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Composition for long-acting supplement of arginine and neutralization of acid environment by targeting immune cells and application thereof

A technology of immune cells and compositions, which is applied in the field of preparation of anti-tumor drugs, can solve the problems of weakening proliferation ability, etc., achieve the effects of starvation tumor weakening, enhancing anti-tumor immune response, and good clinical application potential

Active Publication Date: 2022-07-26
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, melanoma cells resistant to BRAF inhibitors showed a metabolic shift from glucose to arginine dependence accompanied by increased expression of CAT-2, and silencing CAT-2 expression significantly weakened their proliferative ability (Mol Oncol.2017 Dec;11(12):1806-1825)

Method used

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  • Composition for long-acting supplement of arginine and neutralization of acid environment by targeting immune cells and application thereof
  • Composition for long-acting supplement of arginine and neutralization of acid environment by targeting immune cells and application thereof
  • Composition for long-acting supplement of arginine and neutralization of acid environment by targeting immune cells and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Embodiment 1 A kind of preparation method of composition (microsphere dosage form)

[0042] Composition of the composition (microsphere dosage form):

[0043] L-Arginine 5mg

[0044] CAT-2 siRNA / Lipo8000 complex 7nmol (based on siRNA content)

[0045] Poly(lactic-co-glycolic) acid, 1.5w, 50:50 200mg.

[0046] Dissolve the prescription amount of L-arginine and CAT-2 siRNA / Lipo8000 complex in 200μL of pure water as the inner water phase; the prescription amount of Poly(lactic-co-glycolic)acid is dissolved in 4mL dichloromethane , as the oil phase. The inner water phase was added to the oil phase, vortexed for 30 seconds and then phacoemulsified with a 100W probe for 2 minutes. The obtained W / O emulsion was added to 40 mL of an aqueous solution containing 2% PVA, and after high-speed stirring, it was added to 100 mL of an aqueous solution containing 0.2% PVA, and stirred at low speed overnight to remove dichloromethane and complete the solidification of the microsphere...

Embodiment 2

[0047] Example 2 In vitro release of the composition (microsphere dosage form)

[0048] In this example, on the basis of Example 1, the composition (microsphere dosage form) was taken, resuspended in a PBS solution with a pH of 7.4, placed in a constant temperature shaking box at 37°C, sampled at a set time, and collected after high-speed centrifugation In the supernatant, the L-arginine content was determined by HPLC, and the in vitro release behavior of the composition (microsphere dosage form) was investigated. The release profile showed that the composition (microsphere dosage form) exhibited sustained release capability for up to 21 days in PBS solution with pH 7.4 at 37°C ( figure 1 ).

[0049] The HPLC conditions used were:

[0050] Mobile phase: methanol: 0.01M sodium pentanesulfonate=(10:90), 1 mL / min; detection wavelength: 206 nm; chromatographic column: Agilent ZORBAX C18 column (4.6×250 mm, 5 μm).

Embodiment 3

[0051] Embodiment 3 A kind of preparation method of composition (multivesicular liposome dosage form)

[0052] Composition of the composition (multivesicular liposome dosage form):

[0053]

[0054] Dissolve the prescription amount of L-arg and CAT-2 shRNA plasmid / Lipo8000 complex in 1mL of pure water as the first aqueous phase; the prescription amount of egg yolk lecithin E80, cholesterol and α-tocopherol are dissolved in 2mL of dichloromethane , as the oil phase. The first water phase was added to the oil phase, and the 200W probe was ultrasonically emulsified for 4 minutes to prepare a W / O emulsion. The 5 mg / mL sodium chloride aqueous solution containing 2% sodium dodecyl sulfate was used as the second water phase, the prepared W / O emulsion was added to 10 mL of the second water phase, and the W / O / W was prepared by stirring at a low speed 20 mL of 5 mg / mL sodium chloride solution was added to it, stirred in a water bath at 25°C for 5 hours, and the organic solvent was ...

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Abstract

The invention provides a composition for long-acting supplement of arginine and neutralization of an acid environment for targeted immune cells and application thereof. The L-arginine sustained-release preparation consists of L-arginine, a cationic amino acid transporter 2 inhibitor and a pharmaceutically acceptable sustained-release drug storage depot carrier. According to the invention, L-arginine and a cationic amino acid transporter 2 inhibitor are co-loaded in a sustained-release drug reservoir to prepare an antitumor drug. According to the invention, by locally injecting into a tumor part, cationic amino acid transporter protein 2 of cancer cells and immunosuppressive cells is inhibited, and alkaline L-arginine is slowly released in a tumor in a long-acting manner, so that targeted tumor killing immune cell L-arginine supplementation and tumor cell and immunosuppressive cell L-arginine hunger are realized; and the alkalinity of the L-arginine is utilized to neutralize the acidic environment, so that the immunity-promoting improvement on the tumor microenvironment is completed on the two aspects of acidity and nutrition, the anti-tumor immune response can be remarkably enhanced, and the tumor treatment effect can be improved.

Description

technical field [0001] The invention belongs to the field of pharmaceutical preparations, and relates to a composition and application for long-term supplementation of arginine targeting immune cells and neutralizing acid environment, which are mainly used for preparing antitumor drugs. Background technique [0002] In the presence of sufficient oxygen, tumor cells still prefer the sugar metabolism mode of anaerobic glycolysis to synthesize the energy they need, and subsequently produce a large amount of lactic acid, a phenomenon known as the "Warburg" effect. To maintain intracellular homeostasis, tumor cells efflux lactate into the intercellular space, resulting in interstitial acidification. The resulting weak acid milieu is thought to be highly associated with high invasiveness and metastasis of cancer cells, as well as resistance to various therapies including chemotherapy and immunotherapy. More importantly, low pH values ​​are toxic to lymphocytes, inhibiting the pro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/06A61K31/198A61K39/395A61K31/7088A61P35/00
CPCA61K45/06A61K31/198A61K39/395A61K31/7088A61K39/3955A61P35/00A61K2300/00Y02A50/30
Inventor 游剑张俊镭李青坡
Owner ZHEJIANG UNIV
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