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KR-20260067208-A - POLYMER COMPOUND FOR CELL SURFACE MODIFICATION TO ENHANCE DRUG DELIVERY EFFICIENCY

KR20260067208AKR 20260067208 AKR20260067208 AKR 20260067208AKR-20260067208-A

Abstract

The present invention relates to a polymer compound for modifying cell surfaces to improve drug delivery efficiency. A polymer compound for modifying the surface of natural killer cells according to one embodiment of the present invention includes a DSPE lipid having high hydrophobicity, which has the effect of increasing cell membrane immobilization efficiency and binding maintenance period. The polymer compound includes a prodrug at one end, which can improve the efficacy of immunotherapy through a targeted drug delivery system mediated by immune cells such as natural killer cells.

Inventors

  • 김교범
  • 노경무
  • 아속쿠말장기드

Assignees

  • 동국대학교 산학협력단

Dates

Publication Date
20260512
Application Date
20241105

Claims (20)

  1. Hydrophobic moiety that binds to the cell membrane; Cell internalization prevention moiety; Disulfide linker and Polymeric compounds for cell surface modification to improve drug delivery efficiency, comprising anticancer prodrug moiety.
  2. In paragraph 1, A polymer compound for cell surface modification to improve drug delivery efficiency, wherein the hydrophobic moiety is selected from the group consisting of phospholipids having alkyl chains having 12 to 24 carbon atoms, sterol lipids having 10 to 30 carbon atoms, 1,2-bis(diphenylphosphino)ethane (DPPE), and 1,2-bis(dimethylphosphino)ethane (DMPE).
  3. In paragraph 1, A polymeric compound for cell surface modification to enhance drug delivery efficiency, wherein the above hydrophobic moiety is represented by Chemical Formula 1: [Chemical Formula 1] q is an integer greater than 0, and p is an integer greater than 0.
  4. In paragraph 1, A polymeric compound for cell surface modification to enhance drug delivery efficiency, wherein the above-mentioned cell internalization-preventing moiety is represented by Chemical Formula 2: [Chemical Formula 2] n is an integer greater than 0.
  5. In paragraph 4, A polymer compound for modifying the cell surface to improve drug delivery efficiency, wherein the cell internalization-preventing moiety is selected from the group consisting of polyethylene glycol (PEG), polyethylene oxide (PEO), and polyvinyl alcohol (PVA).
  6. In paragraph 1, A polymeric compound for cell surface modification to improve drug delivery efficiency, wherein the above disulfide linker is represented by Chemical Formula 3: [Chemical Formula 3] R and R' are each independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclil, and substituted heterocyclil.
  7. In paragraph 6, A polymer compound for cell surface modification to improve drug delivery efficiency, characterized in that the above alkyl is methylene having 1 to 30 repeating units.
  8. In paragraph 1, A polymer compound for cell surface modification to improve drug delivery efficiency, wherein the above cancer is selected from the group consisting of prostate cancer, thyroid cancer, stomach cancer, colorectal cancer, lung cancer, breast cancer, liver cancer, pancreatic cancer, testicular cancer, oral cancer, basal cell carcinoma, brain tumor, gallbladder cancer, bile duct cancer, laryngeal cancer, retinoblastoma, ampullary cancer, bladder cancer, peritoneal cancer, adrenal cancer, non-small cell lung cancer, tongue cancer, small cell lung cancer, small intestine cancer, meningioma, esophageal cancer, renal pelvis and ureter cancer, kidney cancer, malignant bone tumor, malignant soft tissue tumor, malignant lymphoma, malignant melanoma, eye tumor, urethral cancer, stomach cancer, sarcoma, pharyngeal cancer, cervical cancer, endometrial cancer, uterine sarcoma, metastatic brain tumor, rectal cancer, vaginal cancer, spinal cord tumor, salivary gland cancer, tonsil cancer, squamous cell carcinoma, hematological cancer, and anal cancer.
  9. In paragraph 1, A polymeric compound for cell surface modification to improve drug delivery efficiency, wherein the above-mentioned prodrug is selected from the group consisting of gemcitabine, fludarabine, clofarabine, cladribine, azacitidine, decitabine, cytarabine, nelarabine, nimustine, temozolomide, dacarbazine, thioguanine, carboquone, doxorubicin, entinostat, pemetrexed, and methotrexate.
  10. In paragraph 1, A polymeric compound for cell surface modification to improve drug delivery efficiency, wherein the above anticancer prodrug moiety is covalently bonded to a disulfide linker.
  11. In paragraph 1, The above cell membrane is a polymer compound for modifying the cell surface to improve drug delivery efficiency, wherein the cell membrane is a cell membrane of an immune cell or a drug delivery vehicle coated with an artificial cell membrane.
  12. In Paragraph 11, The above immune cell is a natural killer cell, a polymer compound for cell surface modification to improve drug delivery efficiency.
  13. In paragraph 1, The above polymer compound is a polymer compound for cell surface modification to improve drug delivery efficiency, which delivers an anticancer prodrug dissociated by the cleavage of disulfide bonds by glutathione released from cancer cells to surrounding cancer cells.
  14. Natural killer cells with a surface modified by bonding a polymer compound of any one of claims 1 to 13.
  15. A drug delivery system coated with an artificial cell membrane whose surface is modified by bonding a polymer compound of any one of claims 1 to 13.
  16. (a) A step of activating the carboxyl groups of a disulfide containing carboxyl groups at both ends; (b) a step of attaching a polymeric compound comprising a hydrophobic moiety, an anti-internalization moiety, and an amine group to one end of a disulfide and (c) A method for preparing a polymeric compound comprising a hydrophobic moiety that binds to a cell membrane, a cell internalization prevention moiety, a disulfide linker, and an anticancer prodrug moiety, comprising the step of binding a prodrug to the other end of the disulfide of the polymeric compound in which step (b) is completed.
  17. In Paragraph 16, A method for preparing a polymeric compound comprising a hydrophobic moiety that binds to a cell membrane, a cell internalization-preventing moiety, a disulfide linker, and an anticancer prodrug moiety, wherein the polymeric compound comprising the above hydrophobic moiety; the cell internalization-preventing moiety and an amine group is represented by Chemical Formula 4: [Chemical Formula 4] q is an integer greater than 0, and p is an integer greater than 0.
  18. In Paragraph 16, A method for preparing a polymer compound comprising a hydrophobic moiety that binds to a cell membrane, a cell internalization-preventing moiety, a disulfide linker, and an anticancer prodrug moiety, wherein the polymer compound obtained after completing step (b) above is represented by Chemical Formula 5: [Chemical Formula 5] q is an integer greater than 0, and p is an integer greater than 0, and n is an integer greater than 0, and R and R' are each independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclil, and substituted heterocyclil.
  19. In Paragraph 16, A method for preparing a polymeric compound comprising a hydrophobic moiety that binds to a cell membrane, a cell internalization-preventing moiety, a disulfide linker, and an anticancer prodrug moiety, wherein the polymeric compound comprising the above-mentioned hydrophobic moiety, the cell internalization-preventing moiety, the disulfide linker, and the anticancer prodrug moiety is represented by Chemical Formula 6: [Chemical Formula 6] q is an integer greater than 0, and p is an integer greater than 0, and n is an integer greater than 0, and R and R' are each independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclil, and substituted heterocyclil, and A is selected from gemcitabine, fludarabine, clofarabine, cladribine, azacitidine, decitabine, cytarabine, nelarabine, nimustine, temozolomide, dacarbazine, thioguanine, carboquone, doxorubicin, entinostat, pemetrexed, and methotrexate.
  20. A pharmaceutical composition for the prevention or treatment of cancer, comprising as an active ingredient a polymeric compound comprising a hydrophobic moiety that binds to a cell membrane; a moiety that prevents cell internalization; a disulfide linker; and an anticancer prodrug moiety.

Description

Polymer compound for cell surface modification to enhance drug delivery efficiency The present invention relates to a polymer compound for cell surface modification to improve drug delivery efficiency. Adoptive cell therapy involves collecting lymphocytes or natural killer cells from the body, isolating and proliferating them, and then re-injecting them. CAR-T therapy, which has evolved from the previous method of isolating and proliferating tumor-infiltrating lymphocytes to inject them, involves genetically engineering T lymphocytes to attach chimeric antigen receptors and injecting them. This therapy is gaining attention and is currently being used for blood cancers. However, despite the initial success of natural killer cell-based adoptive cell therapy for blood cancers, the therapeutic effect on solid tumors remains minimal. Solid tumors form a dense extracellular matrix that acts as a physical barrier and secrete immunosuppressive cytokines, inducing the exaustion of peripheral immune cells, particularly through the formation of the tumor microenvironment (TME), and inhibiting the infiltration and cytotoxic function of natural killer cells, thereby promoting the growth and metastasis of tumor cells. Meanwhile, layer-by-layer self-assembly can be utilized as a cell coating technology. The aforementioned layer-by-layer method is a simple and versatile deposition process widely applied to address many issues such as biomolecular deposition, concentration, bioactivity, coating thickness, and release rate. However, utilizing the above-mentioned layer-by-layer method requires surface modification of the cells, and this surface modification presents process difficulties as it involves alternating reactions and stacking of cationic or anionic substrate materials. Furthermore, the covering of the entire cell surface with a coating material may lead to a potential degradation of the function of surface membrane proteins involved in signal transduction and cancer cell recognition. In addition, when cell surface coatings are used for a single purpose, such as preventing cell aggregation, there is often a lack of strategies for multifunctionality that can be expected to provide appropriate immuno-oncology therapeutic effects. The background description of the invention is provided to facilitate a better understanding of the present invention. The matters described in the background description should not be construed as an acknowledgment that they exist as prior art. FIGS. 1a and 1b illustrate, exemplarily, the process of manufacturing a polymer compound for cell surface modification according to one embodiment of the present invention. Figure 2 illustrates the results of the structural feature analysis of DSPE- PEG -ss-Gem according to one embodiment of the present invention. Figure 3 illustrates the results of evaluating the cell viability and proliferation ability of natural killer cells by Gem alone treatment according to one embodiment of the present invention. FIGS. 4a and 4b illustrate the results of evaluating the cell viability and proliferation ability of surface-modified natural killer cells according to various DSPE- PEG -ss-Gem concentrations according to one embodiment of the present invention. FIGS. 4C and 4D illustrate the results of evaluating the anticancer function of GCNK cells coated with a lipid-gemcitabine conjugate at a concentration of 3.3 μg/mL or 33 μg/mL according to one embodiment of the present invention. Figure 5 shows the results of evaluating the solubility of cell membrane components of natural killer cells whose surfaces were modified with DSPE- PEG -ss-Gem according to one embodiment of the present invention. Figure 6 shows the results of measuring the zeta potential of the surface of natural killer cells modified with DSPE- PEG -ss-Gem according to one embodiment of the present invention. FIG. 7a illustrates the results of confirming the gemcitabine release profile by GSH from DSPE- PEG -ss-Gem according to one embodiment of the present invention. FIGS. 7b and 7c illustrate the results of evaluating cell viability of PANC-1 and MIA PaCa-2 exposed to released gemcitabine according to one embodiment of the present invention. FIG. 8 illustrates the results of E/T cluster quantification for effector cells (NK or GCNK cells) and target cells (PANC-1, MIA PaCa-2, and normal fibroblasts) according to one embodiment of the present invention. FIGS. 9a to 9c illustrate the results of an analysis of calcein release from NK and GCNK cells to pancreatic cancer cells and normal fibroblasts according to one embodiment of the present invention. FIGS. 10a and 10b illustrate the results of evaluating MICA/B expression levels in PANC-1 and MIA PaCa-2 exposed to released gemcitabine according to one embodiment of the present invention. FIGS. 11a and 11b illustrate the results of calcein release analysis of PANC-1 and MIA PaCa-2 following treatment of natural killer cells surface-modified with DSPE-