Dynamics of ion-regulated photoinduced electron transfer in BODIPY-BAPTA conjugates

International audienceEfficient Ca2+-switched fluorescent sensors, where fluorescence output is governed by a light-activated ion-gated electron transfer pathway, can be obtained on combining BODIPY chromophores with a readily oxidized biocompatible and selective BAPTA receptor. Herein we report the synthesis and studies of two such conjugates, which vary in the nature of the spacer separating the two electroactive components, namely none (1) or phenyl (2). Single crystal X-ray crystallography and molecular modelling structures and calculations give information on molecular and electronic structure, while steady-state fluorescence experiments show high Ca2+-induced fluorescence enhancement factors of 122 and 23 and Kd values of 0.50 μM and 0.13 μM for 1 and 2, respectively. Notably, studies of the ultrafast photoinduced processes (through transient absorption spectroscopy) give access to electron transfer dynamics in pseudophysiological media as well as in a polar non-protic solvent and information about the fate of the excited molecules in the presence and absence of calcium. In water, electron transfer rates as high as 3.3 × 1012 s−1 and 8.3 × 1011 s−1 are measured for the ion-free, directly connected conjugate and the variant incorporating a phenyl spacer, respectively. This electron transfer pathway is efficiently blocked by the presence of an ion, restoring fluorescence

Drug delivery, biodistribution and anti-EGFR activity: theragnostic nanoparticles for simultaneous in vivo delivery of tyrosine kinase inhibitors and kinase activity biosensors

In vivo delivery of small molecule therapeutics to cancer cells, assessment of the selectivity of administration, and measuring the efficacity of the drug in question at the molecule level, are important ongoing challenges in developing new classes of cancer chemotherapeutics. One approach that has the potential to provide targeted delivery, tracking of biodistribution and readout of efficacy, is to use multimodal theragnostic nanoparticles to deliver the small molecule therapeutic. In this paper, we report the development of targeted theragnostic lipid/peptide/DNA lipopolyplexes. These simultaneously deliver an inhibitor of the EGFR tyrosine kinase, and plasmid DNA coding for a Crk-based biosensor, Picchu-X, which when expressed in the target cells can be used to quantify the inhibition of EGFR in vivo in a mouse colorectal cancer xenograft model. Reversible bioconjugation of a known analogue of the tyrosine kinase inhibitor Mo-IPQA to a cationic peptide, and co-formulation with peptides containing both EGFR-binding and cationic sequences, allowed for good levels of inhibitor encapsulation with targeted delivery to LIM1215 colon cancer cells. Furthermore, high levels of expression of the Picchu-X biosensor in the LIM1215 cells in vivo allowed us to demonstrate, using fluorescence lifetime microscopy (FLIM)-based biosensing, that EGFR activity can be successfully suppressed by the tyrosine kinase inhibitor, released from the lipopolyplexes. Finally, we measured the biodistribution of lipopolyplexes containing 125I-labelled inhibitors and were able to demonstrate that the lipopolyplexes gave significantly higher drug delivery to the tumors compared with free drug

Solution of the Bethe-Salpeter equation for pion-nucleon scattering

A relativistic description of pion-nucleon scattering based on the four-dimensional Bethe-Salpeter equation is presented. The kernel of the equation consists of s- and u-channel nucleon and delta pole diagrams, as well as rho and sigma exchange in the t-channel. The Bethe-Salpeter equation is solved by means of a Wick rotation, and good fits are obtained to the s- and p-wave phase shifts up to 360 MeV pion laboratory energy. The coupling constants determined by the fits are consistent with the commonly accepted values in the literature.Comment: 34 pages, RevTeX; 7 figures. Several references added, a few typos corrected. Accepted for publication in Physical Review