# US 12,178,885 B2 · Method for mediating targeted delivery of a composition to the brain of a subject in need thereof

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- Number: US 12,178,885 B2
- Document ID: US12178885B2
- Status: Granted
- Kind: B2
- Application number: 17/251,061
- Filed: 2019-05-17
- Published: 2021-08-19
- Granted: 2024-12-31
- Earliest claimed: 2018-06-14
- Applicants: Fudan University
- Inventors: Changyou Zhan; Zui Zhang
- Web page: https://patentgrep.com/patent/US12178885B2

## CPC

- A61K 49/0056: {Peptides, proteins, polyamino acids}
- A61K 31/65: Tetracyclines
- A61K 47/62: the modifying agent being a protein, peptide or polyamino acid
- A61K 47/64: Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65)
- A61K 47/6911: {the form being a liposome}
- A61K 47/6925: {the form being a microcapsule, nanocapsule, microbubble or nanobubble}
- A61K 49/0093: {Nanoparticle, nanocapsule, nanobubble, nanosphere, nanobead, i.e. having a size or diameter smaller than 1 micrometer, e.g. polymeric nanoparticle}
- A61P 35/00: Antineoplastic agents
- C07K 7/06: having 5 to 11 amino acids
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

A polypeptide modified complex in the pharmaceutical field that can specifically adsorb apolipoproteins in plasma and can mediate a drug across the blood-brain barrier, a target delivery system, and use thereof in preparation of a formulation for diagnosing and treating brain tumors and other brain diseases. The polypeptide fragment (SP) of the amyloid β (relating to one type) is modified shown that the modified delivery system increases uptake the of the amyloid β by vascular endothelial cells after the modified delivery system forms a protein crown with plasma proteins. The modified liposome delivery system delivers a drug to the lesion site more effectively, significantly improving the therapeutic effect of the drug. After the SP adsorbs plasma proteins, a drug may be mediated across the blood-brain barrier and/or targeted to tumor neovascular and tumor cells, and the modified drug and delivery system thereof obtain a better therapeutic effect when treating brain tumors and other diseases in the brain.

## Claims

### Claim 1

A method for mediating targeted delivery of a composition to a brain of a subject in need thereof, wherein the composition comprises an amyloid β short peptide (SP) combined with a drug molecule, a diagnostic molecule, a delivery system, or combinations thereof, wherein the SP binds to receptors on blood-brain barrier and crosses the blood-brain barrier, thus mediating targeted delivery of the composition to the brain and can adsorb apolipoprotein in plasma, wherein the method comprises administering the composition to the subject in need thereof;
wherein the amyloid β short peptide consists of the sequence GSNKGAIIGLM (SEQ ID No: 1).

### Claim 2 (depends on 1)

The method according to claim 1, wherein the method further comprises diagnosing a brain tumor or a brain disease in the subject, wherein the composition comprises an imaging substance X, wherein the amyloid β short peptide (SP) is linked to the imaging substance X by covalent bond to prepare SP-X, wherein SP-X to image a brain tumor or a diseased brain tissue or cell in the subject.

### Claim 3 (depends on 2)

The method according to claim 2, wherein X is a fluorescent molecule selected from a Fluorescein, or a near-infrared dye molecule selected from Sulfo-Cyanine 5 (Cy5), Sulfo-Cyanine 5.5 (Cy5.5), Sulfo-Cyanine 7 (Cy7), New Indocyanine Green (IR820), Indocyanine Green (ICG), 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindotricarbocyanine iodide (DiR), 1,1′-Dioctadecyl-3,3,3′,3′-tetramethylindodicarbocyanine,4-Chlorobenzenesulfonate Salt (DiD), or 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate (DiI).

### Claim 4 (depends on 1)

The method according to claim 1, wherein the method further comprises targeted intervention of a brain tumor or a brain disease in the subject, wherein the amyloid β short peptide (SP) is linked to an antitumor drug Y by covalent bond to prepare SP-Y, wherein SP-Y targets the brain tumor or the brain disease.

### Claim 5 (depends on 4)

The method according to claim 4, wherein Y comprises gefitinib, icotinib, anlotinib, crizotinib, erlotinib, osimertinib, alectinib, paclitaxel, docetaxel, cabazitaxel, adriamycin, epirubicin, camptothecin, hydroxycamptothecin, 9-nitrocellulose camptothecine or vincristine small molecule antitumor drugs, p53 activating peptide, polypeptide toxin, or polypeptide antitumor drug.

### Claim 6 (depends on 1)

The method according to claim 1, wherein the amyloid β short peptide (SP) is linked to polyethylene glycol-Z by covalent bond to prepare SP- polyethylene glycol-Z, wherein SP- polyethylene glycol-Z is used to prepare a nanometer delivery system.

### Claim 7 (depends on 6)

The method according to claim 6, wherein (1) Z comprises a phospholipid, a polylactic acid, a lactic-co-glycolic acid or a polycaprolactone; (2) wherein the nanometer delivery system comprises a liposome delivery system, a micelle delivery system, a nano-disc delivery system, a polymer nanoparticle delivery system, or combinations thereof; or both (1) and (2).

### Claim 8 (depends on 7)

The method according to claim 7, (a) wherein the SP-polyethylene glycol-phospholipid is used for preparing the liposome delivery system, the micelle delivery system or the nano-disc delivery system; (b) wherein the SP-polyethylene glycol-polylactic acid, the SP-polyethylene glycol- lactic-co-glycolic acid, or the SP-polyethylene glycol-polycaprolactone is used to prepare the micelle delivery system and the polymer nanoparticle delivery system; or both (a) and (b).

### Claim 9 (depends on 8)

The method according to claim 8, wherein the method further comprises diagnosing a brain tumor or a brain disease, and wherein the liposome delivery system, the micellar delivery system, the nano-disc delivery system or the polymer nano-particle delivery system is used to encapsulate a diagnostic molecule to trace the brain tumor or the diseased brain tissue or cell.

### Claim 10 (depends on 9)

The method according to claim 9, wherein the diagnostic molecule encapsulated in the delivery system comprises 5-carboxyfluorescein 5-FAM, near-infrared dye selected from Sulfo-Cyanine 5 (Cy5), Sulfo-Cyanine 5.5 (Cy5.5), Sulfo-Cyanine 7 (Cy7), New Indocyanine Green (IR820), Indocyanine Green (ICG), 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindotricarbocyanine iodide (DiR), 1,1′-Dioctadecyl-3,3,3′,3′-tetramethylindodicarbocyanine,4-Chlorobenzenesulfonate Salt (DiD), or 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate (DiI).

### Claim 11 (depends on 8)

The method according to claim 8, wherein the method further comprises targeting a brain tumor or a diseased brain tissue or cell, wherein the nanoparticle delivery system, the liposome delivery system, the micelle delivery system, the polymer nanoparticle delivery system or the nano-disc delivery system is used for encapsulating an antitumor drug.

### Claim 12 (depends on 11)

The method according to claim 11, wherein the antitumor drug encapsulated in the delivery system comprises gefitinib, icotinib, anlotinib, crizotinib, erlotinib, osimertinib, alectinib, paclitaxel, docetaxel, cabazitaxel, adriamycin, epirubicin, camptothecin, hydroxycamptothecin, 9-nitrocellulose camptothecine, vincristine, p53 activating peptide, or polypeptide toxin.

### Claim 13 (depends on 1)

The method of claim 1, wherein the subject suffers from a brain metastatic tumor, a primary brain tumor, or both.