Multistage delivery of active agents

Abstract

Multistage delivery vehicles are disclosed which include a first stage particle and a second stage particle. The first stage particle is a micro or nanoparticle that contains the second stage particle. The second stage particle includes an active agent, such as a therapeutic agent or an imaging agent. The multistage delivery vehicle allows sequential overcoming or bypassing of biological barriers. The multistage delivery vehicle is administered as a part of a composition that includes a plurality of the vehicles. Methods of making the multistage delivery vehicles are also provided.

1 . A composition comprising
 at least one first stage particle that is a micro or nanoparticle and which has (i) a body, (ii) at least one surface; and (iii) at least one reservoir inside the body, such that the reservoir contains at least one second stage particle that comprises at least one active agent.   
     
     
         2 . The composition of  claim 1 , wherein the first stage particle has a selected non-spherical shape. 
     
     
         3 . The composition of  claim 1 , wherein the body of the first stage particle comprises a biocompatible material. 
     
     
         4 . The composition of  claim 1 , wherein the body of the first stage particle comprises a biodegradable material. 
     
     
         5 . The composition of  claim 1 , wherein the body of the first stage particle comprises silicon, an inorganic oxide material, a polymer oxide material or a ceramic material. 
     
     
         6 . The composition of  claim 1 , wherein the body of the first stage particle comprises a porous or nanoporous material. 
     
     
         7 . The composition of  claim 6 , wherein the porous or nanoporous material is nanoporous silicon. 
     
     
         8 . The composition of  claim 6 , wherein the porous or nanoporous material is a nanoporous oxide material. 
     
     
         9 . The composition of  claim 8 , wherein the nanoporous oxide material is nanoporous silicon dioxide, nanoporous aluminum oxide, nanoporous titanium oxide, nanoporous iron oxide or a combination thereof. 
     
     
         10 . The composition of  claim 6 , wherein the body of the first stage particle comprises a first porous region and a second porous region that differs from the first porous region in at least one property selected from the group of properties consisting of pore density, pore geometry, pore charge, pore surface chemistry and pore orientation. 
     
     
         11 . The composition of  claim 10 , wherein the first porous region is configured to contain a first population of second stage particles and the second porous region is configured to contain a second population of second stage particles. 
     
     
         12 . The composition of  claim 1 , wherein the body of the first stage particle comprises a first region containing a first population of second stage particles and a second region containing a second population of second stage particles. 
     
     
         13 . The composition of  claim 12 , wherein said first and second regions comprise chemical compositions, wherein the chemical composition of said first region is the same as the chemical composition of the second region. 
     
     
         14 . The composition of  claim 12 , wherein said first population contains a first active agent and said second population contains a second active agent that is different than the first active agent. 
     
     
         15 . The composition of  claim 12 , wherein said first and second populations have characteristic release times, wherein the characteristic release time of the first population from the first region is different than the characteristic release time of the second population from the second region. 
     
     
         16 . The composition of  claim 12 , wherein at least one of the first region and the second region is a biodegradable region. 
     
     
         17 . The composition of  claim 12 , wherein the first stage particle is configured to separate into a first component comprising the first region and a second component comprising the second region when exposed to a physiological medium. 
     
     
         18 . The composition of  claim 12 , wherein the first region is configured to bypass a first biological barrier and the second region is configured to bypass a second biological barrier, that is different than the first biological barrier. 
     
     
         19 . The composition of  claim 18 , wherein the first biological barrier and the second biological barrier are each independently selected from the group of biological barriers consisting of a hemo-rheology barrier, a reticulo-endothelial system barrier, an endothelial barrier, a blood brain barrier, a tumor-associated osmotic interstitial pressure barrier, an ionic and molecular pump barrier, a cell membrane barrier, an enzymatic degradation barrier, a nuclear membrane barrier, and any combination of thereof. 
     
     
         20 . The composition of  claim 1 , wherein the first stage particle is configured to bypass a biological barrier selected from a hemo-rheology barrier, a reticulo-endothelial system barrier, an endothelial barrier, a blood brain barrier, a tumor-associated osmotic interstitial pressure barrier, an ionic and molecular pump barrier, a cell membrane barrier, an enzymatic degradation barrier, a nuclear membrane barrier or a combination thereof. 
     
     
         21 . The composition of  claim 1 , wherein the first stage particle comprises (iv) at least one channel connecting said reservoir and said surface. 
     
     
         22 . The composition of  claim 1 , wherein said reservoir comprises a channel connected to the surface. 
     
     
         23 . The composition of  claim 1 , wherein the first stage particle comprises at least one targeting moiety. 
     
     
         24 . The composition of  claim 23 , wherein the at least one targeting moiety is selected from the group consisting of a chemical targeting moiety, a physical targeting moiety, a geometrical targeting moiety and any combination thereof. 
     
     
         25 . The composition of  claim 23 , wherein the at least one targeting moiety is selected from the group consisting of a size of the body of the first stage particle; a shape of the body of the first stage particle; a charge on the surface of the first stage particle; a chemical modification of the first stage particle and any combination thereof. 
     
     
         26 . The composition of  claim 23 , wherein the at least one targeting moiety comprises a chemical targeting moiety disposed on the surface of the first stage particle, wherein said chemical targeting moiety comprises at least one moiety selected from a the group consisting of dendrimer, an aptamer, an antibody, a biomolecule and any combination thereof. 
     
     
         27 . The composition of  claim 1 , wherein the at least one reservoir contains at least one additional agent. 
     
     
         28 . The composition of  claim 27 , wherein the at least one additional agent comprises at least one penetration enhancer, at least one additional active agent, and at least one targeting moiety. 
     
     
         29 . The composition of  claim 27 , wherein the at least one permeation enhancer is selected from the group consisting of a basement membrane permeation enhancer, a tight junction protein (tjp) permeation enhancer and any combination thereof. 
     
     
         30 . The composition of  claim 1 , wherein the first stage particle is configured to release the at least one second stage particle in response to an external stimulus. 
     
     
         31 . The composition of  claim 1 , wherein the first stage particle is configured to release the at least one second stage particle in response to a change in environment of the first stage particle. 
     
     
         32 . The composition of  claim 1 , wherein the at least one second stage particle comprises at least one constituent selected from the group consisting of a liposome, a micelle, an ethosome, a carbon nanotube, a fullerene nanoparticle, a metal nanoparticle, a semiconductor nanoparticle, a polymer nanoparticle, an oxide nanoparticle, a viral particle, a polyionic particle and a ceramic particle. 
     
     
         33 . The composition of  claim 1 , wherein the second stage particle contains at least one third stage particle that comprises the active agent. 
     
     
         34 . The composition of  claim 1 , wherein the second stage particle has a body that comprises the active agent. 
     
     
         35 . The composition of  claim 1 , wherein the second stage particle has a body and a reservoir inside the body, such that the reservoir of the second stage particle contains the active agent. 
     
     
         36 . The composition of  claim 1 , wherein the active agent comprises a therapeutic agent or an imaging agent or a combination thereof. 
     
     
         37 . The composition of  claim 1 , comprising a plurality of the first stage particles and a carrier in which said plurality of the first stage particles are suspended. 
     
     
         38 . A method, comprising
 administering to a subject a composition comprising:   at least one first stage particle, that is a micro or nanoparticle and that has (i) a body, (ii) at least one surface; (iii) at least one reservoir inside the body, such that the reservoir contains at least one second stage particle that comprises at least one active agent.   
     
     
         39 . The method of  claim 38 , wherein the first stage particle is configured to be localized at a first target site in a body of the subject. 
     
     
         40 . The method of  claim 38 , wherein the first target site is an angiogenesis vasculature or a renormalized vasculature or a coopted vasculature. 
     
     
         41 . The method of  claim 38 , wherein the second stage particle is configured to deliver the active agent to a second target site in a body of the subject. 
     
     
         42 . The method of  claim 41 , wherein the second target site is a cell. 
     
     
         43 . The method of  claim 42 , wherein the cell is a cancer cell. 
     
     
         44 . The method of  claim 43 , wherein the cancer cell is a stem cell or a clonogenic cell. 
     
     
         45 . The method of  claim 42 , wherein the second target site comprises a heterogenated lesion. 
     
     
         46 . The method of  claim 42 , wherein the second target site is a nucleus of a cell. 
     
     
         47 . The method of  claim 38 , wherein the second stage particle contains at least one third stage particle that contains the active agent. 
     
     
         48 . The method of  claim 38 , wherein the first stage particle is configured to bypass a biological barrier selected from the group consisting of a hemo-rheology barrier, a reticulo-endothelial system barrier, an endothelial barrier, a blood brain barrier, a tumor-associated osmotic interstitial pressure barrier, an ionic and molecular pump barrier, a cell membrane barrier, an enzymatic degradation barrier, and a nuclear membrane barrier, and combinations thereof. 
     
     
         49 . The method of  claim 38 , wherein the first stage particle comprises a porous or nanoporous material. 
     
     
         50 . The method of  claim 49 , wherein the porous or nanoporous material is nanoporous silicon or a nanoporous oxide material. 
     
     
         51 . The method of  claim 49 , wherein the body of the first stage particle comprises a first porous region and a second porous region that differs from the first porous region in at least one property selected from the group consisting of pore density, pore geometry, pore charge, pore surface chemistry, and pore orientation. 
     
     
         52 . The method of  claim 38 , wherein the body of the first stage particle comprises a first region containing a first population of second stage particles and a second region containing a second population of second stage particles. 
     
     
         53 . The method of  claim 52 , wherein the first population of second stage particles contains a first active agent and the second population of second stage particles contains a second active agent, that is different than the first active agent. 
     
     
         54 . The method of  claim 52 , wherein said first and second populations have characteristic release times, wherein the characteristic release time of the first population from the first region is different than the characteristic release time of the second population from the second region. 
     
     
         55 . The method of  claim 52 , wherein the first stage particle is configured to separate into a first component comprising the first region and a second component comprising the second region when administered to the subject. 
     
     
         56 . The method of  claim 52 , wherein the first region is configured to bypass a first biological barrier and the second region is configured to bypass a second biological barrier, that is different than the first biological barrier. 
     
     
         57 . The method of  claim 38 , wherein the at least one reservoir contains at least one permeation enhancer. 
     
     
         58 . The method of  claim 38 , further comprising exposing the subject to an external stimulus to release the at least one second stage particle from the first stage particle. 
     
     
         59 . The method of  claim 58 , wherein the external stimulus is at least one of a mechanical activation, a irradiation activation, or a magnetic activation. 
     
     
         60 . The method of  claim 38 , wherein the at least one second stage particle comprises at least one constituent selected from the group consisting of a liposome, a micelle, an ethosome, a carbon nanotube, a fullerene nanoparticle, a metal nanoparticle, a semiconductor nanoparticle, a polymer nanoparticle, an oxide nanoparticle, a viral particle, a polyionic particle, and a ceramic particle. 
     
     
         61 . The method of  claim 38 , wherein the active agent comprises a therapeutic agent, an imaging agent or a combination thereof. 
     
     
         62 . The method of  claim 38 , wherein the composition is a suspension comprising a plurality of the first stage particles. 
     
     
         63 . The method of  claim 38 , wherein the body of the first stage particle comprises a first active agent and the second stage particle contains a second active agent, that is different than the first active agent. 
     
     
         64 . The method of  claim 63 , wherein the first stage particle is configured to release the second stage particle for a free circulation in a body of the subject. 
     
     
         65 . The method of  claim 38 , wherein said administering comprises injecting said composition intravascularly. 
     
     
         66 . The method of  claim 65 , wherein the first stage particle has a characteristic dimension from around 700 nm to around 3 microns. 
     
     
         67 . The method of  claim 38 , wherein said administering comprises injecting the composition subcutaneously. 
     
     
         68 . The method of  claim 38 , wherein said administering is performed orally. 
     
     
         69 . The method of  claim 38 , wherein said administering comprises inhaling the composition. 
     
     
         70 . The method of  claim 69 , wherein the first particle has a characteristic dimension from around 5 microns to about 20 microns. 
     
     
         71 . A method of making a multistage delivery composition, comprising:
 (a) providing at least one first stage particle wherein the first stage particle is a micro or nanoparticle, and that has (i) a body, (ii) at least one surface and (iii) at least one reservoir inside the body;   (b) providing at least one second stage particle; and   (c) loading the second stage particle inside the reservoir of the first stage particle.   
     
     
         72 . The method of  claim 71 , wherein the at least one second stage particle contains at least one active agent. 
     
     
         73 . The method of  claim 71 , wherein the body of the first stage particle comprises a nanoporous material. 
     
     
         74 . The method of  claim 73 , wherein the nanoporous material is nanoporous silicon or a nanoporous oxide material. 
     
     
         75 . The method of  claim 73 , wherein providing the at least one first stage particle and providing the at least one second stage particle comprise providing a solution comprising the at least one first stage particle, the at least one second stage particle and a carrier. 
     
     
         76 . The method of  claim 76 , wherein the loading comprises loading via passive diffusion or capillary convection, or by a combination of those. 
     
     
         77 . The method of  claim 76 , further comprising modifying at least one of a pore surface of the body of the first stage particle or a surface of the second stage particle. 
     
     
         78 . The method of  claim 77 , wherein said modifying comprises chemically modifying at least one of the pore surface of the body of the first stage particle or the surface of the second stage particle. 
     
     
         79 . The method of  claim 77 , wherein said modifying comprises modifying a surface electrical charge on at least one of the pore surface of the body of the first stage particle or the surface of the second stage particle. 
     
     
         80 . The method of  claim 75 , wherein the loading comprises varying a concentration of the at least one second stage particle in the solution to achieve a desired load of the second stage particles in the at least one reservoir of the first stage particle. 
     
     
         81 . The method of  claim 71 , wherein the at least one second stage particle comprises a first population of second stage particles and a second population of second stage of second stage particles and wherein the loading comprises loading the first population of second stage particles in a first region of the body of the first stage particle and loading the second population of second stage particles in a second region of the body of the first stage particle, wherein the first region is different from the second region. 
     
     
         82 . The method of  claim 81 , wherein the first population of second stage particles comprises a first active agent and the second population of second stage particles comprises a second active agent, that is different from the first active agent. 
     
     
         83 . The method of  claim 71 , wherein the second stage particle comprises at least one constituent selected from the group consisting of a liposome, a micelle, an ethosome, a carbon nanotube, a fullerene nanoparticle, a metal nanoparticle, a semiconductor nanoparticle, a polymer nanoparticle, an oxide nanoparticle, a viral particle, a polyionic particle, and a ceramic particle. 
     
     
         84 . The method of  claim 71 , further comprising loading at least one additional component inside the reservoir of the first stage particle. 
     
     
         85 . The method of  claim 84 , wherein the at least one additional component comprises at least a penetration enhancer or an additional active agent, or both.