Immunostimulatory micelle compositions

A composition, micellar technology, applied in the field of treatment of diseases and disorders such as cancer, which can solve the problems of accelerating blood clearance of antibodies and destroying the effectiveness of therapeutic nanoparticle delivery systems

Pending Publication Date: 2022-05-17
DANMARKS TEKNISKE UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, repeated injections of therapeutic nanoparticle compositions have been shown to trigger the antibody-accelerated blood clearance (ABC) phenomenon, especially for PEG-based liposomes, which undermines the utility of therapeutic nanoparticle delivery systems

Method used

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  • Immunostimulatory micelle compositions
  • Immunostimulatory micelle compositions
  • Immunostimulatory micelle compositions

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0361] Example 1: Preparation of micelles and liposomes

[0362] Micelles were made from 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG2000) obtained from Lipoid GmbH. Briefly, lipids were dissolved in tert-butanol:water (9:1 by volume) to a final concentration of 5-10 mM in glass vials and placed under magnetic stirring and heated to 50°C until completely dissolved . Solvent was removed by freezing the vial in liquid nitrogen followed by lyophilization overnight. Initial contact between the lipid and solvent was established by dispersing the dried lipid in a buffer solution containing 150 mM NaCl, 10 mM phosphate (pH = 7.4), exposing the vial to gentle vortexing, followed by exposure to sonication Micelles were prepared for 30 minutes to ensure the formation of micellar structures. The dispersion was vortexed again, and then the dispersion was exposed to further sonication for 30 minutes. Store micelles at 4 °C until use an...

Embodiment 2

[0364] Example 2: Preparation of micelles incorporating toll-like receptor 7 (TLR7) agonists

[0365] 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG2000) obtained from Lipoid GmbH and TLR7 agonist 1v270 ( C57H93N6O12P, Mw=1085.4, (2,3-bis(oleoyloxy)propyl phosphate 2-(4-((6-amino-2-(2-methoxyethoxy)-8-oxo- 7H-purin-9(8H)-yl)methyl)benzamido)ethyl ester) into micelles. The chemical structure of 1v270 is outlined in Figure 2. Briefly, lipids were dissolved in tert-butanol: In water (volume ratio 9:1), reach a final concentration of 5-10 mM (DSPE-PEG2000) or 1-3 mM (1v270) in a glass vial, and place under magnetic stirring and heat to 50 degrees Celsius until completely dissolved. The two lipid dispersions were then mixed to the desired ratio (95:5 to 80:20 DSPE-PEG2000:1v270 molar ratio). The solvent was removed by freezing the vial in liquid nitrogen and then lyophilized overnight. Lipids were dispersed in a buffer solution con...

Embodiment 3

[0366] Example 3: Characterization of composition-dependent micelle size and surface charge

[0367] Micelles were prepared as outlined in Figure 1 in an attempt to prepare stable formulations of the TLR7 agonist 1v207 in aqueous solvents allowing injection in saline buffer. Micelles were prepared as described in Example 1+2, and prepared by 5% (w / w) glucose, 10mM HEPES, 1mM CaCl 2 The size (diameter) is measured in nanometers (nm) by dynamic light scattering in a buffer consisting of MilliQ water pH 7.4. The micelles without 1V207 had an average size (according to particle distribution by number) of 11.5 nm, while the micelles containing 1V270 had a particle size ranging from 11.5 nm to 13-14 nm when the 1V270 content was increased from 5% to 20%. Average size (according to distribution by number of particles) (Figures 1B and 1C). with CaCl 2 The zeta potential of empty micelles, measured in glucose buffer in , was about -4 mV, but became more negative when the anionic 1V2...

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Abstract

The present invention relates to immunostimulatory micelle compositions, and their use in the treatment of diseases and disorders, such as cancer. In particular, the present invention relates to micelle compositions comprising a TLR7 agonist, such as 1V270.

Description

technical field [0001] The present invention relates to immunostimulatory micellar compositions, and their use in the treatment of diseases and disorders such as cancer. In particular, the invention relates to micellar compositions comprising TLR7 agonists such as 1V270. Background technique [0002] Toll-like receptors (TLRs) are a class of receptors expressed on various cell types and play a key role in the innate immune system. Upon activation, TLRs activate signal transduction pathways involved in immune activation. Several mammalian TLRs and their many agonists have been identified. For example, guanine- and uridine-rich single-stranded RNAs have been identified as natural ligands for TLR7. In addition, several low-molecular-weight activators of TLR7 have been identified, including imidazoquinolines and purine-like molecules. Although TLR stimulation initiates a common signaling cascade (involving the adapter protein MyD88, the transcription factor NFκB, and pro-inf...

Claims

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Application Information

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IPC IPC(8): A61K9/107A61K31/522A61K31/685A61K39/00A61K39/395A61K45/06A61K47/10A61K47/24A61K47/34A61P29/00A61P31/00A61P35/00A61P37/02A61P37/08
CPCA61K9/1075A61K9/0019A61K45/06A61K31/685A61K47/24A61K47/34A61K47/10A61K39/001186A61K39/001194A61K39/3955A61P35/00A61P31/00A61P29/00A61P37/02A61P37/08A61K39/00117A61K39/00119A61K2300/00A61K31/522A61K31/704A61N2005/1098A61K9/1271A61K9/1272A61K2039/55555A61K39/39C07K16/2818A61K2039/54A61K2039/505A61K31/683A61K39/39558C07K16/2803C07K16/2863C07K16/2887C07K16/2896C07K16/32C07K2317/21C07K2317/24
Inventor J·R·亨里克森T·L·安德森S·S·詹森L·帕哈米法尔R·明特·迪思马尔A·E·汉森C·斯塔万斯贝格E·克里斯滕森
Owner DANMARKS TEKNISKE UNIV
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