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Antibody-mediated autocatalytic, targeted delivery of nanocarriers to tumors

A nanocarrier and antibody technology, applied in antitumor drugs, drug delivery, powder delivery, etc., can solve problems such as limitations

Active Publication Date: 2019-05-24
YALE UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the complexity of such systems may limit the ability to apply the technology in the clinic

Method used

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  • Antibody-mediated autocatalytic, targeted delivery of nanocarriers to tumors
  • Antibody-mediated autocatalytic, targeted delivery of nanocarriers to tumors
  • Antibody-mediated autocatalytic, targeted delivery of nanocarriers to tumors

Examples

Experimental program
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preparation example Construction

[0321] The first is through the incorporation of stabilizers with chemical functional groups during the preparation of the particles, for example during the emulsion preparation of the particles.

[0322] The second is by direct crosslinking of particles and ligands with homobifunctional or heterobifunctional crosslinkers after particle preparation. This second procedure can use an appropriate chemistry and a class of cross-linking agents (CDI, EDAC, glutaraldehyde, etc., as discussed in more detail below) or any other agent that enables the ligand to be modified by chemical modification of the particle surface after preparation. A crosslinker coupled to the particle surface. This second category also includes a method in which amphiphilic molecules, such as fatty acids, lipids, or functional stabilizers, can be passively adsorbed and adhered to particle surfaces, thereby introducing functional end groups attached to ligands.

[0323] Various other methods of manufacturing ac...

example 1

[0417] Example 1: Synthesis and characterization of nanoparticles with and without surface anti-DNA autoantibodies

[0418] Materials and methods

[0419] Materials and Cell Culture

[0420] All chemicals were purchased from Sigma-Aldrich unless otherwise stated. The mouse mammary tumor cell line 4T1 was obtained from the American Type Culture Collection (ATCC) and incubated in a 37°C incubator with 5% CO2 supplemented with 10% fetal bovine serum (Invitrogen). , 100 units / ml penicillin and 100 μg / ml streptomycin (Invitrogen) in DMEM medium (Invitrogen).

[0421] Synthesis of PLGA-PLL

[0422] PLGA-PLL was synthesized according to previously reported procedures (Zhou et al., Biomaterials, 33(2):583-591 (2012); Han et al., Nanomedicine (2016)). Briefly, PLGA (3 g, 50:50 PLGA acid end groups; i.v. about 0.67 dL / g; Absorbable Polymers, AL) and 200 mg poly(ε- Benzyloxycarbonyl-L-lysine) (PLL) (MW 1000-4000 Da, Sigma) was dissolved in 6 mL of dimethylformamide in a dry round bo...

example 2

[0448] Example 2: 3E10 EN Conjugation enhances the interaction of nanoparticles with exDNA

[0449] Materials and methods

[0450] DNA-binding ability of 3E10-conjugated nanoparticles

[0451] Plasmid DNA pGL4.74 (20 μg, Promega) was linearized using BamHI to expose the phosphate group, which was then replaced with N-(3-dimethylaminopropyl)-N'-ethylcarbodiethylene Amine hydrochloride (EDC, 0.20 mg, 1.0 μmol) and N-hydroxysuccinimide (NHS, 0.17 mg, 1.5 μmol) were activated and reacted with NH2-PEG50-NH2 (0.41 mg, 3.0 μmol). Amino-terminated DNA was then thiolated with Trout's reagent (0.68 mg, 5.0 μmol) and coated onto the surface of a glass plate functionalized with maleimide groups (MicroSurfaes). To determine the binding capacity of the nanoparticles, with and without 3E10 EN The IR780-loaded nanoparticles were resuspended in PBS at 1 mg / ml and added to the surface of a glass plate. After incubation for 1 hour at room temperature, the glass plate was rinsed with water...

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Abstract

The present invention provides DNA-targeted nanocarriers for encapsulating an active agent and delivering it to extracellular DNA. The nanocarriers, for example, polymeric particles, liposomes, and multilamellar vesicles have targeting moiety that targets DNA conjugated thereto. The targeting moiety that targets DNA is typically an antibody, or variant, fragment, or fusion protein derived therefrom that binds to DNA or nucleosomes. The targeting moiety can be a circulating autoantibody that binds DNA such as those commonly found in patients with SLE. In some embodiments, the targeting moiety is antibody 3E10 or a variant, fragment, or fusion protein derived therefrom. Pharmaceutical compositions, methods of use, and dosage regimens are also provided.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of and priority to U.S.S.N. 62 / 350,423, filed June 15, 2016, which is hereby incorporated by reference in its entirety. [0003] Reference to Sequence Listing [0004] The sequence listing is filed as a text file named "YU_7013_PCT_ST25.txt", created on June 15, 2017 and having a size of 23,726 bytes, pursuant to 37 C.F.R §1.52(e)(5) Incorporated herein by reference. technical field [0005] The field of the invention is generally the field of targeted drug delivery, in particular the delivery of drugs to sites of extracellular DNA such as those found in and near tumors, wounded and damaged tissues, ischemic tissues, and sites of infection . Background technique [0006] first nanomedicine Doxorubicin (DOX) formulation in liposomal nanocarriers was approved by the FDA in 1995 for the treatment of human patients with AIDS-related Kaposi's sarcoma (Barenholz et al. , Journal o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/68A61K47/69A61P35/00A61P37/00A61P25/00A61P31/00A61P21/00A61P3/00
CPCA61K47/6843A61K47/6935A61K47/6937A61P35/00A61K31/502A61K31/704C07K2317/622C07K2317/77C07K2317/35C07K2317/73C07K16/44
Inventor 周江兵J·汉森
Owner YALE UNIV
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