System for Screening Particles

• US 20090298710A1
• Filed: 12/15/2006
• Published: 12/03/2009
• Est. Priority Date: 12/15/2005
• Status: Active Grant

• Current Assignee: Brigham and Women's Hospital Incorporated, Massachusetts Institute of Technology
• Original Assignee: Brigham and Women's Hospital Incorporated
• Inventors: Farokhzad, Omid C., Langer, Robert S., Radovic-Moreno, Aleksandar Filip
• Granted Patent: US 9,267,937 B2
• Time in Patent Office: Days
• US Class Current: 506/10
• CPC Class Codes: A61K 47/555 pre-targeting systems involving an organic compound, other than a peptide, protein or antibody, for targeting specific cells
• CPC Class Codes: A61K 47/66 the modifying agent being a pre-targeting system involving a peptide or protein for targeting specific cells
• CPC Class Codes: A61K 47/6891 Pre-targeting systems involving an antibody for targeting specific cells
• CPC Class Codes: B82Y 15/00 Nanotechnology for interacting, sensing or actuating, e.g. quantum dots as markers in protein assays or molecular motors
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: C40B 30/06 by measuring effects on living organisms, tissues or cells
• CPC Class Codes: G01N 33/5088 of vertebrates

Abstract

Screening of a library of particles in vivo and/or in vitro using Polyplex Iterative Combinatorial Optimization (PICO) allows for the design of particles for targeting a specific organ, tissue (e.g., cancer), or cell. Particles may, for example, include different targeting agents (e.g., aptamers or plurality of aptamers) on their surfaces, and the aptamer or aptamers may be evolved to provide better targeting of the particles. Libraries of particles are enriched in characteristics of particles that have been found to migrate to a tissue of interest, be taken up by cells, etc. The process may be repeated to engineer particles of a desired specificity or biological function.

Claims

1. A method of screening particles in vivo, the method comprising steps of:

providing a library comprising a plurality of particle populations that vary in at least one particle characteristic, wherein each population comprises a plurality of particles having substantially the same characteristics;

administering the library of particles to an animal under conditions in which the particles can migrate to a targeted tissue or cells; and

recovering a first plurality of particles that have migrated to the targeted tissue or cells.

2. The method of claim 1, wherein the at least one particle characteristic is selected from the group consisting of composition, size, particle density, surface chemistry, targeting agent, density of targeting agents on surface of the particle.

3. The method of claim 2, wherein the targeting agent is one or more of an oligonucleotide, a protein, a polysaccharide, an antibody, an antibody fragment, a nucleic acid ligand, a lipoprotein, folate, transferrin, an asialycoprotein, a carbohydrate, an enzymatic receptor ligand, sialic acid, a glycoprotein, a lipid, a small molecule, metal, metal complex, a bioactive agent, a biomolecule, and an immunoreactive fragment.

4. The method of claim 1 further comprising the step of determining at least one characteristic of a particle of the recovered first plurality from the particles.

5. The method of claim 1, wherein each particle of a population is characterized by an analytical signature provided by a label, wherein the label is selected from the group consisting of a luminescent agent, a chemiluminescent agent, a phosphorescent agent, a fluorescent agent, a radionuclide, a small molecule, a mass spectroscopy tag, a polynucleotide, a polypeptide, a semiconductor particle, a magnetic material an ultrasound contrast agent, an MRI contrast agent, or an x-ray contrast agent.

7. The method of claim 5, wherein the label is disposed on the surface of the particle, in the interior of the particle, or both.

11. The method of claim 1 further comprising the step of recovering a second plurality of particles that have migrated to a non-targeted tissue or cells.

12. The method of claim 11, further comprising steps of:

identifying at least one characteristic of a particle of the first plurality of particles;

identifying at least one characteristic of a particle of the second plurality of particles;

preparing an enriched library of particles having a higher percentage of particles with the at least one characteristic identified in the first plurality of particles; and

repeating the steps of administering the enriched library and recovering a first plurality of particles from the enriched particles library that have migrated to a targeted tissue or cells.

13. The method of claim 1, wherein the characteristic is the identity of a targeting agent.

14. The method of claim 1, wherein the particles are selected from the group consisting of microparticles, nanoparticles, and picoparticles.

17. The method of claim 1, wherein the particles comprise one or more of a polymer, ceramic, metal, or semiconductor.

18. The method of claim 1, wherein the particles are polymeric particles.

21. The method of claim 1, wherein the particles comprise a polymer selected from the group consisting of polyesters, polyamides, polycarbonates, polycarbamates, polyacrylates, polystyrene, polyureas, polyethers, polyamines, polyanhydrides, poly(hydroxyacids), poly(lactic acid), poly(glycolic acid), poly(orthoesters), polyphosphazene, ethylene-vinyl acetate copolymer, polyurethanes, polyacrylates, polymethacrylates, polyacrylonitriles, poly(amidoamine) dendrimers, poly(L-lactide-co-L-lysine), poly(serine ester), poly(4-hydroxy-L-proline ester), polysebacic anhydride, maleimide-poly(ethyleneglycol)-block-poly(D,L-lactic acid);

COOH-poly(ethyleneglycol)-block-poly(D,L-lactic acid);

methoxypoly(ethyleneglycol)-block-poly(D,L-lactic acid);

proteins;

albumin;

collagen;

gelatin;

polysaccharides, PEGylated poly(lactic acid), poly(lactic-co-glycolic acid) (PLGA), PEGylated poly(lactic-co-glycolic acid), PEGylated poly(orthoesters), poly(caprolactone), PEGylated poly(caprolactone), polylysine, PEGylated polylysine, poly(ethylene imine), PEGylated poly(ethylene imine), poly(acrylic acid), and combinations thereof.

22. The method of claim 1, wherein the particles are poly(lactic-co-glycolic acid) (PLGA) particles.

23. The method of claim 1, wherein the particles comprise at least one targeting agent.

24. The method of claim 1, wherein the particles comprise a plurality of targeting agents.

46. A population of particles having a characteristic of the recovered first plurality of particles identified by the method of claim 1.

6. (canceled)

8-10. -10. (canceled)

15-16. -16. (canceled)

19-20. -20. (canceled)

25-45. -45. (canceled)

47. A method of screening particles, comprising:

providing a library comprising a plurality of particle populations, wherein each population of particles is identified by an analytical signature provided by at least one label, and wherein each population comprises a plurality of particles having substantially the same analytical signature and same characteristics;

incubating a population of cells with the library of particles for a predetermined period of time under conditions such that the cells can take up the particles, wherein the particles optionally include a substance that is necessary for the growth or survival of the cells;

recovering particles from the living cells; and

characterizing the recovered particles.

60. The method of claim 47, further comprising:

characterizing the at least one analytical signature present in the living cells and correlating it with the corresponding particle population;

recovering those particles that were not taken up by living cells and identifying at least one characteristic of the recovered particles by characterizing the analytical signature of at least a portion of the recovered particles;

enriching those particles having substantially the same characteristics as at least a first predetermined fraction of particles and less of the characteristics of the second predetermined fraction particles; and

repeating the steps of incubating the cells with the enriched population of particles.

48-59. -59. (canceled)

61-65. -65. (canceled)

66. A method of screening particles, the method comprising steps of:

providing a first library comprising a plurality of particle populations that vary by at least one particle characteristic, wherein each population comprises a plurality of particles having substantially the same characteristics, and wherein each of the particle populations includes a targeting agent conjugated to the surface of the particles;

administering the first library to an animal;

identifying the targeting agent conjugated to those particle populations from the first library that preferentially accumulate in a targeted tissue or cell type;

providing a second library comprising a plurality of particle populations that vary in at least one particle characteristic selected from composition, size, surface chemistry, targeting agent, and density of a targeting agent at the surface of the particle, wherein each population comprises a plurality of particles having substantially the same characteristics; and

identifying the at least one particle characteristic of those particle populations from the second library that preferentially accumulate in a target tissue or cell type.

67-132. -132. (canceled)

133. A method of screening particles, the method comprising steps of:

providing a library of particles, wherein each particle has a different collection of aptamers conjugated to its surface;

administering the library to an animal under conditions suitable for at least one of the particles to migrate to a targeted tissue or cells; and

recovering at least one particle from the targeted tissue or cells.

134-135. -135. (canceled)