In vitro activity of steroidal dendrimers on Trypanosoma cruzi epimastigote form with PAMAM dendrons modified by “click” chemistry

The increasing use of dendrimers shows promise for the treatment of inflammatory diseases, Chagas disease and other conditions such as cancer. In this study, the activity of 1st and 2nd generation dendrimers over T. cruzi in the epimastigote stage was tested. Dendrimers were derived from α-ethynylestradiol (EE) modified with PAMAM-type dendrons through a triazole ring. The activity of each compound was evaluated in five doses (from 1.3 to 20 µmol/mL) by flow cytometry, including benznidazole (Bz) as positive control. The findings show that an equivalent concentration of 14.8 µmol/mL of 2nd generation (G) dendrimer is 8 times more effective than Bz at 24 h, and it maintains its superiority at 48 h with an IC₅₀ = 1.25 ± 0.19 µmol/mL. A TUNEL assay showed that dendrimers induce cell death in T. cruzi epimastigotes mostly via apoptosis, unlike Bz, which induces death via necrosis in more than 50% of cells.     

Clusters of ligands on dendrimer surfaces

The development of methodology that is designed to allow a significant increase in the patterning and in the functionalization of the dendrimer is the ultimate goal of the research described here. Glycoside clusters based on TRIS were formed using click chemistry and were attached to PAMAM dendrimers. A series of dendrimers bearing tris-mannoside and an ethoxyethanol group was synthesized, and the binding interactions of these dendrimers with Concanavalin A were evaluated using inhibition ELISAs. The results of the inhibition ELISAs suggest that tris-mannoside clusters can replace individual sugars on the dendrimer without loss of function. Since tris-mannoside clustering allows for a redistribution of the dendrimers’ surface functionalities, from this chemistry one can envision patterned dendrimers that incorporate multiple groups to increase the function and utility of the dendrimer.     

树枝状聚合物在生物医学领域的应用进展

树枝状聚合物是一种人工合成的新型纳米材料 ,以其独特的结构和性能在生物医学领域受到了日益广泛的关注。作为一种新型非生物载体 ,其安全、高效、无毒 ,在药物输送、基因转移和医疗诊断等方面具有广阔的应用前景。     

Cancer Detection and Treatment: The Role of Nanomedicines

Nanotechnology is a field which has been at the forefront of research over the past two decades. The full potential of nanotechnology has yet to be fully realized. One subset of nanotechnology that has emerged is nanomedicine, which has been able to exploit the unique properties of nano-sized particles for therapeutics. Nanomedicine has the potential to increase the specific treatment of cancer cells while leaving healthy cells intact through the use of novel nanoparticles to seek and treat cancer in the human body. However, there are undoubtedly toxicities, which have not yet been fully elucidated. Various nano-carriers such as nanoshells, nanocrystals, nanopolymers, quantum dots, and dendrimers, and their role in early cancer detection and treatment have been discussed in this article.     

Application of the functionalized congener approach to dendrimer-based signaling agents acting through A2A adenosine receptors

As a continued effort to develop multivalent ligands to enhance the pharmacological effects of monomeric drugs, DITC-APEC, a chemically reactive nucleoside A(2A) adenosine receptor (AR) agonist, was employed to derivatize the surface of third-generation (G3) polyamidoamine (PAMAM) dendrimers. The resulting conjugates carried multiple copies of the agonist attached through a thiourea linkage and differed in the number of attachments and in the presence of a fluorophore or additional surface modification. Computer modeling studies suggested that these DITC-APEC-loaded dendrimers extended the overall diameter of the previously reported PAMAM-CGS21680 dendrimer derivatives (Kim et al., Bioconjugate Chem 2008 19:406-411) by ca. 20 A, potentially increasing the conformational flexibility of the appended ligands to achieve optimal geometry for efficient binding at A(2A) ARs. Increased affinity and selectivity in binding in comparison to the CGS21680 conjugate were envisioned, due to the presence of an extended linker, i.e., a dithioureylenephenyl functionality. In vitro radioligand competition experiments showed effective binding of these PAMAM-DITC-APEC dendrimer conjugates at the human A(2A) and A(3) ARs with submicromolar K (i) values and selectivity in comparison to the human A(1) AR. Furthermore, these nucleoside-loaded dendrimers exhibited an A(2A) AR-mediated inhibitory effect on ADP-induced aggregation of human platelets. The present study demonstrates the potential of applying the functionalized congener concept to engineer dendrimer-based multivalent ligands for G protein-coupled receptors.     

Design considerations for PAMAM dendrimer therapeutics

We have previously shown that methotrexate (MTX) conjugated to a cancer-specific poly amido amine (PAMAM) dendrimer has a higher therapeutic index than MTX alone. Unfortunately, these therapeutics have been difficult to advance because of the complicated syntheses and an incomplete understanding of the dendrimer properties. We wished to address these obstacles by using copper-free click chemistry to functionalize the dendrimer scaffolds and to exploring the effects of two dendrimer properties (the targeting ligand and drug linkage) on cytotoxicity. We conjugated either ester or amide-linker modified MTX to dendrimer scaffolds with or without folic acid (FA). Because of multivalency, the FA and MTX functionalized dendrimers had similar capacities to target the folate receptor on cancer cells. Additionally, we found that the ester- and amide-linker modified MTX compounds had similar cytotoxicity but the dendrimer–ester MTX conjugates were much more cytotoxic than the dendrimer–amide MTX conjugates. These results clarify the impact of these properties on therapeutic efficacy and will allow us to design more effective polymer therapeutics.     

First synthesis of a dihydrido functionalized double-cored oligosilane dendrimer

The reaction of (R₂MeSi)₂SiHCl (2) [R=SiMe₃] with Na-K-alloy yields the double-cored dendritic oligosilane [(R₂MeSi)₂SiH]₂ (4). The structure of 4 was obtained from X-ray diffraction data, which verify a total of 14 silicon atoms and a longest chain of six silicon atoms. The UV-Vis spectra of 4 and the structurally analogous [(R₂MeSi)₂SiMe]₂ (5) exhibit absorption maxima (shoulders) at 269 nm (ε=2.0×10⁴) and 276 nm (ε=2.3×10⁴), respectively, which are the longest so far observed for alkyl substituted oligosilanes with hexasilane chains.     

Cyclen substitution with urea-containing dendrimeric branches. Theoretical study considering the concept of collectivity

Equilibrium structures of novel dendrimeric compounds consisting of 1,4,7,10-tetraazacyclododecane (cyclen) mono- to tetra-substituted with four different dendrimeric branches have been studied. It has been shown using molecular dynamics (MD) that, even in the presence of the macrocycle cyclen, the most stable conformations are those with a globular shape due to close contact interactions between poly-functional branches. No collapse of cyclen occurred, making this cavity available for metal complexation. Terminal branches A=NHCOOtBu, B=OSi(Me)2tBu, C=Imidazole and D=CN have different molecular volumes in the decreasing order: B>A>C>D. This conclusion is in accord with the long range interaction energies, showing that the larger the volume the less the steric hindrance. Considering these energy values, the stability of the systems follows exactly the same tendency as observed for the molecular volume. More polar groups like A=NHCOOtBu and D=CN impart extra stability due to long range interactions between atoms separated by exactly three chemical bonds. The negative charge inside the cyclen cavity increases with the volume of the branches. Besides cyclen, urea groups located at the middle of the branches represent another independent point of negative charge for eventual interaction with small molecules. These compounds show a sum of small contributions of the functionalities in a collective fashion.     

Cyclam cored luminescent dendrimers as ligands for Co(II), Ni(II) and Cu(II) ions

We have investigated the photophysical properties of two dendrimers containing a cyclam core decorated with 4 naphthyl units (G0), 12 dimethoxybenzene and 16 naphthyl units (G2). These dendrimers show fluorescence bands that can be assigned to naphthyl localized excited states (λ_max = 337 nm), naphthyl-amine exciplexes (λ_max = 470 nm) and, for G2, naphthyl excimers (λ_max ca. 400 nm). Cyclam is a very good ligand for transition metal ions and we have investigated complex formation between these dendritic ligands and Ni(II), Co(II) and Cu(II), added as nitrate salts. This process can be monitored by the strong changes, both in shape and intensity, observed in the emission spectra of these dendrimers. Complexation with Cu(II) causes not only changes in the relative intensities of the fluorescence bands, but also the appearance of a new absorption band in the near UV spectral region. An analysis of the titration curves has allowed us to obtain clear evidence for the formation of not only 1:1 species, but also 1:2 metal to ligand species. G2 shows a clear preference, compared to G0, in forming complexes with a 1:2 metal-to-ligand stoichiometry, although it possesses very bulky dendrons appended to the cyclam central unit.     

Synthesis and anticancer activity of open-resorcinarene conjugates

The first example of conjugation of open-resorcinarenes with chlorambucil, ibuprofen, naproxen and indomethacin are presented. The cytotoxic properties of the obtained conjugates were tested against the cancer cell lines U-251, PC-3, K-562, HCT-15, MCF-7 and SKLU-1. It was found that the conjugate with chlorambucil, naproxen or indomethacin (having 8 moieties) was toxic towards cancer cell lines U-251 and K-562, with no activity against non-cancerous COS-7 cells. The conjugates with naproxen and indomethacin showed high selectivity towards U-251 tumor cells.