4PD Functionalized Dendrimers: A Flexible Tool for In Vivo Gene Silencing of Tumor-Educated Myeloid Cells.

Myeloid cells play a key role in tumor progression and metastasis by providing nourishment and immune protection, as well as facilitating cancer invasion and seeding to distal sites. Although advances have been made in understanding the biology of these tumor-educated myeloid cells (TEMCs), their intrinsic plasticity challenges our further understanding of their biology. Indeed, in vitro experiments only mimic the in vivo setting, and current gene-knockout technologies do not allow the simultaneous, temporally controlled, and cell-specific silencing of multiple genes or pathways. In this article, we describe the 4PD nanoplatform, which allows the in vivo preferential transfection and in vivo tracking of TEMCs with the desired RNAs. This platform is based on the conjugation of CD124/IL-4Rα-targeting peptide with G5 PAMAM dendrimers as the loading surface and can convey therapeutic or experimental RNAs of interest. When injected i.v. in mice bearing CT26 colon carcinoma or B16 melanoma, the 4PD nanoparticles predominantly accumulate at the tumor site, transfecting intratumoral myeloid cells. The use of 4PD to deliver a combination of STAT3- and C/EBPß-specific short hairpin RNA or miR-142-3p confirmed the importance of these genes and microRNAs in TEMC biology and indicates that silencing of both genes is necessary to increase the efficacy of immune interventions. Thus, the 4PD nanoparticle can rapidly and cost effectively modulate and assess the in vivo function of microRNAs and mRNAs in TEMCs.

The Binding Interactions between Cyclohexanocucurbit[6]uril and Alkyl Viologens Give Rise to a Range of Diverse Structures in the Solid and the Solution Phases.

The binding interactions between the cyclohexanocucurbit[6]uril (Cy6CB6) host and a series of dialkyl-4,4'-bipyridinium (viologen) dicationic guests were investigated in the solution phase, using (1)H NMR spectroscopy, and in the solid phase, using X-ray diffraction methods. In D2O solution, methyl viologen (MV(2+)) and ethyl viologen (EV(2+)) form 1:1 complexes in which the bipyridinium aromatic nucleus is partially included inside the Cy6CB6 cavity. Propyl viologen (PV(2+)), butyl viologen (BV(2+)), pentyl viologen (FV(2+)), and heptyl viologen (HV(2+)) form 2:1 complexes with Cy6CB6, in which each of the viologen aliphatic chains is included by a host molecule. In the solid state, EV(2+) forms a polypseudorotaxane via pseudorotaxane interdigitation of Cy6CB6 hosts. The PV(2+) guest forms a dumbbell-shaped structure with a Cy6CB6 host residing over each of the terminal propyl groups of the guest. In contrast to this, the BV(2+) guest and Cy6CB6 form a different polypseudorotaxane structure in which dumbbell-shaped structures, formed by two host molecules interacting with a single guest, are interconnected through metal-host coordination.

Peptide-conjugated PAMAM dendrimer as a universal DNA vaccine platform to target antigen-presenting cells.

DNA-based vaccines hold promise to outperform conventional antigen-based vaccines by virtue of many unique features. However, DNA vaccines have thus far fallen short of expectations, due in part to poor targeting of professional antigen-presenting cells (APC) and low immunogenicity. In this study, we describe a new platform for effective and selective delivery of DNA to APCs in vivo that offers intrinsic immune-enhancing characteristics. This platform is based on conjugation of fifth generation polyamidoamine (G5-PAMAM) dendrimers, a DNA-loading surface, with MHC class II-targeting peptides that can selectively deliver these dendrimers to APCs under conditions that enhance their immune stimulatory potency. DNA conjugated with this platform efficiently transfected murine and human APCs in vitro. Subcutaneous administration of DNA-peptide-dendrimer complexes in vivo preferentially transfected dendritic cells (DC) in the draining lymph nodes, promoted generation of high affinity T cells, and elicited rejection of established tumors. Taken together, our findings show how PAMAM dendrimer complexes can be used for high transfection efficiency and effective targeting of APCs in vivo, conferring properties essential to generate effective DNA vaccines.

Drastically decreased reactivity of thiols and disulfides complexed by cucurbit[6]uril.

The cucurbit[6]uril (CB6) host forms stable complexes with 2-aminoethanethiol (cysteamine) and a derivative that contains a bulky terminal group attached to the amine group, as well as with the related disulfide cystamine. In these complexes, the thiol or the disulfide group is encapsulated inside the host cavity. The CB6-complexed thiols show drastically decreased reactivity with several oxidants, while the CB6-bound disulfide also exhibits hindered reactivity with reducing agents, such as dithiothreitol.

Effective recognition of H2PO4- by a new series of dendrimers functionalized with ferrocenyl-urea termini.

A new series of dendrimers with poly(propylene imine) backbones and 4, 8, 16, or 32 peripheral ferrocenyl-urea groups were prepared and characterized; their voltammetric behavior in DMSO solution was very sensitive to the presence of hydrogenphosphate anions at submillimolar concentration levels.