High-density lipoprotein-like peptide-phospholipid scaffold (''HPPS'') nanoparticles

A technology of lipid nanoparticles and phospholipids, applied in the fields of nano-drugs, specific peptides, general/multifunctional contrast agents, etc.

Inactive Publication Date: 2011-04-20
UNIV HEALTH NETWORK
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

More often, treatment results in undesired side effects, for example, due to widespread toxic effects throughout the patient's body

Method used

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  • High-density lipoprotein-like peptide-phospholipid scaffold (''HPPS'') nanoparticles
  • High-density lipoprotein-like peptide-phospholipid scaffold (''HPPS'') nanoparticles
  • High-density lipoprotein-like peptide-phospholipid scaffold (''HPPS'') nanoparticles

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0203] Preparation of starting materials

[0204] 1) Size control peptide (scPep)

[0205] Utilizing commercially available N-α-Fmoc-protected amino acids, Sieber amide resin as a solid support, and using HBTU / HOBt as a carboxyl activator, by utilizing the Fmoc solid-phase peptide synthesis (SPPS) protocol (Novabiochem, Resourceforpeptidesynthesis: http: / / www.emdbiosciences.com / g.asp?f=NBC / peptideres.htm), synthesize some short peptide analogs of amphipathic helices on the peptide synthesizer PS-3 (Protein Technologies, Inc.), such as Ac- DWLKAFYDKVAEKLKEAF ("2F"), AC-DWFKAFYDKVAEKFKEAF ("4F", also referred to herein as "+4F")), and Ac-FAEKFKEAVKDYFAKFWD (-4F). After synthesizing the protected sequence, the N-terminal Fmoc of the peptide-resin was removed with 20% piperidine in N,N-dimethylformamide (DMF) to expose the terminal amine. NH was subsequently capped with 10% pyridine in THF with 10% acetic anhydride 2 -peptide-resin. The Ac-peptide-resin was further treated wi...

Embodiment 2

[0214] Method for the preparation of HPPS nanoparticles

[0215] HPPS is a macromolecular complex that is completely soluble in an aqueous buffer, such as tris saline (10 mM tris-HCl, 150 mM NaCl, 1 mM EDTA, pH 7.5). Tris saline buffer was used as solvent for HPPS in all experiments outlined below.

[0216] 1) HPPS: 3 μmol of DMPC and 0.3 μmol of cholesterol oleate were dissolved in 0.5 mL of chloroform in a test tube. use N 2 The solvent was evaporated off slowly and further dried by high vacuum. Then 1 mL of buffer (10 mM Tris-HCl, pH 8.0, containing 0.1 M KCl, 1 mM EDTA) was added to the dry tube and sonicated at 50° C. for 1 hour to form an emulsion. ScPep 0.8 μmol was added to the solution to form HPPS particles. The particles were then purified by fast protein liquid chromatography (FPLC). The FPLC method will be described below.

[0217] 2) DiR-BOA core-loaded HPPS ((DiR-BOA)HPPS): 3 μmol of DMPC, 0.3 μmol of cholesterol oleate and 0.25 μmol of DiR-BOA were dissol...

Embodiment 3

[0225] Characterization of HPPS nanoparticles prepared by 4F

[0226] 1. Particle and payload stability: Particle and payload stability is important for all nanoparticle-based drug delivery systems. Conventional lipid-based nanocarriers (eg, liposomes and lipid emulsions) cannot maintain stability at ultra-small sizes (<25 nm). The HPPS nanocarrier system of the present invention exhibits remarkable stability. As shown in Table 4, HPPS maintained their size and DiR-BOA payload over a one-month period, as determined by dynamic light scattering (see below) and spectrofluorometry. After storage at 4 °C, no payload leakage was observed. It may be noted that the percentages in the table below indicate the proportion of the population of nanoparticles with the indicated size.

[0227] Table 4. Granule Stability

[0228]

[0229] Note: The table shows the average size, percent composition and DiR-BOA fluorescence intensity

[0230] Stability of all three dosage forms (formula...

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Abstract

The present invention provides a non-naturally occurring High-Density Lipoprotein-like peptide-phospholipid scaffold (''HPPS'') nanoparticle. More particularly, the invention provides a non-naturally occurring peptide-lipid nanoscaffold comprising: (a) at least one phospholipid; (b) at least one unsaturated lipid, preferably an unsaturated sterol ester, further preferably an unsaturated cholesterol ester, further preferably cholsteryl oleate; and (c) at least one peptide, the peptide comprising an amino acid sequence capable of forming at least one amphipathic a- helix; wherein the components a), b) and c) associate to form the peptide-phospholipid nanoscaffold. In embodiments of the present invention, a cell surface receptor ligand is incorporated into the HPPS. In one embodiment, the cell surface receptor ligand is covalently bonded to the peptide scaffold of the HPPS nanoparticles. In other embodiments, a cell surface receptor ligand is coupled to a lipid anchor and is displayed on the surface of the HPPS nanoparticles by incorporation of the lipid anchor into the phospholipids monolayer of the HPPS nanoparticle. The present invention also provides pharmaceutical formulations comprising HPPS nanoparticles and methods of making the HPPS nanoparticles.

Description

technical field [0001] The present invention relates to a drug delivery system based on peptide-stabilized ultra-small nanoparticles that allows the targeted delivery of active agents for the detection and treatment (treatment) of cancer and other diseases. The active agent can be located at the core or the surface of the nanoplatform, while the cell surface receptor ligand is attached to the surface of the nanoplatform. Background technique [0002] nano platform [0003] Nanoplatforms are nanoscale (nanoscale) structures designed as general platforms to form a diverse set of multifunctional diagnostic and therapeutic devices. Such nanoscale devices typically have dimensions of less than 100 nm and are thus comparable in size to other biological entities. They are smaller than human cells (10,000 to 20,000 nm in diameter) and organelles, and are similar in size to larger biomacromolecules such as enzymes and receptors. The diameter of heme (hemoglobin), for example, is a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K17/02A61K47/48A61K48/00A61K49/00A61K51/04A61P35/00C12N15/10C12N15/11G01N33/566G01N33/574C07K14/485C07K14/71C12N15/87
CPCA61K47/48846A61K49/0056G01N33/587A61K49/0002B82Y5/00A61K49/0082G01N2800/00A61K47/48838G01N33/54346A61K49/0032A61K31/713A61K47/6917A61K47/6919A61P11/06A61P27/02A61P29/00A61P31/10A61P31/12A61P35/00
Inventor 郑岗张智红艾安·科尔宾陈涓
Owner UNIV HEALTH NETWORK
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