The search for new and innovative methods of cancer treatment is a major research field in pharmaceutics and biomedical engineering. Besides the development of new cancer drugs for systemic chemotherapy as well as improvements in radiotherapy and surgery, targeted drug delivery to tumour tissue using drug loaded colloidal vehicles is a major approach to increase efficacy and decrease possible side effects of chemotherapy. This strategy usually attempts to exploit the EPR effect to allow passive accumulation of a drug loaded vehicle inside the tumour tissue. A limitation of this strategy however is that the release of the encapsulated drug is primarily controlled by degradation of the vehicle or diffusion of the drug, which can take up to several weeks for complete release.
Another approach to improve chemotherapy is using external triggers for an immediate release of an encapsulated drug on-site. External triggers which should be preferably non-invasive such as laser light, electromagnetic fields, changes in pH or ultrasound are discussed in the literature. The current work concentrates on the use of ultrasound as an external trigger. Publications on US-triggered drug release work with so-called microbubbles. Microbubbles are stabilised gas bubbles that can interact with ultrasonic waves and are commercially used as contrast agents in ultrasound diagnostics. A key mechanism of how microbubbles can be used for drug release is the so-called phenomenon of inertial cavitation. Inertial cavitation describes an event where a bubble in a liquid expands and collapses implosively, emitting shock waves of high energy. This energy may be used for drug delivery. A major limitation of the microbubble approach is that the systemic distribution of MBs in the body is restricted solely to the vascular system. Owing to their size they are not able to accumulate inside tumour tissue.
To overcome these obstacles, a combination of nanomedicine and ultrasound triggered drug release is presented in this thesis. This combination leads to so-called sonosensitive nanoparticles. These particles should be able to accumulate in the tumour and release their payload by an externally applied ultrasonic field. This approach has the potential to improve common systemic chemotherapy substantially, as a localised drug delivery can be achieved.
The concept of this work is based on recent findings that nanoparticles with highly rough and lipophilic surfaces are able to decrease the inertial cavitation threshold of water. Inertial cavitation is the key mechanism for ultrasound triggered drug delivery. The aim of this thesis is therefore the development of different preparation techniques for nanoparticles that can cause inertial cavitation in an ultrasonic field. The ultrasound used for the initiation of cavitation must lie in the therapeutic or diagnostic region, i.e. frequencies ≥ 0.5 MHz or 2 MHz, respectively.
The thesis is divided into three main sections that present and discuss different preparation methods and the physical and acoustic characterisation of the prepared nanostructures. The three principles are a Layer-by-Layer approach, the “Grand Canyon” approach and the “Hub Cap” approach.
Briefly, all of them produce nanoparticles of specific morphology that should be capable to adsorb tiny air bubbles on their surface. These air bubbles are required for the instigation of inertial cavitation. The mechanism is proposed to be as follows. First, nanoparticles of a specific shape are prepared. Subsequently, adsorption of tiny air bubbles on their surface is allowed e.g. by drying and reconstitution. The attached bubbles can grow, oscillate and cavitate inertially in an ultrasonic field which can be measured by passive acoustic detection.
Air adsorption on rough and hydrophobic surfaces for causing cavitation in an ultrasonic field is a generally accepted concept but has never been proven directly on nanoparticles. As part of this work it is therefore intended to obtain evidence of the adsorption of air bubbles on the surface of the prepared nanoparticles
