Theranostics is an emerging treatment approach that combines diagnostics with therapy in order to personalize treatment regimens for individual patients and decrease cancer mortality. Previously, nanoparticles entrapping conventional fluorescent dyes were developed for cancer theranostics, but fluorescent nanoparticles did not allow clinicians to significantly improve cancer treatments. The use of fluorescent dyes that are sensitive to solvent acidity (halo-fluorochromism) and polarity (solvato-fluorochromism) may overcome the limitations of fluorescent nanoparticles and improve cancer therapy by enabling researchers to detect chemical properties within the nanoparticle core environment. The model halo- and solvato-fluorochromic dye Nile blue was attached to the core of nanoscale drug delivery systems called polymer nanoassemblies (PNAs), which were created by tethering hydrophilic polymers and hydrophobic groups to a cationic polymer scaffold. The fluorescence of empty PNAs increased by 100% at pH 5.0 compared to pH 7.4, and the fluorescence of drug-loaded PNAs increased up to 300% compared to empty PNAs. A comparison of the fluorochromic properties between PNAs with various core properties indicated that both hydrophobic pendant groups and scaffold amines contributed to the fluorochromism of PNAs. The halo-fluorochromism of PNAs allowed investigators to minimize the detection of fluorescence signals in healthy organs such as the liver. Fluorescence imaging of halo-fluorochromic PNAs diffused into tissue mimics indicated that fluorescence of PNAs in tissues increased by 100% at pH 7.0 compared to pH 7.4. In addition, halo-fluorochromic PNAs identified the acidic perimeter surrounding metastatic tumors in orthotopic metastatic tumor models. Computational simulations of metastatic lesions verified that some halo-fluorochromic PNAs accumulate in the hypoxic/acidic regions of metastatic tumors following intravenous administration. These simulations also indicated that the accumulation of PNAs in the hypoxic regions of tumors doubles at 12 hours post-treatment compared to 1.8 hours post-treatment. The solvato-fluorochromism of PNAs enabled the fluorescence-based measurement of drug release from the nanoassembly core during dialysis-based drug release measurements. Solvato-fluorochromic methods indicated faster drug release rates than HPLC-based methods. Mechanistic modeling of drug release indicated that solvato-fluorochromic methods were unaffected by released drugs that interfered with HPLC-based methods. However, mechanistic modeling also indicated that drug rebinding and diffusion did not account for all of the differences between drug release rates determined by solvato-fluorochromic- and HPLC-based methods. Based on this evidence, it was hypothesized that solvato-fluorochromic drug release methods measure drug diffusion from near the scaffold of PNAs in a small region of the nanoassembly core, and that this process contributes to overall drug release but does not indicate apparent drug release rates for PNAs. In order to develop PNAs for potential clinical applications, ionizable amines were removed from the polymer scaffold to increase drug loading and sustain the release of model drugs carfilzomib and docetaxel. The removal of primary amines decreased drug diffusivity in the core of PNAs (D from 3.9*10-18 cm2/s to 0.1*10-19 cm2/s) and increased the drug release half-life (t1/2 from 4 to 26 hours). The controlled release of carfilzomib from PNAs reduced drug metabolism by 60% for up to one hour and sustained proteasome inhibition in cancer cells at 72 h post-treatment compared to free drug. Overall, this work provides insight into the design of theranostic nanoparticles with beneficial properties for improving cancer treatment.

Ce travail porte sur la synthèse et l’évaluation de systèmes pi-conjugués en tant matériaux actifs pour des dispositifs opto(électroniques). Un premier chapitre décrit une série d’oligothiophènes cruciformes et leur évaluation dans des dispositifs électrochromes. Le second chapitre décrit la synthèse d’accepteurs moléculaires à base de benzodithiophène et l’analyse de leur potentialités comme matériaux accepteurs dans des cellules solaires organiques. La plus large part du travail porte sur l’analyse des relations structure-propriétés d’une série de petites molécules push-pull comportant un groupe donneur triphénylamine (TPA) relié à un groupe accepteur par un espaceur thiényl. Une première étape a consisté à remplacer l’un des cycles phényles de la TPA par des groupes aromatiques tels que p-fluorophényle, anthryle et naphtyle. Ces modifications ont peu d’influence sur les propriétés électroniques de la molécule mais induisent de large variations des propriétés de transport de charge et de conversion photovoltaïque des matériaux correspondants. Au cours d’une seconde étape l’un des groupes phényles de la TPA a été remplacé par des chaînes alkyle, perfluoroalkyle et oligo(oxyethylene). Les résultats de diffraction X, spectroscopie d’absorption et de fluorescence, génération de second harmonique et électrochimie démontrent que certaines de ces molécules présentent des propriétés d’émission contrôlées par agrégation tandis que les matériaux correspondants se réorganisent spontanément à l’état solide sous forme d’agrégats H ou J dotés de propriétés de transport de charges et de conversion photovoltaïque fortement améliorées et de propriétés d’absorption, d’émission et de génération de second harmonique mécaniquement modulables. / This work deals with the design, synthesis and evaluation of molecular pi-conjugated systems as active materials for (opto)electronics devices. A short first chapter describes three X-shaped oligothiophenes, thecharacterization of their structure and properties and a first evaluation of their performances in electrochromic devices. The second chapter describes the synthesis of molecular acceptors based on a benzodithiophene and the analysis of their potentialities when combined with molecular donors in organic solar cells.The major part of the work is focused on the analysis of structure-properties relationships of a series of smallpush-pull molecules involving di- or tri-arylamine donorblocks linked to an acceptor group by a thienyl bridge. In a first step, a phenyl ring of triphenylamine (TPA) is replaced by p-fluorophenyl, anthryl and naphtyl groups.Optical and electrochemical results show that substitution has little effect at the molecular level but can markedly affect solid-state properties with in particular an improvement of charge-transport and short-circuit current density of solar cells based on these donor materials.In a second step, a phenyl ring of TPA is replaced by alkyl, perfluoroalkyl and oligo(oxyethylene) chains. Results of X-ray diffraction, absorption and photoluminescence spectroscopies, second harmonic generation, and electrochemistry demonstrate that some of these molecules under go aggregation controlled photoluminescence emission wave length while the corresponding materials spontaneous lyre organize in the solid-state to form either H or Jaggregates with enhanced charge mobility, photovoltaic conversion efficiency and mechanically-induced chromism, fluorochromism and NLO-chromism.