Preparation of functional gel particles with a dual crosslink network

• US 8,367,051 B2
• Filed: 10/09/2007
• Issued: 02/05/2013
• Est. Priority Date: 10/09/2006
• Status: Active Grant

• Current Assignee: Carnegie Mellon University
• Original Assignee: Carnegie Mellon University
• Inventors: Matyjaszewski, Krzysztof, Min, Ke, Oh, Jung Kwon, Spanswick, James, Tsarevsky, Nicolay V.
• Primary Examiner(s): Krass, Frederick
• Assistant Examiner(s): Shomer, Isaac
• Application Number:
  US12/311,673
• Publication Number:
  US 20100143286A1
• Time in Patent Office: 1,946 Days
• Field of Search: None
• US Class Current: 424/78.31
• CPC Class Codes: C08F 283/00 Macromolecular compounds obtained by polymerising monomers on to polymers provided for in subclass C08G
• CPC Class Codes: C08F 290/00 Macromolecular compounds obtained by polymerising monomers on to polymers modified by introduction of aliphatic unsaturated end or side groups
• CPC Class Codes: C08F 290/06 Polymers provided for in subclass C08G
• CPC Class Codes: C08F 291/00 Macromolecular compounds obtained by polymerising monomers on to macromolecular compounds according to more than one of the groups C08F251/00 - C08F289/00
• CPC Class Codes: C08F 293/005 using free radical "living" or "controlled" polymerisation, e.g. using a complexing agent

Abstract

Functional gel particle formed from a crosslinked polymeric network including a fraction of stable crosslinks and a second fraction of cleavable crosslinks are disclosed. Functional compounds may be chemically or physically encapsulated within and/or released from the gel particle by selective cleavage of the cleavable crosslinks. The functional compounds may be delivered and released to a pre-selected target site. Peripheral or other accessible functionality on the surface of the gel particle allows attachment of a surface reactive agent, thereby modifying one or more surface properties of the gel particle. Processes of preparing the gel particles and processes of delivering the functional compounds to a target site are also disclosed.

Claims

1. A gel particle comprising a polymeric network comprising:

vinyl monomeric units;

at least one first divinyl monomeric unit, wherein the vinyl groups are connected by a chemically stable linking group which comprises a functionality that degrades in a predetermined chemical or predetermined biological environment over a time period of 7 days to 30 days; and

at least one second divinyl monomeric unit, wherein the vinyl groups are connected by a cleavable linking group,

wherein the polymeric network is formed by a controlled polymerization process and wherein the first divinyl monomeric unit forms chemically stable crosslinks within the polymeric network and the second divinyl monomeric unit forms cleavable crosslinks within the polymeric network; and

wherein the gel particle has a diameter of from 5 nm to 500 nm.

2. The gel particle of claim 1, wherein at least a portion of the cleavable crosslinks are cleavable in a predetermined chemical or predetermined biological environment.

3. The gel particle of claim 1, wherein the cleavable crosslinks are reversibly cleavable crosslinks.

4. The gel particle of claim 1, wherein the cleavable crosslinks comprise one or more cleavable functionality selected from the group consisting of an anhydride, an oligo(lactate) ester, a disulfide, a hydrazine, a hydrazone, an acetal, an oxime, an imine, a Schiff base, a urethane, a degradable oligo/polymer segment, and combinations thereof.

5. The gel particle of claim 4, wherein the cleavable crosslinks comprise a degradable oligo/polymeric segment selected from the group consisting of a polysaccharide, a polyester, a peptide, a protein, a chitin and a chitosan.

6. The gel particle of claim 4, wherein the cleavable crosslinks comprise two or more cleavable functionalities, wherein the two or more cleavable functionalities have different rates of cleavage in different chemical or biological environments.

7. The gel particle of claim 1, wherein the polymeric network comprises one or more polymer segments having a controlled topology, wherein the one or more polymeric segments comprise vinyl monomeric units selected from the group consisting of hydrophilic monomeric units, hydrophobic monomeric units, and combinations thereof.

8. The gel particle of claim 1, wherein the polymeric network degrades during the time period to polymer fragments having a size below the renal threshold.

9. The gel particle of claim 1, further comprising one or more quest compounds, wherein the guest compound or quest compounds are chemically or physically encapsulated within the gel particle.

10. The gel particle of claim 9, wherein the guest compound is selected from the group consisting of a nano-size star macromolecule, a fluorescent molecule, a color pigment, an inorganic nanoparticle, a nanoparticle with a fluorescent core, a biologically active compound, a drug, a cancer drug, a nanocomposite structure, a biospecific molecule, and combinations of any thereof.

11. The gel particle of claim 9, wherein the polymeric network comprises one or more polymeric backbone segments and wherein the encapsulated compound is retained within the gel particle by at least one interaction with one or more polymeric backbone segments in the gel particle, wherein the at least one interaction is selected from the group consisting of chemical affinity, hydrogen bonding, Van der Waal'"'"'s interactions, ionic interactions, hydrophilic interactions, hydrophobic interactions, chemical reactions, and combinations thereof.

12. The gel particle of claim 9, wherein cleavable crosslinks are cleaved to give at least one reactive functional group and wherein the at least one reactive functional group forms at least one chemical bond with the encapsulated compound.

13. The gel particle of claim 9, wherein the guest compound or compounds are active compounds, and are located in the interior portion of the gel particle.

14. The gel particle of claim 1, further comprising a residue of an initiator, wherein the ratio of the first divinyl monomeric unit to the initiator is greater than 1:

1.01.

15. The gel particle of claim 1, further comprising a delivery notification system or an imaging system, wherein the delivery notification system or the imaging system comprise at least one of an imaging agent, magnetic particles, and luminescent compound.

16. The gel particle of claim 1, further comprising at least one functional agent or a residue of at least one functional agent on at least a portion of an outer surface of the gel particle.

17. The gel particle of claim 16, wherein the residue or at least one functional agent forms a chemical bond with a surface reactive agent.

18. The gel particle of claim 17, wherein the surface reactive agent is selected from the group consisting of reactive monomers, reactive macromonomers, reactive oligomers, and combinations thereof, and

the gel particle further comprises a polymeric shell bonded to at least a portion of the surface of the gel particle, wherein the polymeric shell is formed by reaction of the surface reactive agent,

wherein the polymeric shell has a phobicity different than the phobicity of the surface of the gel particle.

19. The gel particle of claim 18, wherein the polymeric shell seals one or more pores on the surface of the gel particle and further encapsulates a chemically or physically encapsulated compound;

and

wherein the polymeric shell is bonded to the surface of the gel particle by one of degradable bonds and stable bonds.

20. The gel particle of claim 17, wherein the surface reactive agent is a functional macromolecule comprising a bioresponsive molecule, wherein the bioresponsive molecule enhances surface properties of the surface of the gel particle to allow transportation of the gel particle to specific target environments.

21. The gel particle of claim 1, wherein the gel particle is a nanogel, a microgel, a macrogel, or a bead.

27. A process for delivering one or more compounds to a target site comprising:

delivering the gel particle of claim 13 to a target site;

cleaving at least a portion of the cleavable crosslinks of the polymeric network; and

increasing a swelling ratio of the gel particle such that the quest compound or compounds are released from the interior portion of the gel particle.

28. The process of claim 27, further comprising:

degrading at least a portion of the chemically stable crosslinks to form polymer fragments having a size below the renal threshold.

29. The process of claim 27, further comprising:

attaching at least one surface reactive agent to at least a portion of a surface of the gel particle, wherein the surface reactive agent alters at least one surface property of the gel particle.

22. A process for preparing a gel particle comprising:

polymerizing by a controlled polymerization process in a biphasic medium a composition comprising;

vinyl monomeric units;

at least one first divinyl monomeric unit, wherein the vinyl groups are connected by a chemically stable linking group which comprises a functionality that degrades in a predetermined chemical or predetermined biological environment over a time period of 7 days to 30 days; and

at least one second divinyl monomeric unit, wherein the vinyl groups are connected by a cleavable linking group; and

forming a polymeric network comprising chemically stable crosslinks and cleavable crosslinks;

wherein the gel panicle has a diameter of from 5 nm to 500 nm.

23. The process of claim 22, further comprising:

encapsulating a functional compound within the gel particle during the polymerization process, and

wherein the functional compound is selected from the group consisting of a nano-size star macromolecule, a fluorescent molecule, a color pigment, an inorganic nanoparticle, a nanoparticle with a fluorescent core, a biologically active compound, a drug, a cancer drug, a nanocomposite structure, a biospecific molecule, and combinations thereof.

24. The process of claim 22, wherein the cleavable crosslinks are reversibly cleavable crosslinks, and

wherein the process further comprises:

cleaving at least a portion of the reversibly cleavable crosslinks to increase the swelling ratio of the gel particle;

adding a compound, wherein the compound migrates into an interior portion of the swelled gel particle; and

reforming the reversibly cleavable crosslinks to decrease the swelling ration of the gel to encapsulate the compound.

25. The process of claim 22, further comprising:

attaching one or more surface reactive agents to at least a portion of an outer surface of the gel particle, wherein the surface reactive agent forms a chemical bond with a functional agent on at least a portion of the outer surface of the gel particle.

26. The process of claim 22, wherein the biphasic medium comprises one of a continuous aqueous phase and a continuous non-aqueous phase, wherein the continuous non-aqueous phase is selected from the group consisting of an organic phase, an ionic liquid, and a supercritical fluid, and

wherein the biphasic polymerizing comprises a microemulsion polymerizing process, a miniemulsion polymerizing process, an emulsion polymerizing process, or a suspension polymerizing process.