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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