Compact multifunctional ligand to enhance colloidal stability of nanoparticles
Inventors
Medintz, Igor L. • Susumu, Kimihiro • Stewart, Michael H.
Assignees
Publication Number
US-9304124-B2
Publication Date
2016-04-05
Expiration Date
2031-08-15
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Abstract
A ligand design allows compact nanoparticle materials, such as quantum dots (QDs), with excellent colloidal stability over a wide range of pH and under high salt concentrations. Self-assembled biomolecular conjugates with QDs can be obtained which are stable in biological environments. Energy transfer with these ligands is maximized by minimizing distances between QDs/nanoparticles and donors/acceptors directly attached to the ligands or assembled on their surfaces.
Core Innovation
The invention relates to a compact multifunctional ligand design for coating nanoparticles, such as quantum dots (QDs), to enhance their colloidal stability over a wide range of pH values and high salt concentrations. This ligand design allows the formation of self-assembled biomolecular conjugates with QDs that maintain stability in biological environments. Furthermore, energy transfer with these ligands is maximized by minimizing distances between QDs or nanoparticles and donors or acceptors directly attached to or assembled on the ligand surfaces.
The problem being addressed is the limited colloidal stability and increased size issues associated with existing nanoparticle ligands. Previous ligands such as DHLA provide limited pH stability mostly in basic conditions and PEG-based ligands, while offering wider pH range stability, introduce undesirably large hydrodynamic size and steric hindrance that impair conjugation and energy transfer. There remains a need for compact multifunctional ligands that combine good colloidal stability across broad pH and ionic conditions, small hydrodynamic size, strong nanoparticle surface attachment, and accessible functional groups for bioconjugation without toxicity.
The invention solves these problems by introducing a new class of compact ligands that rely on inherent zwitterionic character via amino and carboxyl groups for aqueous solubility over a broad pH range. These ligands incorporate anchoring modules such as thioctic acid (TA) or dihydrolipoic acid (DHLA) for strong surface attachment and functionalization modules including amine, carboxyl, hydroxyl, and sulfonate groups. This design reduces the hydrodynamic volume compared to PEG-based ligands, maintains colloidal stability from acidic to basic pH (about pH 4 to 13), tolerates high ionic strength, and supports functionalization including direct His-tagged protein conjugation and chemical coupling, while avoiding toxicity.
Claims Coverage
The patent includes three main independent claims that cover compositions of compact multifunctional ligands, nanoparticles coated with those ligands, and methods of modifying nanoparticles with the ligands.
Composition of compact multifunctional ligands
A composition comprising compounds with chemical structures having anchoring modules (e.g., thioctic acid or dihydrolipoic acid) linked via amide bonds to functional arms selected from 2-hydroxyethyl, 3-carboxypropyl, 2-carboxyethyl, 2-2-aminoethyl, or 2-sulfoethyl groups. These ligands possess zwitterionic character providing colloidal stability and solubility over wide pH and ionic strength ranges.
Nanoparticles coated with the compact ligands
Nanoparticles, including quantum dots or metallic nanoparticles, coated with the compact multifunctional ligand composition. These coated nanoparticles can have small hydrodynamic diameters (less than 10 nm) and can further comprise cell penetrating peptides attached. The coated nanoparticles retain colloidal stability and functionality in biological environments.
Method of modifying nanoparticles using the compact ligands
A method comprising contacting nanoparticles with the compact multifunctional ligand composition to modify their surfaces. This method can include attaching cell penetrating peptides, using ligands that have both carboxyl and tertiary amine groups, and applying to quantum dots or metallic nanoparticles to achieve stable functionalized nanoparticles.
The claims collectively cover the specific chemical compositions of the compact ligands, their use to coat nanoparticles resulting in stable, compact, functionalized nanomaterials, and methods of preparing such modified nanoparticles, emphasizing structural features that provide extended colloidal and chemical stability with functional handles for bioconjugation.
Stated Advantages
Provides excellent colloidal stability of nanoparticles over a wide pH range (approximately pH 4 to 13).
Maintains nanoparticle stability in high salt concentrations and biological environments for extended periods (months).
Reduces hydrodynamic size of ligand-coated nanoparticles compared to PEG-based ligands, facilitating efficient energy transfer and direct conjugation with biomolecules.
Allows direct self-assembly of His-tagged proteins and peptides to nanoparticle surfaces due to minimal steric hindrance.
Possesses multiple ionizable groups that enhance aqueous solubility without introducing toxicity.
Has a modular chemical design that enables facile synthesis, chemical functionalization, and compatibility with various nanoparticles including quantum dots and gold nanoparticles.
Documented Applications
Cellular labeling and in vivo imaging using biocompatible quantum dots stabilized with the compact ligands.
Assembly of His-tagged peptides, proteins, and DNA molecules onto quantum dot surfaces for biosensing and imaging applications.
Conjugation of fluorescent dye-labeled proteins and peptides to nanoparticles to facilitate Förster resonance energy transfer (FRET) assays.
Delivery of quantum dots into cells via microinjection and cell penetrating peptide-mediated cellular uptake.
Functionalization and colloidal stabilization of gold nanoparticles for biological and chemical applications.
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