Method for the revival of microglia and astrocytes and applications thereof
AssigneeUniversity of South Carolina
InventorsPeisheng Xu, Mingming Wang
Life of this patent
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Abstract
Methods are described for treatment of Alzheimer's Disease as well as other neurodegenerative disorders in which microglia and/or astrocyte abilities have been altered and impaired. Methods include brain-targeting of PD-L1 using a brain targeted nanogel loaded with PDL1 antibody and functionalized with two particular targeting ligands. The nanogels can successfully cross the blood brain barrier to release the antibody and reduce PD-L1 expression in the brain while preserving the integrity of the BBB.
Claims19
A method for reviving function in impaired microglia and/or astrocytes comprising delivering a nanogel to the microglia and/or astrocytes, the nanogel comprising a crosslinked network that includes a first copolymer and a second copolymer, the first copolymer comprising a first backbone, a first group pendant to the first backbone, the first group comprising a first poly(ethylene glycol), and a second group pendant to the first backbone that is conjugated to a PD-L1 antibody via a first disulfide bond, the second copolymer including a second backbone, a third group pendant to the second backbone, the third group comprising a second poly(ethylene glycol), and a fourth group pendant to the second backbone that is conjugated to a nictotinic acetylcholine receptor (nAChR) targeting ligand via a second disulfide bond, the nanogel further comprising a receptor for advanced glycation endproducts (RAGE) targeting ligand conjugated at a surface of the nanogel via a third disulfide bond;
- wherein
- following delivery of the nanogel to the impaired microglia and/or astrocytes, the first, second, and third disulfide bonds are degraded, thereby releasing the PD-L1 antibody, and wherein
- following release of the PD-L1 antibody, PD-L1 expressed by the microglia and/or astrocytes is degraded and the function of the impaired microglia and/or astrocytes is revived.
A method for treatment of a neurodegenerative disorder, the method comprising:
- delivering a pharmaceutical composition to a subject, the composition comprising a nanogel and a pharmaceutically effective carrier, the nanogel comprising a crosslinked network that includes a first copolymer and a second copolymer, the first copolymer comprising a first backbone, a first group pendant to the first backbone, the first group comprising a first poly(ethylene glycol), and a second group pendant to the first backbone that is conjugated to a PD-L1 antibody via a first disulfide bond, the second copolymer including a second backbone, a third group pendant to the second backbone, the third group comprising a second poly(ethylene glycol), and a fourth group pendant to the second backbone that is conjugated to a nictotinic acetylcholine receptor (nAChR) targeting ligand via a second disulfide bond, the nanogel further comprising a receptor for advanced glycation endproducts (RAGE) targeting ligand conjugated at a surface of the nanogel via a third disulfide bond;
- wherein
- following delivery of the pharmaceutical composition to the subject, the nanogel crosses the blood brain barrier;
- and wherein
- the first, second, and third disulfide bonds are degraded following the crossing of the blood brain barrier, thereby releasing the PD-L1 antibody, and wherein
- following release of the PD-L1 antibody, PD-L1 expressed by microglia and/or astrocytes is degraded and the function of impaired microglia and/or astrocytes in the brain is revived.
Dependencies are inferred from the claim text.