Nanoparticle (NP) therapeutics have the potential to significantly alter the in vivo biological properties of the pharmaceutically active agents that they carry. Here we describe the development of a polymeric NP, termed M-NP, comprising poly(d,l-lactic-co-glycolic acid)-block-poly(ethylene glycol) (PLGA-PEG), stabilized with poly(vinyl alcohol) (PVA), and loaded with a water soluble platinum(IV) [Pt(IV)] prodrug, mitaplatin. Mitaplatin, c,c,t-[PtCl2(NH3)2(OOCCHCl2)2], is a compound designed to release cisplatin, an anticancer drug in widespread clinical use, and the orphan drug dichloroacetate following chemical reduction. An optimized preparation of M-NP by double emulsion and its physical characterization are reported and the influence of encapsulation on the properties of the platinum agent is evaluated in vivo. Encapsulation increases the circulation time of Pt in the bloodstream of rats. The biodistribution of Pt in mice is also affected by nanoparticle encapsulation, resulting in reduced accumulation in the kidneys. Finally, the efficacy of both free mitaplatin and M-NP, measured by tumor growth inhibition in a mouse xenograft model of triple-negative breast cancer, reveal that controlled release of mitaplatin over time from the nanoparticle treatment produces long-term efficacy comparable to that of free mitaplatin, which might limit toxic side effects.
The generation of bio‐targetable photosensitizers is of utmost importance to the emerging field of photodynamic therapy and antimicrobial (photo‐)therapy. A synthetic strategy is presented in which chelating dipyrrin moieties are used to enhance the known photoactivity of iridium(III) metal complexes. Formed complexes can thus be functionalized in a facile manner with a range of targeting groups at their chemically active reaction sites. Dipyrrins with N‐ and O‐substituents afforded (dipy)iridium(III) complexes via complexation with the respective Cp*‐iridium(III) and ppy‐iridium(III) precursors (dipy=dipyrrinato, Cp*=pentamethyl‐η5‐cyclopentadienyl, ppy=2‐phenylpyridyl). Similarly, electron‐deficient [IrIII(dipy)(ppy)2] complexes could be used for post‐functionalization, forming alkenyl, alkynyl and glyco‐appended iridium(III) complexes. The phototoxic activity of these complexes has been assessed in cellular and bacterial assays with and without light; the [IrIII(Cl)(Cp*)(dipy)] complexes and the glyco‐substituted iridium(III) complexes showing particular promise as photomedicine candidates. Representative crystal structures of the complexes are also presented.
The Cu(II) complexes of cyclen and two of its heterosubstituted analogues were shown to be efficient oxidative DNA cleavers. The reactivity strongly depends on the heteroatom inserted into the macrocycle (O > S > N).
This microreview summarizes recent research in the field of artificial nucleases, in particular those based on copper(II) in an N‐donating ligand environment. This review is divided into three parts describing different ligand classes that have shown promising results in DNA cleavage chemistry: aromatic N‐donors, aliphatic N‐donors, and peptide ligands. Whereas nature has created very efficient nucleases, artificial nucleases aim at different selectivities and higher stability under various conditions. Artificial nucleases based on metal complexes comprise Lewis acidic or redox‐active metal centers allowing for either hydrolytic or oxidative DNA cleavage. The focus of our research and thus also of this microreview is copper, whose CuII ion combines both properties. Depending on the ligand scaffold and reaction conditions, either pathway or even both are thus conceivable. Those different pathways lead to molecular biological and medicinal applications.
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