Compact multifunctional ligand to enhance colloidal stability of nanoparticles

Inventors

Medintz, Igor L.Susumu, KimihiroStewart, Michael H.

Assignees

US Department of Navy

Publication Number

US-8512755-B2

Publication Date

2013-08-20

Expiration Date

2031-08-15

Interested in licensing this patent?

MTEC can help explore whether this patent might be available for licensing for your application.


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 discloses a design of compact multifunctional ligands for nanoparticles, such as quantum dots (QDs) and metallic nanoparticles, that enhance the colloidal stability of the nanoparticles across a wide pH range and under high salt concentrations. These ligands allow self-assembled biomolecular conjugates with QDs which remain stable in biological environments and maximize energy transfer by minimizing the distances between nanoparticles and donors or acceptors attached to the ligands or assembled on their surfaces.

The problem addressed involves the limitations of previously used ligands for nanoparticles, which often provide colloidal stability only over narrow pH ranges and increase the hydrodynamic size of nanoparticles due to long PEG chains or other bulky components. Existing ligands such as DHLA provide good attachment but have limited aqueous solubility and pH stability, while PEG-based ligands enlarge nanoparticle size and hinder efficient conjugation and energy transfer. There remains a need for compact multifunctional ligands that impart a desired combination of aqueous solubility, extended pH and salt stability, biocompatibility, functionality, and reduced hydrodynamic size.

The invention provides a new class of compact ligands with a modular design incorporating anchoring modules (such as thioctic acid or dihydrolipoic acid groups) and functionalization modules (including amino, carboxyl, hydroxy, and sulfo groups) which impart inherent zwitterionic character. This design enables aqueous solubility across a wide pH range mainly from about pH 4 to 13, salt stability, and chemical handles for further bioconjugation. The compact ligands are smaller and simpler to synthesize than PEG-based ligands, resulting in nanoparticle coatings that maintain small hydrodynamic diameters (less than 10 nm for 4-nm core QDs) while providing long-term colloidal stability, minimal toxicity, and facilitating direct conjugation of biomolecules such as His-tagged proteins.

Claims Coverage

The patent includes multiple claims and features several independent claims relating to compositions comprising the novel compounds and methods of modifying nanoparticles using these compounds. Below are the main inventive features from these independent claims.

Composition comprising novel compact ligands

A composition comprising compounds characterized by specific chemical structures that include anchoring modules derived from thioctic acid or dihydrolipoic acid and functionalization arms selected from 2-hydroxyethyl, 3-carboxypropyl, 2-carboxyethyl, 2-2-aminoethyl, and 2-sulfoethyl, forming zwitterionic ligands with both carboxyl and tertiary amine groups.

Nanoparticles coated with the novel ligands

Nanoparticles, including quantum dots or metallic nanoparticles, coated with the compact multifunctional ligands, resulting in coated nanoparticles having hydrodynamic diameters less than 10 nm and facilitating attachment of cell penetrating peptides.

Method of modifying nanoparticles with the novel ligands

A method comprising contacting a nanoparticle, such as a quantum dot or metallic nanoparticle, with the novel multifunctional compact ligands to coat the nanoparticles, optionally further attaching a cell penetrating peptide, and conferring pH and salt stability.

The independent claims collectively cover the novel zwitterionic compact multifunctional ligand compounds, their use in coating nanoparticles to achieve small hydrodynamic size and stability, and methods for modifying nanoparticles by contacting them with these compounds, including optional conjugation with cell penetrating peptides.

Stated Advantages

Provides long-term colloidal stability across a wide pH range (approximately pH 4 to pH 13).

Maintains small hydrodynamic nanoparticle size, reducing steric hindrance compared to PEGylated ligands.

Allows direct self-assembly of His-tagged proteins and peptides onto nanoparticle surfaces.

Offers a modular design enabling facile and high-yield synthesis in bulk quantities.

Exhibits broad tolerance to high ionic strength (salt stability).

Provides chemical handles (e.g., carboxyl groups) for further functionalization and conjugation.

Exhibits minimal toxicity and potential for biocompatibility in biological environments.

Documented Applications

Use in biological contexts such as cellular labeling and in vivo imaging studies using quantum dots and metallic nanoparticles.

Preparation of stable nanoparticle-bioconjugates via His-tag mediated assembly of proteins and peptides for sensing, imaging, and cellular probing.

Conjugation of cell penetrating peptides to nanoparticle-ligand constructs to facilitate cellular uptake via endocytic pathways.

Microinjection delivery of ligand-coated quantum dots into cells for intracellular imaging and sensing applications.

Surface functionalization of gold nanoparticles leading to well-defined particle dispersions useful in cellular and biochemical assays.

JOIN OUR MAILING LIST

Stay Connected with MTEC

Keep up with active and upcoming solicitations, MTEC news and other valuable information.