Lipid vesicle compositions and methods of use
Inventors
Irvine, Darrell J. • MOON, Jaehyun
Assignees
Massachusetts Institute of Technology • US Army Medical Research and Development Command
Publication Number
US-9149432-B2
Publication Date
2015-10-06
Expiration Date
2031-03-19
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Abstract
The invention provides delivery systems comprised of stabilized multilamellar vesicles, as well as compositions, methods of synthesis, and methods of use thereof. The stabilized multilamellar vesicles comprise terminal-cysteine-bearing antigens or cysteine-modified antigens, at their surface and/or internally.
Core Innovation
The invention provides delivery systems comprised of stabilized multilamellar vesicles, including interbilayer-crosslinked multilamellar vesicles (ICMVs) that have crosslinked lipid bilayers. These vesicles comprise terminal-cysteine-bearing antigens or cysteine-modified antigens at their surface and/or internally, enabling enhanced encapsulation and delivery of agents such as protein antigens and adjuvants with slow and sustained release kinetics suitable for in vivo applications.
The background recognizes difficulties with conventional liposomes and other particle delivery systems, such as low encapsulation efficiency of macromolecular drugs, unsecured retention leading to premature leakage, and damage to therapeutics caused by organic solvents or harsh environments during synthesis. The invention addresses these issues by providing vesicles with improved loading capacity, the ability to simultaneously carry hydrophobic and hydrophilic agents, and longer release profiles using aqueous-based synthesis that avoids harsh conditions.
The invention further provides compositions comprising these stabilized multilamellar lipid vesicles, methods for their synthesis involving divalent cation-induced fusion of liposomes and crosslinking of adjacent bilayers, and their use in stimulating immune responses. The vesicles can carry antigens such as malaria antigen (VMP), adjuvants including TLR agonists, and can be surface-modified with polyethylene glycol (PEG). Functionalized lipids such as maleimide phosphoethanolamine are employed to facilitate crosslinking and conjugation.
Claims Coverage
The claims include one independent claim covering multilamellar lipid vesicles with terminal-cysteine-bearing antigens and covalent crosslinks between lipid bilayers, and related compositions and methods. The inventive features focus on the structural composition of the vesicles, the antigen presentation, and functionalization.
Multilamellar lipid vesicle with terminal-cysteine-bearing antigen and covalent interbilayer crosslinks
A multilamellar lipid vesicle comprising a terminal-cysteine-bearing antigen and having covalent crosslinks between at least two lipid bilayers through reactive headgroups crosslinked by covalent crosslinkers.
Inclusion of cysteine-modified antigens
The vesicle may comprise antigens that are cysteine-modified, enabling conjugation or enhanced presentation.
Use of specific lipid components
The vesicle comprises phosphocholine and/or phosphoglycerol lipids and includes maleimide functionalized lipids to provide reactive sites for crosslinking and conjugation.
Multiple antigen presentation modalities
The antigen can be a whole protein or a fragment thereof, and may be presented on the vesicle surface, encapsulated between lipid bilayers, and/or present in the vesicle core.
Incorporation of adjuvants and PEGylation
The vesicle may further comprise adjuvants and can be surface-conjugated to polyethylene glycol (PEG) to improve stability and circulation properties.
Pharmaceutical compositions including the vesicles
Compositions comprising the multilamellar lipid vesicles with or without adjuvants, pharmaceutically acceptable carriers, and optionally in lyophilized form.
The claims cover multilamellar lipid vesicles stabilized by covalent interbilayer crosslinks comprising terminal-cysteine-bearing or cysteine-modified antigens with configurations allowing internal and surface presentation, optionally including adjuvants and PEGylation, as well as pharmaceutical compositions thereof.
Stated Advantages
Greatly enhanced protein encapsulation efficiency compared to simple liposomes and lipid-coated nanoparticles.
Sustained retention and slower release of encapsulated agents in the presence of serum, enabling prolonged delivery in vivo.
Synthesis in aqueous buffer avoiding organic solvents and harsh conditions, preserving structural integrity and function of fragile agents.
Capability to co-encapsulate both protein antigens and lipid-based adjuvants within the vesicle architecture.
Induction of robust humoral and cellular immune responses, including CD8+ T-cell activation and antibody production, comparable to strong live vaccine vectors.
Documented Applications
Use as vaccine delivery systems for protein antigens, including malaria antigen (VMP) and ovalbumin as models, to elicit potent humoral and cellular immune responses.
Delivery of prophylactic, therapeutic, or diagnostic agents including protein antigens, adjuvants (such as TLR agonists), imaging agents, anti-infectives, anti-cancer agents, and immunomodulators.
Vaccination against infectious diseases (bacterial, viral, fungal, parasitic, mycobacterial), cancer immunotherapy, allergy and asthma treatment, autoimmune disease modulation, and transplant therapy.
In vitro delivery applications such as cell culture and tissue engineering requiring controlled release of bioactive agents.
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