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A new self-immolative linker motif, Ortho Hydroxy-Protected Aryl Sulfate (OHPAS), was devised, and OHPAS-containing antibody drug conjugates (ADC) were tested in vitro and in vivo. Conveniently synthesized using Sulfur Fluorine Exchange (SuFEx) chemistry, it is based structurally on diaryl sulfate, with one aryl acting as a payload and the other as a self-immolative sulfate unit having a latent phenol function at the ortho position. The chemically stable OHPAS linker was stable in plasma samples from 5 different species, yet it can release the payload molecule smoothly upon chemical or biological triggering. The payload release proceeds via intramolecular cyclization, producing a cyclic sulfate coproduct that eventually hydrolyzes to a catechol monosulfate. A set of OHPAS-containing ADCs based on Trastuzumab were prepared with a drug to antibody ratio of ∼2, and were shown to be cytotoxic in 5 different cancer cell lines in vitro and dose-dependently inhibited tumor growth in a NCI-N87 mouse xenograft model. We conclude that OHPAS conjugates will be of considerable use for delivering phenol-containing payloads to tissues targeted for medical intervention.

Electrode-to-cell/tissue interfaces with high biocompatibility, low impedance, and long-term chemical and mechanical stability are of paramount importance in numerous biological and biomedical applications. For meticulous monitoring of biological parameters, there is a rapidly growing interest in sensing at subcellular levels with radically improved spatiotemporal resolution, which necessitates ultra-miniaturized electrodes with significant reduction in electrode contact sizes. Such aggressive electrode downsizing inevitably impacts the electrochemical interfaces, with the consequences still poorly understood. This paper reports the first systematic analysis of the interfacial electrochemical impedance spectroscopy of electrodes comprising a variety of biocompatible electrode materials consisting of gold (Au), platinum (Pt), indium tin oxide, and titanium nitride (TiN) coated with/without an organic polymer, poly­(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS), with electrode diameters (D) ranging from millimeter to subcellular (<10 μm) dimensions. PEDOT:PSS-coated electrodes have greater Faradaic charge-transfer capability and capacitive coupling compared to their uncoated counterparts. At D = 10–200 μm, the PEDOT:PSS coating reduces the electrode interfacial impedance at 1 kHz by up to ×101.6, while at D > 200 μm, the effect is lessened due to the dominance of solution, or bulk electrolyte, and routing resistance. The low interfacial impedance of PEDOT:PSS-coated electrodes makes them promising candidates for next-generation bioelectrical interfaces with subcellular spatial resolution.

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