Carefully consider the following- a research group develops some very bright, water soluble emissive quantum dots (QDs). What next? While pretty to look at, they don’t “do” anything! A good use of such a sample is for biological imaging, and most likely we need to tag the QD to a biological agent. If we want to use the QD as a chemical sensor, we have to attach an organic dye to the QD.

Our group was the first to create ~100% efficient methods for QD functionalization (JACS, 2008 and ACS Nano, 2009), and since then we have increased the “tool-kit” available to a wide range of researchers by making all of this easy. More recent reviews are available from our studies in PCCP and Accounts of Chemical Research.

Water solubilization

To impart water solubility to QDs made in a hydrophobic solvent, the two most wide-spread approaches are to replace the hydrophobic ligands with hydrophilic ones or to wrap QDs in amphiphilic polymers. Cap exchange makes very small QDs (good for biological studies!) but it comes at a price- the samples are not very stable in water and will precipitate in hours to days at best. Polymer encapsulation makes near-permanently stable QDs, but they can be quite large (>25 nm); this renders them somewhat biologically incompatible. Our group recently demonstrated a technique to make cap exchanged QDs much more stable in water by using an organometallic species as the cap in the exchange process (see our ACS Nano article). We did this by coordinating zinc to the water-solubilizing mercapto-acids that are commonly used to cap exchange QDs. This increases the brightness and stability of the water-soluble cap-exchanged NCs by a significant extent- we can coat QDs with small molecules like cysteine to make aqueous nanocrystals that are stable for weeks as opposed to hours. We followed up on this research to create silica-coated QDs with only a mono-layer of silane, the smallest shell physically possible!

Functionalization

Whether we cap-exchange or encapsulate QDs with polymers, we now must functionalize them if they are ever to do anything useful. Given that QDs are generally coated with carboxylic acids (-COOH), many research groups activate carboxylic acid coated QDs with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (called EDC), which “primes” carboxylic acids to react with amines. However, our group and others have shown that EDC causes QDs to precipitate out of solution permanently, thus destroying the sample. Unfortunately, there are no other commercially available water soluble carbodiimide reagents.

We recently found a solution to the functionalization problem as published in ACS Nano. We realized that the carbodiimide functionality (R₁-N=C=N-R₂) is not responsible for the observed precipitation of QDs; rather, it’s the fact that EDC is cationic and the QDs are highly negatively charged. Thus, the solution is to make a carbodiimide that has no net charge at all! Shown here is the method we used to make a carbodiimide functional methyl polyethylene glycol (PEG) polymer. It does not cause QDs to precipitate and may functionalize NCs with 95% reaction efficiency! We have followed up on this work demonstrating other reagents that are effective for this purpose.

We are also developing new polymer-encapsulation techniques that significantly enhance the solubility of NCs such that they can be functionalized, in high yield, with highly cationic cell-penetrating peptides and other biological materials that are known to cause NC precipitation and quenching.