Design and evaluation of drug loaded microbubbles for ultrasound guided cancer therapy

Cancer is a genetic disease, caused by mutations in the genome of normal cells. Chemical and physical damage to the cellular genome can induce these mutations resulting in the transformation of a healthy cell into a tumor cell. Over the past years, researchers have acquired a basic understanding of tumor onset. Several important proto-oncogenes and proteins involved in angiogenesis have been identified, leading to the development and clinical use of several new anticancer agents. We succeeded in preparing microbubbles which are able to carry genetic (pDNA, siRNA) and chemotherapeutic (doxorubicin) drugs. We proved that these microbubbles can selectively deliver their genetic or chemotherapeutic drugs to melanoma cells upon ultrasound exposure. We also showed that the activity of currently available drug carriers (pDNA or siRNA lipoplexes and doxorubicin-liposomes) was significantly improved by microbubble coupling and ultrasound exposure. This enables us to obtain a space and time controlled drug delivery guided by ultrasound. The fact that ultrasound and microbubbles have already been approved for ultrasound contrast imaging and are currently used in daily clinic, makes it very plausible that the microbubble concept reported in this thesis may find its way as an advanced drug delivery system

Ultrasound assisted siRNA delivery using PEG-siPlex loaded microbubbles

Short interfering RNA (siRNA) attracts much attention for the treatment of various diseases. However, its delivery, especially via systemic routes, remains a challenge. Indeed, naked siRNAs are rapidly degraded, while complexed siRNAs massively aggregate in the blood or are captured by macrophages. Although this can be circumvented by PEGylation, we found that PEGylation had a strong negative effect on the gene silencing efficiency of siRNA-liposome complexes (siPlexes). Recently, ultrasound combined with microbubbles has been used to deliver naked siRNA but the gene silencing efficiency is rather low and very high amounts of siRNA are required. To overcome the negative effects of PEGylation and to enhance the efficiency of ultrasound assisted siRNA delivery, we coupled PEGylated siPlexes (PEG-siPlexes) to microbubbles. Ultrasound radiation of these microbubbles resulted in massive release of unaltered PEG-siPlexes. Interestingly, PEG-siPlexes loaded on microbubbles were able to enter cells after exposure to ultrasound, in contrast to free PEG-siPlexes, which were not able to enter cells rapidly. Furthermore, these PEG-siPlex loaded microbubbles induced, in the presence of ultrasound, much higher gene silencing than free PEG-siPlexes. Additionally, the PEG-siPlex loaded microbubbles only silenced the expression of genes in the presence of ultrasound, which allows space and time controlled gene silencing

Fraturas de Ossos Longos em Aves de Rapina: Análise de Casos do Centro de Fauna de Torreferrussa

Moreau Jean-Paul, Lentacker Firmin. Pierre Flatres ; Atlas et Géographie du Nord et de la Picardie, 1980. In: Hommes et Terres du Nord, 1981/2. Spécial Picardie. pp. 85-86

Choose your models wisely: how different murine bone marrow-derived dendritic cell protocols influence the success of nanoparticulate vaccines in vitro

A