Nucleolin-targeting aptamers and methods of using the same
Inventors
Sullenger, Bruce A. • Goldstein, Michael • Pratico, Elizabeth D. • Kastan, Michael • Gray, Bethany
Assignees
Publication Number
US-12312588-B2
Publication Date
2025-05-27
Expiration Date
2038-09-10
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Abstract
Provided herein are compositions including aptamers capable of binding to and/or inhibiting the activity of nucleolin. Methods of treating cancer in a subject by administering such compositions are also provided.
Core Innovation
The invention provides aptamers—single-stranded oligonucleotides—that specifically bind to and/or inhibit nucleolin, a protein essential for the repair of DNA double-stranded breaks. These aptamers are defined by having high sequence identity to specified SEQ ID numbers and can be unmodified or contain various nucleotide modifications to enhance stability, detection, or therapeutic potential. The compositions may include aptamers alone, as dimers, trimers, or tetramers, and may further combine with carriers or agents such as stability agents or detectable moieties.
The patent addresses the problem that most human tumors overexpress nucleolin on the cell surface, making nucleolin a tumor-preferential target. Inhibiting nucleolin in cancer cells results in sensitization to DNA-damaging agents, potentially increasing the effectiveness of therapies like ionizing radiation or chemotherapeutic agents. There is a need for selective agents that bind to and/or inhibit nucleolin to facilitate cancer treatments and possibly deliver therapeutic or diagnostic agents to the nucleus.
Methods are described for using these nucleolin-binding aptamers to treat cancer in a subject by administering a therapeutically effective amount of the compositions. Additional methods include labeling or inhibiting nucleolin by contacting it—either in vitro or in vivo—with the aptamer-containing compositions. The invention encompasses aptamers with high binding affinities, optional modifications for improved therapeutic or diagnostic performance, and combinatorial use with chemotherapeutic agents or radiation.
Claims Coverage
There are three independent claims covering three main inventive features.
Aptamer comprising a polynucleotide with specified sequence identity and nucleotide modification
An aptamer comprising: - A polynucleotide having at least 80% sequence identity to any one of SEQ ID NOS: 1-12, 22-473, 475-479, 481, 483-484, 486, 490-502, or 504-515. - The polynucleotide being either unmodified or in a modified form that contains at least one nucleotide base modification. The modifications include, but are not limited to, 2′fluoro, 2′O-methyl, 5′ or 3′ modifications.
Dimer, trimer, or tetramer comprising the aptamer
A composition comprising: - A dimer, trimer, or tetramer that includes the aptamer as defined above, i.e., a polynucleotide with at least 80% sequence identity to the specified sequences and optionally comprising a nucleotide modification. The claim includes these higher-order aptamer constructs for potential increased stability or function.
Method for treating cancer by administering the aptamer composition
A method comprising: - Treating cancer in a subject by administering a therapeutically effective amount of the aptamer or aptamer-containing composition as defined in the claims. The method may be performed in mammals and optionally in combination with chemotherapeutic agents or radiation therapy.
The inventive features are directed to a new class of nucleolin-specific aptamers with defined sequence identity and optional modifications, higher-order aptamer assemblies, and methods for using these compositions in cancer treatment.
Stated Advantages
Aptamers can specifically sensitize tumor cells to DNA-damaging agents while sparing normal cells, targeting and internalizing into cancerous cells.
Aptamers have advantages over traditional antibody targeting agents, including ease of synthesis, amenability to chemical modification, smaller size for efficient tumor penetration, and ability to distinguish proteins differing by just a few amino acids.
Aptamers can facilitate delivery of agents to the nucleus of a cell, enabling targeted therapeutic or diagnostic interventions.
Modified aptamers exhibit increased stability and extended circulation time in vivo.
Aptamer compositions can serve as cancer-specific radio- and chemosensitizers, potentially improving current cancer therapy regimens.
Documented Applications
Treatment of cancer in subjects, including administering aptamer compositions to sensitize tumors to DNA-damaging agents such as chemotherapeutics or radiation therapy.
Use of aptamer compositions for labeling or inhibiting nucleolin, either in vitro (by adding to cells) or in vivo (by administering to subjects).
Facilitation of agent delivery to the nucleus of a cell using nucleolin-binding aptamers.
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