Compositions and methods of treating therapy resistant cancer and uses thereof

Abstract

The present disclosure is directed to a composition for the sustained-release delivery of an active agent to a target cell of an individual. The compositions disclosed herein comprise of at least one porous particle; at least one polymer; and at least one active agent. In an embodiment, the porous particle comprises a plurality of microscale reservoirs. In an exemplary embodiment, the at least one active agent is covalently linked to the at least one polymer to form a polymer-active agent conjugate, and the polymer-active agent conjugate is contained in the plurality of microscale reservoirs of the porous particle. In some embodiments, the active agent is released with zero-order or near zero-order kinetics following administration of the composition. The present disclosure is also directed to a method of treating a tumor by administering to an individual the composition described supra.

What is claimed is: 
     
         1 . A method of delivering an active agent to a target cell in a subject, said method comprising:
 administering to the subject a composition comprising:
 at least one porous particle, 
 wherein the porous particle comprises a plurality of reservoirs, and 
   wherein the plurality of reservoirs comprise an open cavity that is open to a surface of the porous particle;   at least one polymer; and   at least one active agent,
 wherein the at least one active agent is covalently linked via a cleavable bond to the at least one polymer to form a polymer-active agent conjugate, 
 wherein the cleavable bond is cleavable in response to an environmental condition within the target cell, and 
 wherein the polymer-active agent conjugate is dispersibly contained in the plurality of reservoirs of the least one porous particle; 
   wherein the polymer-active agent conjugate is released at a target cell from the porous particle;   wherein the released polymer-active agent conjugate self-assembles into nanoparticles upon coming in contact with an aqueous environment;   wherein the polymer-active agent conjugate enters the target cell via a vesicular transport system; and   wherein the active agent is released from the polymer-active agent conjugate after cleavage of the cleavable bond.   
     
     
         2 . The method of  claim 1 , wherein the porous particle is a microparticle. 
     
     
         3 . The method of  claim 1 , wherein the porous particle comprises pores with diameters ranging from 0.2 μm to 4 μm. 
     
     
         4 . The method of  claim 1 , wherein the plurality of reservoirs comprise nanoscale reservoirs. 
     
     
         5 . The method of  claim 4 , wherein the nanoscale reservoirs have a size ranging from about 5 nm to about 200 nm. 
     
     
         6 . The method of  claim 1 , wherein the porous particle is configured into a shape selected from the group consisting of discoidal, spheroid, non-spheroid, oblate spheroid, and combinations thereof. 
     
     
         7 . The method of  claim 1 , wherein the porous particle is a porous silicon oxide material. 
     
     
         8 . The method of  claim 1 , wherein the porous particle is a porous etched material comprising silicon. 
     
     
         9 . The method of  claim 1 , wherein the porous particle undergoes physiological degradation to release the polymer-active agent conjugate. 
     
     
         10 . The method of  claim 1 , wherein the porous particle further comprises at least one targeting moiety on its surface, wherein the targeting moiety is specifically directed against the target cell. 
     
     
         11 . The method of  claim 10 , wherein the at least one targeting moiety is selected from the group consisting of antibodies, antibody fragments, peptides, aptamers, small molecules, and combinations thereof. 
     
     
         12 . The method of  claim 1 , wherein the polymer-active agent conjugate is dispersibly contained in the plurality of reservoirs of the at least one porous particle as single molecules. 
     
     
         13 . The method of  claim 1 , wherein the at least one active agent is a biologically active compound selected from the group consisting of peptides, proteins, therapeutic agents, hydrophobic drugs, hydrophilic drugs, diagnostic agents, non-biological materials, genes, nucleic acids, shRNAs, siRNAs, DNA fragments, RNA fragments, plasmids, and combinations thereof. 
     
     
         14 . The method of  claim 1 , where the active agent is a hydrophobic drug. 
     
     
         15 . The method of  claim 1 , where the active agent is a hydrophilic drug. 
     
     
         16 . The method of  claim 15 , where the active agent is doxorubicin. 
     
     
         17 . The method of  claim 1 , wherein the active agent is released with zero-order or near zero-order release kinetics. 
     
     
         18 . The method of  claim 1 , wherein the polymer is selected from the group consisting of poly-L-glutamic acid, poly(lactic acid), poly(glycolic acid), poly(D-lactic-co-glycolic acid), poly(L-lactic-co-glycolic acid), poly(D,L-lactic-co-glycolic acid), poly(caprolactone), poly(valerolactone), poly(hydroxybutyrate), poly(hydrovalerate), polydioxnanone, derivatives thereof, and combinations thereof. 
     
     
         19 . The method of  claim 1 , wherein the environmental condition within the target cell is acidic. 
     
     
         20 . The method of  claim 1 , wherein the cleavable bond is pH sensitive. 
     
     
         21 . The method of  claim 1 , wherein the cleavable bond comprises a hydrazone bond. 
     
     
         22 . The method of  claim 1 , wherein the target cell of the subject is a tumor cell. 
     
     
         23 . The method of  claim 22 , wherein the tumor cell is a therapy-resistant cancer cell. 
     
     
         24 . The method of  claim 22 , wherein the tumor cell comprises tumor stem cells. 
     
     
         25 . The method of  claim 22 , wherein the method is utilized to treat a cancer in the subject. 
     
     
         26 . The method of  claim 25 , wherein the cancer is selected from the group consisting of breast cancer, lung cancer, prostate cancer, ovarian cancer, brain cancer, liver cancer, cervical cancer, bone cancer, esophageal cancer, bladder cancer, uterine cancer, testicular cancer, leukemia, lymphoma, stomach cancer, pancreatic cancer, and combinations thereof. 
     
     
         27 . The method of  claim 25 , wherein the method is utilized to circumvent multi-drug resistance against the cancer. 
     
     
         28 . A composition for the delivery and sustained release of an active agent to a target cell of a subject, comprising:
 at least one porous particle, wherein the porous particle comprises a plurality of reservoirs, wherein the plurality of reservoirs comprise an open cavity that is open to a surface of the porous particle;   at least one polymer; and   at least one active agent,
 wherein the at least one active agent is covalently linked via a cleavable bond to the at least one polymer to form a polymer-active agent conjugate, 
 wherein the cleavable bond is cleavable in response to an environmental condition within the target cell, 
 wherein the polymer-active agent conjugate is dispersibly contained in the plurality of reservoirs of the at least one porous particle as single molecules, 
 wherein the porous particle undergoes physiological degradation to release the polymer-active agent conjugate, 
 wherein the released polymer-active agent conjugate is capable of self-assembling into nanoparticles upon contacting an aqueous environment, and 
 wherein the active agent is released with zero-order or near zero-order release kinetics following administration of the composition. 
   
     
     
         29 . The composition of  claim 28 , wherein the at least one active agent is a biologically active compound selected from the group consisting of peptides, proteins, therapeutic agents, hydrophobic drugs, hydrophilic drugs, diagnostic agents, non-biological materials, genes, nucleic acids, shRNAs, siRNAs, DNA fragments, RNA fragments, plasmids, and combinations thereof. 
     
     
         30 . The composition of  claim 28 , wherein the therapeutic agent is a hydrophobic drug. 
     
     
         31 . The composition of  claim 28 , where the therapeutic agent is doxorubicin. 
     
     
         32 . The composition of  claim 28 , wherein the polymer is selected from the group consisting of poly-L-glutamic acid, poly(lactic acid), poly(glycolic acid), poly(D-lactic-co-glycolic acid), poly(L-lactic-co-glycolic acid), poly(D,L-lactic-co-glycolic acid), poly(caprolactone), poly(valerolactone), poly(hydroxybutyrate), poly(hydrovalerate), polydioxnanone, derivatives thereof, and combinations thereof. 
     
     
         33 . The composition of  claim 28 , wherein the polymer is poly-L-glutamic acid. 
     
     
         34 . The composition of  claim 28 , wherein the porous particle is a silicon particle. 
     
     
         35 . The composition of  claim 28 , wherein the cleavable bond comprises a hydrazone bond. 
     
     
         36 . The composition of  claim 28 , wherein the plurality of reservoirs comprise nanoscale reservoirs. 
     
     
         37 . The composition of  claim 36 , wherein the nanoscale reservoirs have a size ranging from about 5 nm to about 200 nm.