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Conjugate and application thereof in treating inner ear diseases

A technology for conjugates and diseases, which can be applied in sensory diseases, ear treatment, drug devices, etc., and can solve problems such as inner ear cell protection or repair that cannot be targeted, drug targeting problems, middle ear mucosal stimulation, etc. , to achieve the effect of improving the effect of drugs, facilitating sustained release and action, and reducing irritation

Active Publication Date: 2022-08-05
SUN YAT SEN MEMORIAL HOSPITAL SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, even if local administration can solve the problem of side effects of systemic administration and the effective concentration of the drug, it still cannot solve the problem of drug targeting. In the prior art, even if the drug can enter the inner ear through the round window membrane, it cannot It diffuses in the cochlea along with the perilymph, and cannot target the specific structures and cells of the inner ear for protection or repair
Therefore, in order to improve the protective or therapeutic effect of its action on the corresponding structure or cells, it is still necessary to increase the concentration to increase the chance of acting on the corresponding structure and cells, and it is still unavoidable to avoid the effect of high-concentration drugs; and high-concentration drugs will also affect The mucous membrane of the middle ear is irritated, and the effect of the medicine is reduced, which affects the overall therapeutic effect

Method used

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  • Conjugate and application thereof in treating inner ear diseases
  • Conjugate and application thereof in treating inner ear diseases
  • Conjugate and application thereof in treating inner ear diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Synthetic Preparation of A665-NAC

[0036] In this example, A665-NAC is prepared by conventional polypeptide solid-phase synthesis technology, and the targeting polypeptide A665 is coupled with NAC by covalent bonding, and the prepared A665-NAC conjugate has the structural formula as follows figure 1 A shown.

[0037] Specifically, the above-mentioned preparation process includes the following processes:

[0038] 1. Peptide sequence: Leu-Ser-Thr-His-Thr-Thr-Glu-Ser-Arg-Ser-Met-Val-Cys (Ac-Cys); 2. Description of preparation process: using solid-phase organic synthesis method, using Fmoc-protected amino acid strategy, SPPS solid-phase synthesis technology, completes the main chain assembly, cleavage, and purification of the target product after oxidation reaction.

[0039] Among them, the preparation process is specifically:

[0040] (1) Solid-phase synthesis: use Fmoc-Cys(Trt)-CTC resin, and then according to the above peptide sequence, with Fmoc-protected amino acid...

Embodiment 2

[0051] Detection of the ability of A665-NAC to enter auditory cells HEI-OC1

[0052] In order to detect the ability of A665-NAC to enter auditory cells, HEI-OC1 cells expressing the A665 target transmembrane protein prestin were selected in this example to study the ability of A665-NAC to enter auditory cells.

[0053] In this example, the inventor added fluorescein Cy5.5 to A665-NAC and random peptide-NAC (named RP-NAC), and marked A665-NAC with fluorescein as Cy5.5-A665-NAC, RP-NAC with fluorescein is Cy5.5-RP-NAC. After the HEI-OC1 cells were plated overnight, 5 mM Cy5.5-A665-NAC / Cy5.5-RP-NAC was co-incubated on ice for 5 minutes, then the medium was changed, and washed 3 times with PBS, using After trypsinization, flow cytometry was performed.

[0054] The result is as figure 2 shown, wherein Ctrl is the control group, RP-NAC is the random peptide-NAC treatment group, and A665-NAC is the corresponding A665-NAC treatment group. In addition, there is also a group of exp...

Embodiment 3

[0059] A665-NAC enhances the antioxidant capacity of HEI-OC1 against cisplatin cytotoxicity.

[0060] 1. Detection of cisplatin-induced cell damage

[0061] In this example, cisplatin was used for the cytotoxicity experiment. The HEI-OC1 cells were treated with cisplatin (Cisplatin, CDDP) 30 μM for 24 hours, and the cell damage reached 50%. image 3 A shown. However, when RP-NAC or A665-NAC 2.5mM and CDDP were used at the same time, the cell damage was less than that of CDDP alone, and the damage of A665-NAC was less than that of RP-NAC group, indicating that A665-NAC can Resists the cytotoxic effect of CDDP and is stronger than RP-NAC.

[0062] And the inventors compared the cell survival situation under the action of different concentrations, and found that the protective effect of A665-NAC at 2.5 mM was stronger than that of RP-NAC 10 mM, such as image 3 shown in B.

[0063] The inventors also obtained the early apoptosis and apoptosis of HEI-OC1 cells caused by cispla...

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Abstract

The invention discloses a conjugate and application thereof in inner ear diseases, the conjugate is formed by combining an inner ear targeting polypeptide and a main drug for diagnosing, preventing or treating the inner ear diseases, so that the main drug is assisted to target an inner ear or a specific structure and cells in the inner ear by virtue of the inner ear targeting polypeptide, the enrichment of the main drug is realized, and the inner ear diseases are prevented and treated. Therefore, targeted inner ear structures or cells can be accurately acted on; the efficiency of transporting the medicine to the inner ear can be improved through the inner ear targeting polypeptide, so that the content of the medicine reaching the inner ear is remarkably improved, and the inner ear bioavailability of the medicine is improved. The invention further provides application of the conjugate to the inner ear diseases, and diagnosis, prevention or treatment of the inner ear diseases can be conveniently achieved through the main medicine in the conjugate. More specifically, the delivery and medicinal process of the conjugate targeting inner ear outer hair cells is realized by locally delivering the conjugate A665-NAC. When the conjugate is applied to an inner ear acted by cis-platinum, hearing loss caused by cis-platinum can be reduced, and the cis-platinum ear toxicity prevention and treatment effects are achieved.

Description

technical field [0001] The present invention relates to the field of pharmacy, and more particularly, to a conjugate and its application in the treatment of inner ear diseases. Background technique [0002] Inner ear diseases mainly include vertigo, deafness, etc., which are mostly caused by damage to inner ear hair cells, auditory nerve and other structures. For example, a variety of sensorineural hearing loss is mainly caused by damage to hair cells in the cochlea, especially the external Damage to hair cells. Inner ear diseases will not only bring direct physical health problems to patients, but also directly affect the normal life of patients and bring inconvenience to the normal life of patients. Therefore, the treatment of inner ear diseases has always been a key research object in the field of current ear diseases. Patients with inner ear diseases are also in urgent need of effective inner ear disease treatment drugs or programs. [0003] At present, the treatment o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/64A61K31/198A61K9/06A61P27/16A61M31/00A61F11/00
CPCA61K47/64A61K31/198A61K9/06A61K9/0019A61K9/0046A61P27/16A61M31/00A61F11/00A61M2210/0662A61M2210/0668A61M2210/005
Inventor 庞嘉祺许小丁郑亿庆
Owner SUN YAT SEN MEMORIAL HOSPITAL SUN YAT SEN UNIV
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