Functionalized liposomes useful for the delivery of bioactive compounds
Inventors
Ventosa Rull, Leonor • Veciana Miró, Jaume • Cabrera Puig, Ingrid • ELIZONDO SAEZ DE VICUÑA, ELISA • Melgarejo Diaz, Marta • Royo Expósito, Miriam • Albericio Palomera, Fernando • Pulido Martinez, Daniel • Sala Vergés, Santiago • CORCHERO NIETO, Jose Luis • Schwartz Navarro, Simón • Abasolo Olaortua, Ibane • Villaverde Corrales, Antonio Pedro
Assignees
FUNDACIO PARC CIENTIFIC DE BARCELONA • Consejo Superior de Investigaciones Cientificas CSIC • Universitat Autonoma de Barcelona UAB • Universitat de Barcelona UB • Fundacio Privada Institut de Recerca Biomedica IRB • Centro de Investigacion Biomedica en Red CIBER • Fundacio Institut de Recerca Hospital Universitari Vall dHebron
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Publication Number
US-9744247-B2
Publication Date
2017-08-29
Expiration Date
Abstract
The invention relates to conjugates in which a sterol is functionalized by an ether bond with a water-soluble polymer to which a guiding ligand is bound. These conjugates improve the physico-chemical and delivery properties of their carrying vesicles, making these more stable, homogeneous and effective. A method for their preparation, a pharmaceutical composition containing said liposomes, and their therapeutic use are described as well.
Core Innovation
The invention relates to sterol–polyethylene glycol conjugates for functionalizing liposomes. A conjugate includes a sterol, a chain of polyethylene glycol covalently bound by its proximal end to the sterol via an alkyl ether bond, and a guiding ligand covalently bound to the distal end, wherein the guiding ligand is a peptide. The guiding ligand is capable of selectively binding one or several receptors present in a target cell.
A key aspect is that the polyethylene glycol is linked to the sterol through an alkyl ether bond rather than a carbamate-type linkage. The document states that ether-linked conjugates yield more stable liposome suspensions, characterized by slower sedimentation, and more homogeneous particle-size distributions, described as monomodal rather than bimodal in comparison to carbamate-linked systems.
The document further states improved cellular internalization and therapeutic delivery for liposomes functionalized with the ether-linked sterol–PEG–peptide conjugates. Peptide guiding ligands include RGD-containing peptides, including cRGDfK (SEQ ID NO: 1) with the specified L- and D-amino acid composition, and therapeutic use includes α-galactosidase (GLA) for Fabry disease, including effects described in terms of Gb3 loss and improved enzymatic activity in the provided in vitro context.
Claims Coverage
The document includes one independent claim directed to a sterol–PEG–peptide conjugate with an alkyl ether bond, and dependent claims add quantitative and structural constraints and specific therapeutic/liposomal contexts. Across the inventive subject matter, the core inventive features are the ether-linked sterol–PEG architecture combined with a distal peptide guiding ligand that selectively binds receptors on target cells.
Ether-bonded sterol–PEG conjugate
A conjugate comprising a sterol and a chain of polyethylene glycol whose proximal end is covalently bound to the sterol via an alkyl ether bond.
Distal peptide guiding ligand for receptor selectivity
A conjugate in which a guiding ligand capable of selectively binding to one or several receptors present in a target cell is covalently bound to the distal end of the polyethylene glycol, wherein the guiding ligand is a peptide.
RGD-containing peptide guiding ligand
The conjugate in which the guiding ligand includes an RGD sequence.
Specific RGD peptide sequence
The conjugate in which the guiding ligand is a peptide with sequence SEQ ID NO: 1.
Functionalized liposome with defined particle size and Z potential
A liposome characterized by an average particle size between 25 and 500 nanometers and an average Z potential (absolute value) between 20 and 90 mV.
Fabry disease treatment with therapeutically effective liposome dose
A method that administers a therapeutically effective amount of the liposome of claim 9, formulated with pharmaceutically acceptable excipients or carriers, to a subject with Fabry disease.
Overall, the claim set centers on an ether-linked sterol–PEG conjugate coupled to a distal peptide guiding ligand that selectively binds receptors on target cells, with further dependent refinements specifying RGD-based peptide guidance, liposome particle-size and Z-potential thresholds, and use in a Fabry disease treatment context.
Stated Advantages
More stable liposome suspensions with slower sedimentation.
More homogeneous particle-size distributions described as monomodal (as contrasted with bimodal for carbamate-linked systems).
Improved cellular internalization and therapeutic delivery.
Improved enzymatic activity and Gb3 loss in the provided in vitro context (as stated in the document summary).
Documented Applications
Therapeutic delivery in Fabry disease, including use of α-galactosidase (GLA) and effects described in terms of Gb3 loss and enzymatic activity in vitro.
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