Multivalent Copper(II)-Conjugated Phosphorus Dendrimers with Noteworthy In Vitro and In Vivo Antitumor Activities: A Concise Overview.

Dendrimers are macromolecules with well-defined, homogeneous, and monodispersed structures that form a branch-like structure. In general, they have a symmetric core, inner shells, and an outer shell. Over the past decade, metallodendritic architectures have developed into a new area in nanomedicine. Due to their versatility and facile customization, phosphorus dendrimers represent interesting platforms for biomedical applications. Metallo-conjugated phosphorus dendrimers have been developed within the dendrimer space, an important part of the chemical space. The first investigation was made using phosphorus dendrimers bearing copper(II) groups on their surface as the original anticancer drug candidates. The aim of this minireview is to present our powerful strategy to find and develop original multivalent copper(II)-conjugated phosphorus dendrimers. The most potent of them is G3 dendrimers with N-(pyridine-2-ylmethylene)ethanamine as the chelating motif complexed with Cu(II) (1G3-Cu), showing very good in vitro and in vivo antiproliferative efficacy. On the basis of these results, 1G3-Cu is a potential clinical candidate having progressed from hit to preclinical candidate status.

Effect of subgroup-specific multimodal therapy on chronic spinal back pain and function-a prospective inpatient multicentre clinical trial in Germany.

Treatment modalities of spinal pain patients are discussed diversely, and different multimodal therapy programs have been developed. Purpose of the present study was to evaluate therapy outcome and effectiveness of an inpatient interdisciplinary and multimodal treatment program.This prospective multicentre clinical trial has been performed with patients from orthopedic hospitals receiving a functional musculoskeletal therapy pathway. Outcome measures were pain intensity and back-specific function (Oswestry Disability Index) before (T1) and after the intervention (T2) as well as after 6 and 12 months (T3, T4). Statistical approach included parametric (t test) and nonparametric (Wilcoxon-test) tests and the calculation of effect sizes. Additionally, a statistical subgroup analysis based on selected parameters (degree of pain chronicity, gender, and age) was performed using linear mixed models.In total, 249 patients (42.6% men, 57.4% women) with spinal pain were included, 133 patients were accessible for follow-up at T3 and 106 patients at T4.Average pain (AP) reduced significantly (P <.001) from T1 to T4 with an effect size of 0.99. Back-specific function also improved (P <.001) over all measuring time points (TP) (effect size: 0.63). Furthermore, the statistical subgroup analysis demonstrated the efficacy of the treatment concept within the subgroup parameters chronicity degree and age.A functional musculoskeletal therapy pathway including treatment of musculoskeletal dysfunctions appears to be beneficial in terms of treating pain and function. Pain chronicity and age seems to be factors influencing therapy outcome. Further studies are needed to examine the superiority of these inpatient programs for back pain including control groups.

Anticancer copper(II) phosphorus dendrimers are potent proapoptotic Bax activators.

A multivalent phosphorus dendrimer 1G3 and its corresponding Cu-complex, 1G3-Cu have been recently identified as agents retaining high antiproliferative potency. This antiproliferative capacity was preserved in cell lines overexpressing the efflux pump ABC B1, whereas cross-resistance was observed in ovarian cancer cell lines resistant to cisplatin. Theoretical 3D models were constructed: the dendrimers appear as irregularly shaped disk-like nano-objects of about 22 Å thickness and 49 Å diameter, which accumulated in cells after penetration by endocytosis. To get insight in their mode of action, cell death pathways have been examined in human cancer cell lines: early apoptosis was followed by secondary necrosis after multivalent phosphorus dendrimers exposure. The multivalent plain phosphorus dendrimer 1G3 moderately activated caspase-3 activity, in contrast with the multivalent Cu-conjugated phosphorus dendrimer 1G3-Cu which strikingly reduced the caspase-3 content and activity. This decrease of caspase activity is not related to the presence of copper, since inorganic copper has no or little effect on caspase-3. Conversely the potent apoptosis activation could be related to a noticeable translocation of Bax to the mitochondria, resulting in the release of AIF into the cytosol, its translocation to the nucleus and a severe DNA fragmentation, without alteration of the cell cycle. The multivalent Cu-conjugated phosphorus dendrimer is more efficient than its non-complexed analog to activate this pathway in close relationship with the higher antiproliferative potency. Therefore, this multivalent Cu-conjugated phosphorus dendrimer 1G3-Cu can be considered as a new and promising first-in-class antiproliferative agent with a distinctive mode of action, inducing apoptosis tumor cell death through Bax activation pathway.