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CN-121986123-A - Block copolymer nanoparticles for sustained drug delivery

CN121986123ACN 121986123 ACN121986123 ACN 121986123ACN-121986123-A

Abstract

Disclosed herein are POEGMA-based block copolymers having phase transition and self-assembly properties. The disclosed block copolymers can take advantage of these properties to form particles that can effectively encapsulate and deliver drugs. An exemplary block copolymer comprises a first block comprising POEGA having ethylene glycol side chains of 2 monomers, 3 monomers, or a combination of both, and a second block comprising POEGA having ethylene glycol side chains of 1 monomer, 2 monomers, or a combination of both. Also disclosed herein are compositions comprising the block copolymers, methods of treating diseases or disorders, and methods of delivering drugs.

Inventors

  • A. Kirkotti
  • P. Xiloxi
  • B. E. Silverstein

Assignees

  • 杜克大学

Dates

Publication Date
20260505
Application Date
20241009
Priority Date
20231009

Claims (20)

  1. 1. A block copolymer comprising: A first block (A), wherein the first block comprises repeating units of formula (I) (I), Wherein x is 2 or 3, and A second block (B), wherein the second block comprises repeat units having the formula (II) (II), Wherein y is 1 or 2.
  2. 2. The block copolymer of claim 1, wherein the repeating unit having formula (I) has a degree of polymerization of 10 to 300 and the repeating unit having formula (II) has a degree of polymerization of 10 to 300.
  3. 3. The block copolymer of claim 1, wherein: the repeating unit of formula (I) comprises a unit having a polymerization degree of 0 to 100 and x of 2 and a unit having a polymerization degree of 20 to 250 and x of 3, and The repeating unit having formula (II) comprises a unit having a polymerization degree of 0 to 100 and y of 1 and a unit having a polymerization degree of 20 to 250 and y of 2.
  4. 4. The block copolymer of claim 1, wherein x is 3 and y is 2.
  5. 5. The block copolymer of claim 4, comprising the first block and the second block each comprising greater than 25% of the total polymer length in terms of degree of polymerization.
  6. 6. The block copolymer of claim 1, wherein x is 3 and the second block comprises a random copolymer comprising repeat units having formula (II).
  7. 7. The block copolymer of claim 1, having a transition temperature (T t ) above 37 ℃ at a concentration below 200 μm.
  8. 8. The block copolymer of claim 1 having a T t below 37 ℃ at a concentration above 10 μm.
  9. 9. The block copolymer of claim 1, having a T t of about 22 ℃ to about 46 ℃ at a concentration of about 10 μΜ to about 200 μΜ.
  10. 10. The block copolymer of claim 1, having a Critical Micelle Temperature (CMT) of about 15 ℃ to about 45 ℃ at a concentration of about 1 μΜ to about 200 μΜ.
  11. 11. The block copolymer of claim 1 having a T t above 37 ℃ and a CMT below 37 ℃ at a concentration of about 1 μm to about 200 μm.
  12. 12. The block copolymer of claim 1 having a T t below 37 ℃ and a CMT below 25 ℃ at a concentration of about 1 μm to about 200 μm.
  13. 13. The block copolymer of claim 1, having a number average molecular weight of about 5,000 daltons (Da) to about 100,000 Da as measured by SEC-MALS.
  14. 14. The block copolymer of claim 1, wherein the block copolymer is an A-B diblock copolymer or an A-B-A triblock copolymer.
  15. 15. The block copolymer of claim 1, wherein the block copolymer is a 10-300 -B 10-300 or a 10-250 -B 10-200 -A 10-250 .
  16. 16. The block copolymer of claim 1, wherein the block copolymer has a reduced immune response relative to polyethylene glycol (PEG).
  17. 17. The block copolymer of claim 1, wherein the block copolymer does not induce an anti-POEGMA antibody response.
  18. 18. The block copolymer of claim 1, wherein the block copolymer is non-reactive with pre-existing anti-PEG antibodies in a subject.
  19. 19. A composition comprising: A plurality of block copolymers as claimed in claim 1, self-assembled into particles, and A drug encapsulated within the particle.
  20. 20. The composition of claim 19, wherein the drug comprises a peptide-based drug, a hydrophobic chemotherapeutic agent, or a combination thereof.

Description

Block copolymer nanoparticles for sustained drug delivery Cross Reference to Related Applications The present application claims priority from U.S. provisional patent application No. 63/543,143 filed on day 10, 2023 and U.S. provisional patent application No. 63/678,955 filed on day 8, 2024, both of which are incorporated herein by reference in their entirety. Statement regarding federally sponsored research The present invention was completed with government support under federal grant No. R01 DK124276-04 awarded by national institute of diabetes and digestive and renal disease/national institutes of health （National Institutes of Diabetes and Digestive and Kidney Disease / National Institutes of Health）（NIH/NIDDK）. The federal government has certain rights in this invention. Technical Field The present disclosure relates to block copolymers that are capable of self-assembling into nanoparticles and capable of effectively delivering drugs for biomedical applications (e.g., drug delivery). Introduction to the invention Polyethylene glycol (PEG) is the most common hydrophilic block in self-assembled block copolymer Nanoparticles (NPs) because PEG crowns provide "stealth" behavior that imparts long plasma residence times to NPs. However, the ubiquitous presence of pre-existing anti-PEG antibodies in more than 60% of the population raises several concerns, including opsonization of PEG NPs (resulting in their premature clearance through the reticuloendothelial system), and rare but potentially fatal anaphylactoid reactions. In addition, the core-forming blocks in these NPs may be composed of more hydrophobic or relatively less hydrophilic polymers such as polypropylene oxide (PPO), polystyrene oxide (PSO), polylactic acid (PAA), and the like, some of which are difficult to degrade or potentially toxic. Thus, biomaterials comprising amphiphilic block copolymers that can overcome these aforementioned problems would be beneficial in the drug delivery field. Disclosure of Invention In one aspect, a block copolymer is disclosed comprising a first block (A), wherein the first block comprises repeat units having formula (I) (I), Wherein x is 2 or 3, and a second block (B) comprising repeat units of formula (II) (II), Wherein y is 1 or 2. In another aspect, compositions are disclosed that comprise a plurality of block copolymers as disclosed herein self-assembled into a particle, and a drug encapsulated within the particle. In another aspect, disclosed is a method of treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a composition as disclosed herein. In another aspect, disclosed is a method of delivering a drug to a subject in need thereof, the method comprising systemically or locally administering to the subject a composition as disclosed herein, wherein the drug is released from the particles after administration. In another aspect, disclosed is a method of delivering a scaffold to a subject in need thereof, the method comprising administering a block copolymer as disclosed herein to a site of the subject, the block copolymer exhibiting a phase change behavior defined by T t upon administration to the site, the block copolymer forming a porous network above T t. Drawings The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawings will be provided by the office upon request and payment of the necessary fee. FIG. 1 is a schematic representation of a poly [ oligo (ethylene glycol) methyl ether methacrylate ] (poly [ oligo (ethylene glycol) METHYL ETHER METHACRYLATE ]) (POEGA) copolymer as disclosed herein. FIG. 2A is a schematic design of POEGA diblock copolymers containing EG2 and EG3 side chains in the respective blocks that can self-assemble into nanoscale particles in aqueous media. Fig. 2B is a graph illustrating a Size Exclusion Chromatography (SEC) chromatogram of an exemplary diblock for determining M n、Mw and polydispersity index (PDI). Fig. 2C is a table showing a summary of M n、Mw and PDI of an exemplary copolymer determined by SEC-MALS. The ID of the diblock POEGMA represents the Degree of Polymerization (DP) of the individual blocks determined by dividing M n by the molecular weight of the corresponding monomer. For simplicity, each polymer was given a random letter as a label. FIG. 3A is a graph of optical density of polymer D, EG3 167-EG285, at various concentrations as a function of temperature. The heating curve is represented by a solid line and the cooling curve is represented by a dashed line. The sharp increase in absorbance at 42 ℃ indicates the cloud point/transition temperature (T t) of this polymer. Fig. 3B is a graph showing the change in size distribution of polymer D from 25 ℃ (below CMT) to 37 ℃ (above CMT but below T t) at low concentration (12.5 μm) and high concentration (200 μm). Fig. 3C is a