Amine‐carbamate self‐immolative (SI) spacers represent practical and versatile tools in targeted prodrugs, but their slow degradation mechanism limits drug activation at the site of disease. We engineered a pyrrolidine‐carbamate SI spacer with a tertiary amine handle which strongly accelerates the spacer cyclization to give a bicyclic urea and the free hydroxy groups of either cytotoxic (Camptothecin) or immunostimulatory (Resiquimod) drugs. In silico conformational analysis and pKa calculations suggest a plausible mechanism for the superior efficacy of the advanced SI spacer compared to state‐of‐art analogues.
Pseudomonas
aeruginosa is a ubiquitous
multi-drug-resistant bacterium, capable of causing serious illnesses
and infections. This research focuses on the development of a thermal
sensor for the indirect detection of P. aeruginosa infection using molecularly imprinted polymers (MIPs). This was
achieved by developing MIPs for the detection of pyocyanin, the main
toxin secreted by P. aeruginosa. To
this end, phenazine was used as a dummy template, evaluating several
polymeric compositions to achieve a selective MIP for pyocyanin recognition.
The sensitivity of the synthesized MIPs was investigated by UV–vis
analysis, with the best composition having a maximum rebinding capacity
of 30 μmol g–1 and an imprinting factor (IF)
of 1.59. Subsequently, the MIP particles were immobilized onto planar
aluminum chips using an adhesive layer, to perform thermal resistance
measurements at clinically relevant concentrations of pyocyanin (1.4–9.8
μM), achieving a limit of detection (LoD) of 0.347 ± 0.027
μM. The selectivity of the sensor was also scrutinized by subjecting
the receptor to potential interferents. Furthermore, the rebinding
was demonstrated in King’s A medium, highlighting the potential
of the sensor for the indirect detection of P. aeruginosa in complex fluids. The research culminates in the demonstration
of the MIP-based sensor’s applicability for clinical diagnosis.
To achieve this goal, an experiment was performed in which the sensor
was exposed to pyocyanin-spiked saliva samples, achieving a limit
of detection of 0.569 ± 0.063 μM and demonstrating that
this technology is suitable to detect the presence of the toxin even
at the very first stage of its production.
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