The design and study of efficient polymer-based drug delivery systems for the controlled release of anticancer drugs is one of the pillars of nanomedicine. The fight against metastatic and invasive ...cancers demands therapeutic candidates with increased and selective toxicity towards malignant cells, long-term activity and reduced side effects. In this sense, polyphosphazene nanocarriers were synthesized for the sustained release of the anticancer drugs camptothecin (CPT) and epirubicin (EPI). Linear poly(dichloro)phosphazene was modified with lipophilic tocopherol or testosterone glycinate, with antioxidant and antitumor activity, and with hydrophilic Jeffamine M1000 to obtain different polyphosphazene nanocarriers. It allowed us to encapsulate the lipophilic CPT and the more hydrophilic EPI. The encapsulation process was carried out via solvent exchange/precipitation, attaining a 9.2-13.6 wt% of CPT and 0.3-2.4 wt% of EPI. CPT-loaded polyphosphazenes formed 140-200 nm aggregates in simulated body physiological conditions (PBS, pH 7.4), resulting in an 80-100-fold increase of CPT solubility. EPI-loaded polyphosphazenes formed 250 nm aggregates in an aqueous medium. CPT and EPI release (PBS, pH 7.4, 37 °C) was monitored for 202 h, being almost linear during the first 8 h. The slow release of testosterone and tocopherol was also sustained for 150 h in PBS (pH 7.4 and 6.0) at 37 °C. The co-delivery of testosterone or tocopherol and the anticancer drugs from the nanocarriers was expected. Cells of the human breast cancer cell line MCF-7 demonstrated good uptake of anticancer-drug-loaded nanocarriers after 6 h. Similarly, MCF-7 spheroids showed good uptake of the anticancer-drug-loaded aggregates after 72 h. Almost all anticancer-drug-loaded polyphosphazenes exhibited similar or superior toxicity against MCF-7 cells and spheroids when compared to raw anticancer drugs. Additionally, cell-cycle arrest in the G2/M phase was increased in response to the drug-loaded nanocarriers. Almost no toxicity of anticancer-drug-loaded aggregates against primary human lung fibroblasts was observed. Furthermore, the aggregates displayed no hemolytic activity, which is in contrast to the parent anticancer drugs. Consequently, synthesized polyphosphazene-based nanocarriers might be potential nanomedicines for chemotherapy.
Hydroxypyr(id)ones are versatile ligands for the synthesis of organometallic anticancer agents, equipping them with fine-tunable pharmacological properties. Herein, we report on the preparation, mode ...of action, and in vitro anticancer activity of RuII− and OsII−arene complexes with alkoxycarbonylmethyl-3-hydroxy-2-pyridone ligands. The hydrolysis and binding to amino acids proceed quickly, as characterized by NMR spectroscopy and ESI mass spectrometry. However, the reaction with amino acids causes cleavage of the pyridone ligands from the metal center because the amino acids act as multidentate ligands. A similar behavior was also observed during the reactions with the model proteins ubiquitin and cytochrome c, yielding mainly protein + M(η6-p-cymene) adducts (M = Ru, Os). Notably the ligand cleavage of the Os derivative was significantly slower than of its Ru analogue, which could explain its higher activity in in vitro anticancer assays. Furthermore, the reaction of the compounds to 5′-GMP was characterized and coordination to the N7 of the guanine moiety was demonstrated by 1H NMR spectroscopy and X-ray diffraction analysis. CDK2/Cyclin A protein kinase inhibition studies revealed potent activity of the Ru and Os complexes.
This report details the first systematic screening of free-radical-produced methacrylate oligomer reaction mixtures as alternative vaccine adjuvant components to replace the current benchmark ...compound squalene, which is unsustainably sourced from shark livers. Homo-/co-oligomer mixtures of methyl, butyl, lauryl, and stearyl methacrylate were successfully synthesized using catalytic chain transfer control, where the use of microwave heating was shown to promote propagation over chain transfer. Controlling the mixture material properties allowed the correct viscosity to be achieved, enabling the mixtures to be effectively used in vaccine formulations. Emulsions of selected oligomers stimulated comparable cytokine levels to squalene emulsion when incubated with human whole blood and elicited an antigen-specific cellular immune response when administered with an inactivated influenza vaccine, indicating the potential utility of the compounds as vaccine adjuvant components. Furthermore, the oligomers' molecular sizes were demonstrated to be large enough to enable greater emulsion stability than squalene, especially at high temperatures, but are predicted to be small enough to allow for rapid clearance from the body.
This feature article briefly highlights some of the recent advances in polymers in which phosphorus is an integral part of the backbone, with a focus on the preparation of functional, highly ...branched, soluble polymers. A comparison is made between the related families of materials polyphosphazenes, phosphazene/phosphorus‐based dendrimers and polyphosphoesters. The work described herein shows this to be a rich and burgeoning field, rapidly catching up with organic chemistry in terms of the macromolecular synthetic control and variety of available macromolecular architectures, whilst offering unique property combinations not available with carbon backbones, such as tunable degradation rates, high multivalency and facile post‐polymerization functionalization. As an example of their use in advanced applications, we highlight some investigations into their use as water‐soluble drug carriers, whereby in particular the degradability in combination with multivalent nature has made them useful materials, as underlined by some of the recent studies in this area.
Phosphorus‐based polymers present a viable alternative to carbon‐based polymers for advanced applications, particularly due to them offering tunable degradability, high multivalency and straight‐forward post‐polymerization functionalization. Recent synthetic advances bring hitherto inaccessible controlled and/or highly branched architectures for phosphorus main‐chain polymers. Water‐soluble, degradable phosphorus‐based branched polymers are especially of interest for use as polymer therapeutics.
A simple polymerization of trichlorophosphoranimine (Cl3P = N−SiMe3) mediated by functionalized triphenylphosphines is presented. In situ initiator formation and the subsequent polymerization ...progress are investigated by 31P NMR spectroscopy, demonstrating a living cationic polymerization mechanism. The polymer chain lengths and molecular weights of the resulting substituted poly(organo)phosphazenes are further studied by 1H NMR spectroscopy and size exclusion chromatography. This strategy facilitates the preparation of polyphosphazenes with controlled molecular weights and specific functional groups at the α‐chain end. Such well‐defined, mono‐end‐functionalized polymers have great potential use in bioconjugation, surface modification, and as building blocks for complex macromolecular constructs.
Well‐defined, mono‐end‐functionalized polyphosphazenes are prepared via living cationic polymerization. Dichlorophosphoranes with (protected) functional groups are prepared in situ from commercially available triphenylphosphines and employed as initiators for the polymerization of trichlorophosphoranimine. NMR spectroscopy and SEC analysis show that the molecular weights can be controlled via the monomer:initiator ratio to give α‐chain‐functionalized poly(organo)phosphazenes for the preparation of macromolecular constructs.
Herein, we present the design, synthesis, and characterization of fully degradable, hybrid, star-branched dendritic polyols. First multiarmed polyphosphazenes were prepared as a star-branched ...scaffold which upon functionalization produced globular branched hydroxyl-functionalized polymers with over 1700 peripheral functional end groups. These polyols with unique branched architectures could be prepared with controlled molecular weights and relatively narrow dispersities. Furthermore, the polymers are shown to undergo hydrolytic degradation to low molecular weight degradation products, the rate of which could be controlled through postpolymerization functionalization of the phosphazene backbone.
A new synthetic procedure is described for the preparation of poly(organo)phosphazenes with star‐branched and star dendritic molecular brush type structures, thus describing the first time it has ...been possible to prepare controlled, highly branched architectures for this type of polymer. Furthermore, as a result of the extremely high‐arm density generated by the phosphazene repeat unit, the second‐generation structures represent quite unique architectures for any type of polymer. Using two relativity straight forward iterative syntheses it is possible to prepare globular highly branched polymers with up to 30 000 functional end groups, while keeping relatively narrow polydispersities (1.2–1.6). Phosphine mediated polymerization of chlorophosphoranimine is first used to prepare three‐arm star polymers. Subsequent substitution with diphenylphosphine moieties gives poly(organo)phosphazenes to function as multifunctional macroinitiators for the growth of a second generation of polyphosphazene arms. Macrosubstitution with Jeffamine oligomers gives a series of large, water soluble branched macromolecules with high‐arm density and hydrodynamic diameters between 10 and 70 nm.
A route to previously unattainable branched polyphosphazenes with controlled dimensions is presented. Furthermore, the star branched polyphosphazenes undergo macromolecular substitution with diphenylphosphine groups which can act as macroinitiators for the grafting of a second generation of polyphosphazenes. This subsequently gives dendritic molecular brush type structures with novel, highly branched, water‐soluble, globular architectures.
Pyrone scaffolds are often present in natural products and many derivatives therefore exhibit favorable biocompatibility and toxicity profiles. Hydroxypyrones are obtained from natural sources or can ...be synthesized by different well established approaches and may easily be converted into the analogous thiopyrones and hydroxypyridones. These features make them well suited to drug development and other biological applications. Herein, we summarize recent literature on the use of (thio)pyr(id)ones in bioinorganic chemistry with a focus on their metal ion chelating properties. Selected examples and different approaches using (thio)pyr(id)ones are presented and the influence of structural modifications on their chemical, physical and biological properties are discussed.
Recent literature on the use of (thio)pyr(id)ones in bioinorganic chemistry is summarized, highlighting in particular their ion metal chelating properties. Selected examples and different approaches using (thio)pyr(id)ones are presented and the influence of structural modifications on the chemical, physical and biological properties are discussed.
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► (Thio)pyr(id)onato ligands and their metal complexes. ► Application in medicinal inorganic chemistry. ► Tunable ligand system with regard to metal complex stability. ► Potent anticancer active compounds.
The control of chain‐ends is fundamental in modern macromolecular chemistry for directed one‐to‐one bioconjugation and the synthesis of advanced architectures such as block copolymers or bottlebrush ...polymers and the preparation of advanced soft materials. Polyphosphazenes are of growing importance as elastomers, biodegradable materials and in biomedical drug delivery due to their synthetic versatility. While controlled polymerization methods have been known for some time, controlling both chain‐ends with high fidelity has proven difficult. We demonstrate a robust synthetic route to hetero and homo α,ω‐chain‐end functionalized polyphosphazenes via end‐capping with easily accessible, functionalized triphenylphosphine‐based phosphoranimines. A versatile thiol‐ene “click”‐reaction approach then allows for subsequent conversion of the end‐capped polymers with various functional groups. Finally, we demonstrate the utility of this system to prepare gels based on homo α,ω‐chain‐end functionalized polyphosphazenes. This development will enhance their progress in various applications, particularly in soft materials and as degradable polymers.
Within this work we aimed to improve the pharmacodynamics and toxicity profile of organoruthenium and -rhodium complexes which had previously been found to be highly potent in vitro but showed ...unselective activity in vivo. Different organometallic complexes were attached to a degradable poly(organo)phosphazene macromolecule, prepared via controlled polymerization techniques. The conjugation to hydrophilic polymers was designed to increase the aqueous solubility of the typically poorly soluble metal-based half-sandwich compounds with the aim of a controlled, pH-triggered release of the active metallodrug. The synthesized conjugates and their characteristics have been thoroughly studied by means of
P NMR and UV-Vis spectroscopy, ICP-MS analyses and SEC coupled to ICP-MS. In order to assess their potential as possible anticancer drug candidates, the complexes, as well as their respective macromolecular prodrug formulations were tested against three different cancer cell lines in cell culture. Subsequently, the anticancer activity and organ distribution of the poly(organo)phosphazene drug conjugates were explored in vivo in mice bearing CT-26 colon carcinoma. Our investigations revealed a beneficial influence of this macromolecular prodrug by a significant reduction of adverse effects compared to the free metallodrugs.
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