Properties and morphology of segmented copoly(ether urea)s with uniform hard segments

Block copoly(ether urea)s with uniform hard blocks consisting of two urea groups possess appealing elastomeric properties. The crystal structure of a model bisurea illustrates the formation of long stacks of hydrogen-bonded urea groups. Thermal anal. of these polymers demonstrates the reversible melting of the hard blocks, causing the material to flow. The low glass transition temp. ensures excellent low-temp. flexibility. The morphol. of the material consists of long stacks of assocd. hard blocks embedded in the soft phase. Elongation of the materials demonstrates their highly elastic behavior, with a strain at break ranging from 1000 to 2100%. During tensile testing, irreversible deformation and reorganization of the hard blocks occur, resulting in a significant amt. of tensile set. These well-defined polymers proved to be superior compared to a less-defined analog having a polydisperse hard block

Pretargeting kit for imaging or therapy comprising a trans - cyclooctene dienophile and a diene

\u3cp\u3eDescribed is a pretargeting method, and related kits, for targeted medical imaging and/or therapeutics, wherein use is made of abiotic reactive chemical groups that exhibit bio-orthogonal reactivity towards each other. The invention involves the use of [4+2] inverse electron demand (retro) Diels-Alder chemistry in providing the coupling between a Pre-targeting Probe and an Effector Probe. To this end one of these probes comprises an electron-deficient tetrazine or other suitable diene, and the other an E-cyclooctene which has a flattened structure as a result of the position of at least two exocyclic bonds.\u3c/p\u3

Click-to-release from trans-cyclooctenes:mechanistic insights and expansion of scope from established carbamate to remarkable ether cleavage

\u3cp\u3eThe bioorthogonal cleavage of allylic carbamates from trans-cyclooctene (TCO) upon reaction with tetrazine is widely used to release amines. We disclose herein that this reaction can also cleave TCO esters, carbonates, and surprisingly, ethers. Mechanistic studies demonstrated that the elimination is mainly governed by the formation of the rapidly eliminating 1,4-dihydropyridazine tautomer, and less by the nature of the leaving group. In contrast to the widely used p-aminobenzyloxy linker, which affords cleavage of aromatic but not of aliphatic ethers, the aromatic, benzylic, and aliphatic TCO ethers were cleaved as efficiently as the carbamate, carbonate, and esters. Bioorthogonal ether release was demonstrated by the rapid uncaging of TCO-masked tyrosine in serum, followed by oxidation by tyrosinase. Finally, tyrosine uncaging was used to chemically control cell growth in tyrosine-free medium.\u3c/p\u3

Efficient functionalization of additives at supramolecular material surfaces

Selective surface modification reactions can be performed on additives that are supramolecularly incorporated into supramolecular materials. Hereby, processing of the material, that regularly requires harsh processing conditions (i.e., the use of organic solvents and/or high temperatures), and functionalization can be decoupled. Moreover, high-resolution depth profiling by time-of-flight (ToF) secondary-ion mass spectrometry clearly shows distinct differences in surface and bulk material composition

Highly reactive trans-cyclooctene tags with improved stability for diels-alder chemistry in living systems

\u3cp\u3eOne of the challenges of pretargeted radioimmunotherapy, which centers on the capture of a radiolabeled probe by a preinjected tumor-bound antibody, is the potential immunogenicity of biological capturing systems. A bioorthogonal chemical approach may circumvent this drawback, but effective in vivo chemistry in mice, larger animals, and eventually humans, requires very high reagent reactivity, sufficient stability, and retained selectivity. We report here that the reactivity of the fastest bioorthogonal reaction, the inverse-electron- demand-Diels-Alder cycloaddition between a tetrazine probe and a trans-cyclooctene-tagged antibody, can be increased 10-fold (k\u3csub\u3e2\u3c/sub\u3e = 2.7 × 10\u3csup\u3e5\u3c/sup\u3e M\u3csup\u3e-1\u3c/sup\u3e s\u3csup\u3e-1\u3c/sup\u3e) via the trans-cyclooctene, approaching the speed of biological interactions, while also increasing its stability. This was enabled by the finding that the trans-cyclooctene tag is probably deactivated through isomerization to the unreactive cis-cyclooctene isomer by interactions with copper-containing proteins, and that increasing the steric hindrance on the tag can impede this process. Next, we found that the higher reactivity of axial vs equatorial linked TCO can be augmented by the choice of linker. The new, stabilized, and more reactive tag allowed for improved tumor-to-nontumor ratios in pretargeted tumor-bearing mice.\u3c/p\u3

Triggered drug release from an antibody-drug conjugate using fast click-to-release chemistry in mice

\u3cp\u3eThe use of a bioorthogonal reaction for the selective cleavage of tumor-bound antibody-drug conjugates (ADCs) would represent a powerful new tool for ADC therapy, as it would not rely on the currently used intracellular biological activation mechanisms, thereby expanding the scope to noninternalizing cancer targets. Here we report that the recently developed inverse-electron-demand Diels-Alder pyridazine elimination reaction can provoke rapid and self-immolative release of doxorubicin from an ADC in vitro and in tumor-bearing mice.\u3c/p\u3

An all-aromatic polypyridine:Monomer and polymer synthesis; film formation and crosslinking; a candidate fuel cell membrane

\u3cp\u3e2,6-di (3-pyridyl)phenol and the title polymer are synthesized at 1 kg scale. Polymer is processed and crosslinked without the introduction of non-aromatic moieties after shaping into membranes. Attractive proton conduction, at high temperature (140–180 °C: 300 mS cm\u3csup\u3e−1\u3c/sup\u3e) and at room temperature (60 mS cm\u3csup\u3e−1\u3c/sup\u3e) are recorded in the dry state (higher numbers at modest humidity) and excellent retention of properties after challenge by humidity (in contrast with state-of-the-art PBI membranes). Functional fuel cells are made and tested. In prolonged use the membrane is plasticized and this seems attributable to curing reversal at the hydrogen electrode. For high temperature fuel cell use, another curing scheme (again without the introduction of aliphatic character) must be found.\u3c/p\u3

Synthesis of phosphine and antibody-azide probes for in vivo staudinger ligation in a pretargeted imaging and therapy approach

\u3cp\u3eThe application of intact monoclonal antibodies (mAbs) as targeting agents in nuclear imaging and radioimmunotherapy is hampered by the slow pharmacokinetics of these molecules. Pretargeting with mAbs could be beneficial to reduce the radiation burden to the patient, while using the excellent targeting capacity of the mAbs. In this study, we evaluated the applicability of the Staudinger ligation as pretargeting strategy using an antibody-azide conjugate as tumor-targeting molecule in combination with a small phosphine-containing imaging/therapeutic probe. Up to 8 triazide molecules were attached to the antibody without seriously affecting its immunoreactivity, pharmacokinetics, and tumor uptake in tumor bearing nude mice. In addition, two \u3csup\u3e89\u3c/sup\u3eZr- and \u3csup\u3e67/68\u3c/sup\u3eGa-labeled desferrioxamine (DFO)-phosphines, a \u3csup\u3e177\u3c/sup\u3eLu-1,4,7,10-tetraazacyclododecane-1,4,7,10- tetraacetic acid (DOTA)-phosphine and a \u3csup\u3e123\u3c/sup\u3eI-cubyl phosphine probe were synthesized and characterized for their pharmacokinetic behavior in nude mice. With respect to the phosphine probes, blood levels at 30 min after injection were <5% injected dose per gram tissue, indicating rapid blood clearance. In vitro Staudinger ligation of 3.33 μM antibody-azide conjugate with 1 equiv of radiolabeled phosphine, relative to the azide, in aqueous solution resulted in 20-25% efficiency after 2 h. The presence of 37% human serum resulted in a reduced ligation efficiency (reduction max. 30% at 2 h), while the phosphines were still >80% intact. No in vivo Staudinger ligation was observed in a mouse model after injection of 500 μg antibody-azide, followed by 68 μg DFO-phosphine at t = 2 h, and evaluation in blood at t = 7 h. To explain negative results in mice, Staudinger ligation was performed in vitro in mouse serum. Under these conditions, a side product with the phosphine was formed and ligation efficiency was severely reduced. It is concluded that in vivo application of the Staudinger ligation in a pretargeting approach in mice is not feasible, since this ligation reaction is not bioorthogonal and efficient enough. Slow reaction kinetics will also severely restrict the applicability of Staudinger ligation in humans.\u3c/p\u3

Author Correction: Chemically triggered drug release from an antibody-drug conjugate leads to potent antitumour activity in mice:(Nature Communications, (2018), 9, 1, (1484), 10.1038/s41467-018-03880-y)

\u3cp\u3eThe original version of this Article omitted the following from the Acknowledgements: ‘This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs, through the Breast Cancer Research Program under Award No. W81XWH-15-1-0692. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the Department of Defense’. This error has now been corrected in the PDF and HTML versions of the Article.\u3c/p\u3

Chemically triggered drug release from an antibody-drug conjugate leads to potent antitumour activity in mice

\u3cp\u3eCurrent antibody-drug conjugates (ADCs) target internalising receptors on cancer cells leading to intracellular drug release. Typically, only a subset of patients with solid tumours has sufficient expression of such a receptor, while there are suitable non-internalising receptors and stroma targets. Here, we demonstrate potent therapy in murine tumour models using a non-internalising ADC that releases its drugs upon a click reaction with a chemical activator, which is administered in a second step. This was enabled by the development of a diabody-based ADC with a high tumour uptake and very low retention in healthy tissues, allowing systemic administration of the activator 2 days later, leading to efficient and selective activation throughout the tumour. In contrast, the analogous ADC comprising the protease-cleavable linker used in the FDA approved ADC Adcetris is not effective in these tumour models. This first-in-class ADC holds promise for a broader applicability of ADCs across patient populations.\u3c/p\u3