USA As Represented by Secretary of the Navy

Florida State University Research Foundation, Inc.

Massachusetts Institute of Technology

University of Chicago

Hedi M Mattoussi

Igor L Medintz

Goutam Palui

Moungi G Bawendi

George P Anderson

Philip E Dawson

J Matthew Mauro

Jeffrey R Deschamps

James B Delehanty

Vikram C Sundar

Glyn Dawson

Juan Bautista Blanco-Canosa

Kelly Boeneman

Hyon Bin Na

Kimihiro Susumu

Michael H Stewart

Harry Tetsuo Uyeda

Wentao Wang

Dorothy Farrell

Igor Alabugin

Thomas Pons

Lorenzo Berti

Paolo Facci

Naiqian Zhan

Ryan Walters

Johanna Scheinost

Bing C Mei

Tommaso Avellini

A series of multicoordinating and multifunctional ligands optimized for the surface-functionalization of luminescent quantum dots (QDs) and gold nanoparticles (AuNPs) alike is disclosed. An L-aspartic acid precursor is modified with functionality, through simple peptide coupling chemistry, one or two lipoic acid (LA) groups and poly(ethylene glycol) (PEG) moieties in the same ligand. These ligands were combined with a new photoligation strategy to yield hydrophilic and reactive QDs that are colloidally stable over a broad range of conditions, including storage at nanomolar concentration and under ambient conditions.

Controlling the architecture, coordination, and reactivity of nanoparticle coating utilizing an amino acid central scaffold

The disclosure is directed to a set of multi-coordinating imidazole- and zwitterion-based ligands suited for surface-functionalizing quantum dots (QDs). The polymeric ligands are built using a one-step nucleophilic addition reaction between poly(isobutylene-alt-maleic anhydride) and distinct amine-containing functionalities.

Multifunctional and multicoordinating amphiphilic polymer ligands for interfacing semiconducting, magnetic, and metallic nanocrystals with biological systems

The disclosure is directed to multi-coordinating polymers as ligands that combine two distinct metal-chelating groups, lipoic acid and imidazole, for the surface functionalization of QDs. These ligands combine the benefits of thiol and imidazole coordination to reduce issues of thiol oxidation and weak binding affinity of imidazole. The ligand design relies on the introduction of controllable numbers of lipoic acid and histamine anchors, along with hydrophilic moieties and reactive functionalities, onto a poly(isobutylene-alt-maleic anhydride) chain via a one-step nucleophilic addition reaction. We further demonstrate that this design is fully compatible with a novel and mild photoligation strategy to promote the in-situ ligand exchange and phase transfer of hydrophobic QDs to aqueous media under borohydride-free conditions. Ligation with these polymers provides highly fluorescent QDs that exhibit great long-term colloidal stability over a wide range of conditions.

Photoligation of an amphiphilic polymer with mixed coordination provides compact and reactive quantum dots

A method for the photo-mediated phase transfer of inorganic nanocrystals, such as luminescent quantum dots, QDs, is provided. Irradiation, specifically UV excitation (&#x3bb;&#x3c;400 nm), promotes the in-situ ligand exchange of hydrophobic quantum dots with hydrophilic ligands and their facile transfer to polar solvents and buffer media. The technique enables transfer of quantum dots and other nanocrystal materials from hydrophobic to polar and hydrophilic solutions.

Photo-induced phase transfer of luminescent quantum dots

The disclosure is directed to polymer ligands that are optimally suited for surface-functionalizing magnetic nanoparticles. The amphiphilic polymers are prepared by coupling several amine-terminated anchoring groups, polyethylene glycol moieties, and reactive groups onto a poly(isobutylene-alt-maleic anhydride) (PIMA) chain. The reaction of maleic anhydride groups with amine-containing molecules is highly-efficient and occurs in one-step. The availability of several dopamine groups in the same ligand greatly enhances the ligand affinity, via multiple-coordination, to the magnetic NPs, while the hydrophilic and reactive groups promote colloidal stability in buffer media and allow subsequent conjugation with target biomolecules. Nanoparticles ligated with terminally reactive polymers have been easily coupled to target dyes and tested in live cell imaging with no measurable cytotoxicity.

Polymer ligands for nanoparticles

In a composition aspect of the invention, a nanoparticle coating comprises repeating polyacrylic acid monomers covalently bound together in an aliphatic chain having a plurality of carboxylic acid functional groups and modified carboxylic acid functional groups extending therefrom. A first portion of the modified carboxylic acid functional groups are modified by a PEG oligomer having a terminal methoxy functional group and a second portion of the modified carboxylic acid functional groups are modified by a PEG oligomer having at least one terminal sulfur moiety.

Polyethylene glycol based oligomers for coating nanoparticles, nanoparticles coated therewith, and related methods

In a composition aspect of the invention, a nanoparticle coating comprises repeating polyacrylic acid monomers covalently bound together in an aliphatic chain having a plurality of carboxylic acid functional groups and modified carboxylic acid functional groups extending therefrom. A first portion of the modified carboxylic acid functional groups are modified by a PEG oligomer having a terminal methoxy functional group and a second portion of the modified carboxylic acid functional groups are modified by a PEG oligomer having at least one terminal catechol group.

In a composition aspect of the invention, a nanoparticle coating comprises repeating polyacrylic acid monomers covalently bound together to form an aliphatic chain having a plurality of carboxylic acid functional groups and modified carboxylic acid functional groups extending therefrom. A first portion of the modified carboxylic acid functional groups are modified by a PEG oligomer having a terminal methoxy functional group and a second portion of the modified carboxylic acid functional groups are modified by a PEG oligomer having at least one terminal sulfur moiety.

A modular linker includes an inorganic binding entity having an affinity for a substantially inorganic substance, and an organic binding entity capable of binding with an organic substance covalently bonded thereto. The modular linker is capable of being stored in a stable condition for later use. The modular linker may be synthesized by modifying the inorganic binding entity to be covalently bonded to an organic binding entity and storing the modular linker in an inert environment from about a day up to at least 1 week. The modular linker may be conjugated to an organic substance and to a substantially inorganic substance in substantially a 1:1 ratio. The modular linker may have more than one organic binding entity covalently bonded to an inorganic binding entity or vice-versa. Also, a particular modular linker may have an organic binding entity capable of binding with a nucleic acid sequence.

Modular linkers for conjugation of organic substances to substantially inorganic substances and methods of manufacture and use thereof

A peptide attached to a nanoparticles (such as quantum dots) selectively directs the nanoparticles to neurons in a tissue or organism.

Delivery of nanoparticles to neurons

A peptide directs nanoparticles (such as quantum dots) to the plasma membrane of mammalian cells. A method of delivery of a nanoparticle to a plasma membrane of a cell includes providing to the cell a nanoparticle attached to a peptide configured to direct the nanoparticle the plasma membrane, and allowing the cell to take up the nanoparticle. The nanoparticle can be a FRET donor to an organic dye.

Modular functional peptides for delivery of nanoparticles

Described are nucleic acids encoding a polypeptide for delivery of a nanoparticle to the cytosol, the peptide comprising: (a) a nanoparticle association domain, (b) a spacer domain, (c) an uptake domain, and (d) a vesicle escape domain, wherein the domains (a) through (d) appear in the same order as listed above, and wherein the peptide, upon addition of a non-hydrolyzable lipophilic moiety to the vesicle escape domain and binding to a nanoparticle, is effective to induce uptake of a nanoparticle by a cell and delivery of the nanoparticle to the cytosol of the cell. Also described are methods of delivery of a nanoparticle to the cytosol of a cell, the method comprising providing to a cell a nanoparticle attached to such a peptide. Exemplary nanoparticles include quantum dots.

Modular functional peptides for the intracellular delivery of nanoparticles

Described are peptides for delivery of a nanoparticle to the cytosol, the peptide comprising: (a) a nanoparticle association domain; (b) a proline-rich spacer domain; (c) an uptake domain; and (d) a vesicle escape domain comprising a non-hydrolyzable lipid moiety, wherein the spacer domain is between the nanoparticle association domain and the uptake and vesicle escape domains, and wherein the peptide, when attached to an extracellular nanoparticle, is effective to induce uptake of the nanoparticle by a cell and delivery of the nanoparticle to the cytosol of the cell. Also described are methods of delivery of a nanoparticle to the cytosol of a cell, the method comprising providing to a cell a nanoparticle attached to such a peptide. Exemplary nanoparticles include quantum dots.

A method for covalent attachment of peptides to luminescent quantum dots or other inorganic nanoparticles. The first step in the method involves functionalizing at least a portion of a surface of the quantum dot or nanoparticle with one or more materials having at least one reactive functional group therein. Subsequently, a peptide having a reactive functional group is reacted with at least some of the quantum dot or nanoparticle reactive functional groups to covalently bond at least some of the peptide to the quantum dots or nanoparticles. Modifications of the basic method are disclosed which provide methods allowing customized fabrication of quantum dots having a variety of different functional properties and combinations of functional properties. Also disclosed are quantum dots and nanoparticles made by the methods of the present invention.

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Alexandria, VA, United States of America

Hedi M Mattoussi