Lipid-peptide-polymer conjugates and nanoparticles thereof
Inventors
Xu, Ting • Dong, He • Shu, Jessica
Assignees
Lawrence Berkeley National Laboratory • University of California San Diego UCSD
Publication Number
US-9044514-B2
Publication Date
2015-06-02
Expiration Date
2031-03-11
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Abstract
The present invention provides a conjugate having a peptide with from about 10 to about 100 amino acids, wherein the peptide adopts a helical structure. The conjugate also includes a first polymer covalently linked to the peptide, and a hydrophobic moiety covalently linked to the N-terminus of the peptide, wherein the hydrophobic moiety comprises a second polymer or a lipid moiety. The present invention also provides helix bundles form by self-assembling the conjugates, and particles formed by self-assembling the helix bundles. Methods of preparing the helix bundles and particles are also provided.
Core Innovation
The invention provides a conjugate comprising a peptide of about 10 to 100 amino acids that adopts a helical structure, a first polymer covalently linked to the peptide at an amino acid other than the N- or C-terminus, and a hydrophobic moiety covalently linked to the N-terminus of the peptide. The hydrophobic moiety includes a second polymer or a lipid moiety having from 1 to 6 C10-20 alkyl groups. These conjugates self-assemble to form helix bundles composed of from 2 to 6 conjugates, which further self-assemble into nanoparticles made up of about 20 to 200 conjugates.
The problem addressed is the difficulty in preparing monodisperse nanoparticles with diameters in the range of tens of nanometers that are stable at room temperature and low cost. Existing nanoparticles like liposomes, dendrimers, polymersomes, and synthetic virus-like particles have size, stability, synthesis complexity, and purification challenges that limit their extensive use. The invention overcomes these challenges by providing lipid-peptide-polymer conjugates capable of forming stable, monodisperse nanoparticles of about 10-20 nm diameter, overcoming limitations of particle size, aggregation, and storage instability.
The conjugates utilize coiled-coil 3-helix bundle-forming peptides with hydrophobic di-alkyl tails at the N-terminus and hydrophilic polymers such as polyethylene glycol coupled to the peptide, forming amphiphilic molecular building blocks with cone-shaped geometry. Upon dissolution in aqueous buffer, these conjugates phase separate and self-assemble into nanoparticles. The peptide helix acts as a rigid scaffold that positions polymer chains radially, generating spring-like forces that enhance micelle stability through negative lateral pressure. This design allows chemical specificity unavailable in liposomes, tunable size and shape, and the inclusion of cargo such as therapeutic and diagnostic agents.
Claims Coverage
The patent includes five independent claims that define inventive features centered around the conjugate composition, helix bundles, particles formed, and methods of particle formation.
Conjugate composition with specified peptide, polymer, and hydrophobic moiety
A conjugate comprising a helix bundle-forming helical peptide selected from SEQ ID NO: 1, 2, or 5; a first polymer covalently linked at an amino acid other than the N- or C-terminus; and a hydrophobic moiety covalently linked to the N-terminus of the peptide, consisting of a second polymer or a lipid moiety with 1 to 6 C10-20 alkyl groups.
Helix bundle formed by multiple conjugates
A helix bundle comprising from 2 to 6 conjugates of the specified conjugate composition.
Particle formed by assembly of conjugates
A particle comprising from about 20 to about 200 conjugates of the specified conjugate composition, optionally including therapeutic agent, diagnostic agent, DNA, or oligonucleotides.
Method of forming particles by self-assembly
A method comprising contacting a plurality of the specified conjugates such that they self-assemble to form the particles.
The claims cover the composition of conjugates with defined peptide, polymer, and hydrophobic components, their assembly into helix bundles and larger nanoparticles, and methods for forming these nanoparticles by self-assembly, including particles carrying therapeutic or diagnostic cargos.
Stated Advantages
The nanoparticles formed are monodisperse with diameters in the tens of nanometers range, addressing the challenge of producing small, uniform particles.
The particles exhibit excellent thermal stability and long shelf-life at room temperature, eliminating the need for refrigeration.
The assembly process is straightforward and occurs by simple dissolution in aqueous media without complex multi-step processes.
The peptide helix imparts chemical specificity and functionalization capability unavailable with liposomes and polymersomes.
The design allows for tunable size, shape, and chemical functionalization for targeted delivery applications.
The nanoparticles can stably encapsulate hydrophobic drugs or conjugate therapeutic and diagnostic agents with minimal leakage over time.
Documented Applications
Biomedical and pharmaceutical applications, such as drug delivery including chemotherapeutic agents like doxorubicin and rapamycin.
Diagnostic agent delivery including imaging agents and radionuclides for medical imaging techniques.
Gene therapy and nucleic acid delivery, including DNA, RNA, oligonucleotides, and vaccines.
Treatment of diseases including cancer (various types including brain cancer such as Glioblastoma multiforme) and Parkinson's disease.
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