Modification of ultrasmall gold nanoparticles (AuNPs) with the lipoic acid derivative of folic acid was found to enhance their accumulation in the cancer cell, as compared to AuNPs without addressing units. The application of lipoic acid enabled the control of the gold nanoparticle functionalities leading to enhanced solubility and allowing for attachment of both the folic acid and the cytotoxic drug, doxorubicin. More robust attachment of doxorubicin to the nanoparticle through the amide bond resulted in toxicity comparable with that of the drug alone, opening a new perspective for designing more potent, but less toxic nanopharmaceuticals. The increased uptake was accompanied by pronounced nuclear accumulation and observable cytotoxicity. Doxorubicin binding via covalent amide bonds enhanced stability of the whole drug vehicle and provided much better control over doxorubicin release in the cell environment, as compared to physical adsorption or pH sensitive bonding commonly used for anthracycline carriers. Confocal microscopy revealed that the bond was stable in the cytoplasm for 22 h. The ability to slow down the rate of drug release may be crucial for the application in sustained anticancer drug delivery. Biological analyses performed using MTT assay and confocal microscopy confirmed that the ultrasmall AuNPs with the lipoic acid derivative of folic acid exhibit relatively low cytotoxicity, however when loaded with a chemotherapeutic, they cause a significant reduction in the cell viability.

Compound 1 was designed and prepared as a heteroditopic ion-pair receptor that contains two urea groups for anion complexation and N-benzyl-18-crown-6 for cation recognition. These ion-binding domains are assembled together by the l-ornithine scaffold. Qualitative cation coordination studies of receptor 1, supported by quantitative data received for monotopic N-(3-nitrobenzyl)-aza-18-crown-6 (3a), have shown that 1 has a strong affinity for Na, K and NH cations. Anion binding studies revealed that in the absence of cations coordinated to 1 (TBA salts), anions are bound with a relatively moderate strength with the selectivity: BzO > AcO > Cl> NO > Br. However, in the presence of cations coordinated to the N-benzyl-18-crown-6 the anion binding affinity increases considerably with the notable exception of carboxylates. For example, chloride binding is increased by over five times in the presence of K cations and the selectivity trend for salt binding is: KCl > KOBz > KOAc > KNO > KBr. Liquid/liquid extraction studies revealed that receptor 1 is an effective extractant for KCl and NHCl salts from aqueous to organic phase.

Compounds 2 and 3 were designed and prepared as heteroditopic ion-pair receptors. The design features a 2,2-bis(aminomethyl)propionic acid core to connect and pre-organize binding groups. The cation binding is provided by a sodium selective N-acyl aza-18-crown-6 subunit whereas for anion complexation, two urea groups (receptor 2) or two squaramide groups (receptor 3) were introduced. Beyond acting as anion binding sites, the urea and squaramide groups were used to support sodium cation complexation through metal carbonyl oxygen lone pair interactions. The receptors were found to bind sodium salts of chloride, bromide and nitrate much more strongly than the corresponding ions accompanied by counterions that do not coordinate to the receptor. For example, chloride binding to receptor 2 enhances the strength of sodium complexation by up to 23 times. Conversely, sodium binding enhances chloride recognition by a factor of three. Receptor 3 containing squaramide units, binds sodium chloride and bromide with a similar albeit lower cooperativity. Moreover, unprecedentedly tight binding of these salts was achieved, with association constants as high as log K = 6.52 M for NaCl salt complexation.

Structurally simple, heteroditopic receptor is capable of extracting hydrophilic potassium acetate and other carboxylate salts from water to organic phase.

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