The viability of a drug delivery system which encapsulates chemotherapeutic drugs (Doxorubicin) in the hydrophobic core of polymeric micelles and triggers release by ultrasound application was investigated at an applied frequency of 500 kHz. The investigation also included elucidating the mechanism of drug release at 70 kHz, a frequency which had previously been shown to induce drug release. A fluorescence detection chamber was used to measure in vitro drug release from both Pluronic and stabilized micelles and a hydrophone was used to monitor bubble activity during the experiments. A threshold for release between 0.35 and 0.40 in mechanical index was found at 70 kHz and shown to correspond with the appearance of the subharmonic signal in the acoustic spectrum. Additionally, drug release was found to correlate with increase in subharmonic emission. No evidence of drug release or of the subharmonic signal was detected at 500 kHz. These findings confirmed the role of cavitation in ultrasonic drug release from micelles. A mathematical model of a bubble oscillator was solved to explore the differences in the behavior of a single 10 um bubble under 70 and 500 kHz ultrasound. The dynamics were found to be fundamentally different; the bubble follows a period-doubling route to chaos at 500 kHz and an intermittent route to chaos at 70 kHz. It was concluded that this type of "intermittent subharmonic" oscillation is associated with the apparent drug release. This research confirmed the central role of cavitation in ultrasonically-triggered drug delivery from micelles, established the importance of subharmonic bubble oscillations as an indicator, and expounded the key dynamic differences between 70 and 500 kHz ultrasonic cavitation.

Les chromophores classiques ne sont pas toujours efficaces en absorption à deux photons. Leur faible efficacité nécessite l'utilisation de fortes puissances laser et de grandes concentrations en colorants. Dans ce sens, la microscopie à deux photons in vivo requière le développement de nouvelles stratégies de marquage utilisant des chromophores spécialement dédiés à la microscopie à deux photons. Dans le cadre de collaborations avec des chimistes spécialisés dans la synthèse de molécules à forte section efficace d'absorption à deux photons, différents chromophores ont été synthétisés. Ces molécules organiques sont souvent hydrophobes et ne sont pas utilisables directement pour les applications en biologie. Le travail effectuer ici a consisté à encapsuler ces molécules dans des micelles de copolymères biocompatibles, les Pluronic. Les Pluronic sont des matériaux pouvant s'auto assembler en milieu aqueux sous forme de micelles et permettent de solubiliser des composés hydrophobes. Cette stratégie est déjà utilisé pour permettre de transporter différents composés hydrophobes dans les organismes vivants et a été utilisée ici pour transporter des chromophores ultrasensibles à deux photons dans le sang de manière à imager la vascularisation in vivo. / Classic fluorescent dyes are not necessary efficient in two-photon absorption. Their low two-photon absorption efficiency often requires high laser power and important dye concentrations. Therefore, new dyes and other administration strategies need to be developed specifically for intravital two-photon microscopy. In collaboration with chemists, specialized in the synthesis of molecules with a high two-photon absorption cross-section, different dyes have been synthesized. Most of these dyes are hydrophobic and not directly suitable for biological applications. The work presented in this thesis consisted of encapsulating hydrophobic molecules in biocompatible Pluronic block copolymers. In water, Pluronic unimers with hydrophobic and hydrophilic blocks self-assembled in hydrophilic micelles forming a hydrophobic core around the molecules. This strategy has been used already for the transport and delivery of different hydrophobic molecules in living organism. In the present study, this strategy has been transposed to transport ultra sensitive two-photon dyes in the blood plasma for deep vascular imaging in vivo.