System for screening particles

• US 9,267,937 B2
• Filed: 12/15/2006
• Issued: 02/23/2016
• 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, Massachusetts Institute of Technology
• Inventors: Farokhzad, Omid C., Radovic-Moreno, Aleksandar Filip, Langer, Robert S.
• Primary Examiner(s): Flinders, Jeremy C
• Application Number:
  US12/097,118
• Publication Number:
  US 20090298710A1
• Time in Patent Office: 3,357 Days
• Field of Search: 506/10
• US Class Current: 1/1
• 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 high throughput, iterative, combinatorial screening method of identifying targeting agents or particle properties providing enhanced uptake of particles into targeted cells in tissue, the method comprising the steps of

providing a plurality of synthetic polymeric particle populations,

wherein the particles of each population have substantially the same composition, size, density, surface chemistry, targeting agent or density of targeting agent bound thereto, wherein the particles of a given particle population differ from the particles of another given particle population by at least one particle characteristic, and

wherein each particle of a given population has at least one detectable label which is different from the detectable label of the particles of another given particle population and is different from the targeting agent;

administering the plurality of particle populations to an animal under conditions in which the particles are taken up by cells of a targeted tissue; and

enriching the uptaken particles by repeating the process with different populations of particles,

each population having at least one different particle characteristic, thereby determining the particle characteristics which enhance uptake of the particles by the cells of the targeted tissue.

2. The method of claim 1, wherein the particles have on the surface thereof a targeting agent selected from the group consisting of an oligonucleotide, a polysaccharide, an antibody, an antibody fragment, a nucleic acid ligand, a lipoprotein, folate, transferrin, an asialycoprotein, an enzymatic receptor ligand, sialic acid, a glycoprotein, a lipid, a small molecule, metal, metal complex, a bioactive agent, and an immunoreactive fragment.

3. The method of claim 1, wherein the detectable 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, and an x-ray contrast agent.

4. The method of claim 3, wherein the label is disposed on the surface of the particle, in the interior of the particle, or both.

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

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

7. The method of claim 1, wherein the polymer is 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), 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;

polysaccharides, PEGylated poly(hydroxy acids), PEGylated poly(orthoesters), poly(caprolactone), PEGylated poly(caprolactone), polylysine, PEGylated polylysine, poly(ethylene imine), PEGylated poly(ethylene imine), and combinations thereof.

8. The method of claim 7, wherein the particles are poly(lactic-co-glycolic acid) (PLGA) particles.

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

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

11. The method of claim 1 wherein the particles of each of the given particle populations have a different collection of aptamers conjugated to their surface.

12. The method of claim 1, wherein the particles comprise a poly(hydroxy acid) polymer or copolymer or pegylated poly(hydroxy acid) polymer or copolymer.