibitors, cell cycle control inhibitors, cell cycle control inhibitors, checkpoint inhibitors that interfere with the normal function of cell cycle checkpoints, checkpoint inhibitors that interfere with the normal function of cell cycle S/G2 checkpoint, checkpoint inhibitors that interfere with the normal function of cell cycle G2/M checkpoint, checkpoint inhibitors that interfere with the normal function of cell cycle G1/S checkpoint, topoisomerase inhibitors, camptothecins, enzymes necessary for DNA replication, enzymes necessary for DNA transcription, receptor tyrosine kinase inhibitors, apoptosis inducing agents, antimetabolites, gemcitabine, hydroxyurea, telomerase inhibitors, cyclin-dependent kinase inhibitors, cytoskeletal proteins, transcription factors, tumor suppresser genes, DNA damaging agents, DNA repair inhibitors, anti-angiogenic agents, mitochondrial poisons, DNA damaging agents, carboplatin, cisplatin, cyclophosphamide, doxorubicin, daunorubicin, epirubicin, mitomycin C, mitoxantrone, DNA repair inhibitors, 5-fluorouracil (5-FU), FUDR, gemcitabine, methotrexate, topoisomerase I inhibitors, camptothecin, irinotecan, topotecan, S/G2 checkpoint inhibitors, G2/M checkpoint inhibitors, bleomycin, docetaxel, doxorubicin, etoposide, paclitaxel, vinblastine, vincristine, vindesine, vinorelbine, G1/early-S checkpoint inhibitors, receptor tyrosine kinase inhibitors, genistein, trastuzumab, ZD1839, cytotoxic agents, apoptosis-inducing agents, cell cycle control inhibitors, a TB therapeutic agent, ethambutol, isoniazid, pyrazinamide, rifampicin, streptomycin, aminoglycosides, amikacin (AMK), kanamycin (KM), polypeptides, capreomycin, viomycin, enviomycin, fluoroquinolones, ciprofloxacin (CIP), levofloxacin, moxifloxacin (MXF), thioamides, ethionamide, prothionamide, cycloserine, p-aminosalicylic acid (PAS or P), rifabutin, macrolides, clarithromycin (CLR), linezolid (LZD), thioacetazone (T), thioridazine, arginine, vitamin D, R207910, SQ641, an asthma or COPD therapeutic agent, short-acting selective beta 2 -adrenoceptor agonists, adrenergic agonists, anticholinergic medications and long-acting β 2 -agonists, or a pharmaceutically acceptable salt of one of the foregoing. 
     
     
         10 . The delivery system of  claim 1 , wherein the nanoparticles include PEG protective coatings. 
     
     
         11 . The delivery system of  claim 1  further comprising a pharmaceutically acceptable carrier. 
     
     
         12 . A method of treating a condition comprising administering a delivery system to a patient in need thereof, the delivery system including a gel microparticle, a plurality of nanoparticles associated with the gel microparticle, and one or more drugs associated with at least one of the nanoparticles. 
     
     
         13 . The method of  claim 12 , wherein the step of administering includes intravenous injection. 
     
     
         14 . The method of  claim 12 , wherein the step of administering includes intra-arterial injection. 
     
     
         15 . The method of  claim 12 , wherein the delivery system further includes at least one of one or more targeting agents associated with the nanoparticles or one or more chemopotentiators associated with the nanoparticles. 
     
     
         16 . The method of  claim 12 , wherein the nanoparticles are linked to the gel microparticle. 
     
     
         17 . The method of  claim 12 , wherein the gel microparticles have a size of 1-60 μm. 
     
     
         18 . The method of  claim 12 , wherein the gel microparticles have a size selected from the group consisting of 6-10 μm and 50-60 μm. 
     
     
         19 . The method of  claim 12 , wherein the one or more drugs includes a substance selected from the group consisting of an asthma therapeutic agent, a chronic obstructive pulmonary disease therapeutic agent, a tuberculosis therapeutic agent, a cancer therapeutic agent, a non-small cell lung cancer therapeutic agent, signal transduction inhibitors, cytotoxic agents, cell cycle inhibitors, cell cycle control inhibitors, cell cycle control inhibitors, checkpoint inhibitors that interfere with the normal function of cell cycle checkpoints, checkpoint inhibitors that interfere with the normal function of cell cycle S/G2 checkpoint, checkpoint inhibitors that interfere with the normal function of cell cycle G2/M checkpoint, checkpoint inhibitors that interfere with the normal function of cell cycle G1/S checkpoint, topoisomerase inhibitors, camptothecins, enzymes necessary for DNA replication, enzymes necessary for DNA transcription, receptor tyrosine kinase inhibitors, apoptosis inducing agents, antimetabolites, gemcitabine, hydroxyurea, telomerase inhibitors, cyclin-dependent kinase inhibitors, cytoskeletal proteins, transcription factors, tumor suppresser genes, DNA damaging agents, DNA repair inhibitors, anti-angiogenic agents, mitochondrial poisons, DNA damaging agents, carboplatin, cisplatin, cyclophosphamide, doxorubicin, daunorubicin, epirubicin, mitomycin C, mitoxantrone, DNA repair inhibitors, 5-fluorouracil (5-FU), FUDR, gemcitabine, methotrexate, topoisomerase I inhibitors, camptothecin, irinotecan, topotecan, S/G2 checkpoint inhibitors, G2/M checkpoint inhibitors, bleomycin, docetaxel, doxorubicin, etoposide, paclitaxel, vinblastine, vincristine, vindesine, vinorelbine, G1/early-S checkpoint inhibitors, receptor tyrosine kinase inhibitors, genistein, trastuzumab, ZD1839, cytotoxic agents, apoptosis-inducing agents, cell cycle control inhibitors, a TB therapeutic agent, ethambutol, isoniazid, pyrazinamide, rifampicin, streptomycin, aminoglycosides, amikacin (AMK), kanamycin (KM), polypeptides, capreomycin, viomycin, enviomycin, fluoroquinolones, ciprofloxacin (CIP), levofloxacin, moxifloxacin (MXF), thioamides, ethionamide, prothionamide, cycloserine, p-aminosalicylic acid (PAS or P), rifabutin, macrolides, clarithromycin (CLR), linezolid (LZD), thioacetazone (T), thioridazine, arginine, vitamin D, R207910, SQ641, an asthma or COPD therapeutic agent, short-acting, selective beta 2 -adrenoceptor agonists, adrenergic agonists, anticholinergic medications and long-acting β 2 -agonists, or a pharmaceutically acceptable salt of one of the foregoing. 
     
     
         20 . The method of  claim 12 , wherein the delivery system further includes a pharmaceutically acceptable carrier. 
     
     
         21 . A method of making the delivery system including a gel microparticle, a plurality of nanoparticles associated with the gel microparticle, and one or more drugs associated with the nanoparticles comprising:
 i. synthesizing the nanoparticles to be loaded with the one or more drugs; and   ii. associating the nanoparticles with the gel microparticles.   
     
     
         22 . The method of  claim 21 , wherein the step of associating the nanoparticles with the gel microparticles includes forming micron sized aqueous particles by mixing functionalized polymers, the nanoparticles, crosslinking initiator and solvent in a hydrophobic fluid. 
     
     
         23 . The method of  claim 21  further comprising: loading nanoparticles with the one or more drugs; and
 the step of associating the nanoparticles with the gel microparticles includes mixing functionalized polymers, the nanoparticles, crosslinking initiator and solvent to form the discontinuous phase; providing a hydrophobic fluid as the continuous phase; making small droplets using emulsification techniques, wherein the small droplets contain functionalized macromers, the nanoparticles, crosslinking initiator and solvent; and crosslinking the droplets. 
 
     
     
         24 . The method of  claim 21  further comprising loading the nanoparticles with the one or more drugs; and
 the step of associating the nanoparticles with the gel microparticles includes mixing functionalized polymers, the nanoparticles, crosslinking initiator and solvent to form an inner liquid filament; providing a hydrophobic fluid with crosslinking initiator as a sheath fluid; flowing the sheath fluid past the inner liquid filament to form droplets; and crosslinking the droplets. 
 
     
     
         25 . The method of  claim 21  further comprising loading the nanoparticles with at least one of the one or more drugs; and
 the step of associating the nanoparticles with the gel microparticles includes mixing functionalized polymers, the nanoparticles, crosslinking initiator and solvent to form the discontinuous phase; providing a hydrophobic fluid with crosslinking initiator as the continuous phase; making small droplets containing functionalized macromers, the nanoparticles, crosslinking initiator and solvent by emulsification techniques; and crosslinking the droplets.