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Nanoparticles for chemotherapy, targeted therapy, photodynamic therapy, immunotherapy, and any combination thereof

A nanoparticle, immunotherapy technology, applied in biochemical equipment and methods, drug combinations, active ingredients of phosphorus compounds, etc., can solve problems such as difficult delivery of anticancer agents

Pending Publication Date: 2019-02-05
UNIVERSITY OF CHICAGO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, many small molecule chemotherapeutics are highly hydrophobic, making delivery of anticancer agents to tumors difficult

Method used

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  • Nanoparticles for chemotherapy, targeted therapy, photodynamic therapy, immunotherapy, and any combination thereof
  • Nanoparticles for chemotherapy, targeted therapy, photodynamic therapy, immunotherapy, and any combination thereof
  • Nanoparticles for chemotherapy, targeted therapy, photodynamic therapy, immunotherapy, and any combination thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0335] Prodrug Synthesis

[0336] Several anticancer drugs such as etoposide (ET), paclitaxel (PTX), dihydroartemisinin (DHA) and NLG919 are conjugated to cholesterol, while camptothecin (CPT) is conjugated to oleic acid via a disulfide bond ( OA). Synthesis of prodrugs can involve conversion of hydroxyl groups in lipids (Chol) or anticancer drugs (CPT) to acid chlorides, which are then combined with drugs that also have one or more hydroxyl groups (ET, PTX, NLG919) or lipids (OA) Direct conjugation. Anticancer drugs can be prepared by functionalizing first with bis(2-hydroxyethyl) disulfide (OH-S-S-OH), followed by lipid conjugation (Chol-ET, Chol-PTX, and Chol-NLG919) or first with OH -S-S-OH modification of lipids followed by anticancer drug conjugation (OA-CPT) to introduce disulfide bonds into prodrugs.

[0337]

[0338] Scheme 3. Synthesis of Chol-S-S-OH.

[0339] Chol-S-S-OH

[0340] Cholesterol (1 eq) and 4-N,N-dimethylaminopyridine (DMAP, 4 eq) in anhydrous ...

Embodiment 2

[0385] Nanoscale coordination polymer core-shell nanoparticles loaded with etoposide for the treatment of small cell lung cancer

[0386] Synthesis of Zinc Pyrophosphate Particles

[0387] First by adding 4 mL of Na 4 P 2 o 7 10H 2 O (25 mg / mL in water) and 4 mL of Zn (NO 3 ) 2 ·6H 2 O (100 mg / mL in water) forms a microemulsion. The individual microemulsions were stirred vigorously at room temperature for 15 min, and 400 μL of DOPA solution (200 mg / mL of CHCl 3 solution) added to Na 4 P 2 o 7 10H 2 O solution and continued to stir for 15 minutes until a clear solution formed. Then, Zn(NO 3 ) 2 ·6H 2 O solution was slowly added to Na 4 P 2 o 7 10H 2 O solution, the combined solution was allowed to react at room temperature for 30 minutes. The pellet was pelleted after adding 400 mL of ethanol and obtained by centrifugation at 12000 rpm for 30 minutes. The resulting precipitate was further washed once with 50% EtOH / cyclohexane, twice with 50% EtOH / THF, and...

Embodiment 3

[0398] Paclitaxel-loaded nanoscale coordination polymer core-shell nanoparticles for the treatment of non-small cell lung cancer

[0399] Preparation and characterization of Zn / PTX.

[0400] At 60°C, add 80 μL of THF solution of DSPC, cholesterol, Chol-PTX (molar ratio 1:1:0.3), DSPE-PEG2k (20 mol%) and zinc pyrophosphate bare particles to 500 μL of 30% (v / v)EtOH / H 2 O to obtain Zn / PTX. THF and EtOH were evaporated and the solution was cooled to room temperature before use. The particle size and distribution were determined by DLS, the Z-average diameter was 94.15±0.61 nm, the number-average diameter was 55.83±6.20 nm, the PDI was 0.119±0.01, and the ζ-potential was -0.67±1.02 mV. The drug loading of Zn / PTX particles was 7.14%.

[0401] In vitro cytotoxicity against non-small cell lung cancer cells

[0402] H460 and A549 cells seeded on 96-well plates at a density of 2000 cells / well were treated with Zn / PTX and free PTX at various etoposide concentrations for 72 hours....

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Abstract

Prodrugs containing lipid moieties attached to drug derivatives, such as anti-cancer drug derivatives, via linkers comprising disulfide groups are described. Also described are nanoparticles coated with a lipid layer containing the prodrugs, formulations comprising the nanoparticles, and the use of the nanoparticles in methods of treating diseases, such as cancer, alone or in combination with additional drug compounds, targeting agents, and / or immunotherapy agents, such as immunosuppression inhibitors that target the CTLA-4, PD-1 / PD-L1, IDO, LAG-3, CCR-7 or other pathways, or multiple immunosuppression inhibitors targeting a combination of such pathways. Optionally, the nanoparticles can comprise a photosensitizer or a derivative thereof and can be used in methods involving photodynamic therapy. Synergistic therapeutic effects result from combinations of multiple modalities provided by the disclosed nanoparticles and / or nanoparticle formulations.

Description

[0001] related application [0002] The presently disclosed subject matter claims the benefit of U.S. Provisional Patent Application Serial No. 62 / 339,594, filed May 20, 2016, the disclosure of which is incorporated herein by reference in its entirety. [0003] government interest [0004] This invention was made with government support under Grant No. U01CA198989 awarded by the National Institutes of Health. The government has certain rights in this invention. technical field [0005] The presently disclosed subject matter provides prodrugs (eg, prodrugs of chemotherapeutic agents) comprising a drug moiety bound to a lipid moiety via a disulfide-containing linker. The presently disclosed subject matter also provides nanoparticles comprising a prodrug. Nanoparticles can comprise, for example, a lipid coating layer comprising a prodrug and a nanoscale coordination polymer (NCP) nanoparticle core, which itself can optionally comprise a chemotherapeutic agent analog or a prodr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/66A61K9/14C12N15/11
CPCA61K31/136A61K31/337A61K31/357A61K31/4745A61K31/475A61K31/704A61K31/7048A61K31/7068C12N15/111C12N2310/11C12N2310/14C12N2310/141C12N2320/32A61K9/51A61P35/00A61K47/543A61K9/1277A61K31/66A61K45/06
Inventor 林文斌段晓品陈怀芷韩文博
Owner UNIVERSITY OF CHICAGO
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