Proton radiotherapy has a dosimetric advantage over photon therapy to spare healthy tissue closely positioned to the tumor mainly due to the absent exit dose. In The Netherlands, the Proton therapy centers currently take a relative biological effectiveness (RBE) of 1.1 compared to photons to deliver an iso-effective treatment. However, initial clinical evidence indicates a variable proton RBE in brain patients with the linear energy transfer (LET) as an important physical parameter. The LET significantly increases at the end of the radiation field, and contributes to an increased probability to develop brain lesions. With the introduction of radiation response models, the first goal of this thesis is to evaluate the impact of the RBE/LET effect in intensity-modulated proton therapy (IMPT) plans. Furthermore, the main goal is to reduce the RBE/LET effect in treatment planning.

We incorporated the probability of lesions origin (POLO) model published in literature to determine the RBE model-based normal tissue complication probability (NTCP) for three glioma patients treated with IMPT at HollandPTC, The Netherlands. The dose and LET distributions were computed using a Monte Carlo system. For the investigation of the RBE/LET effect in treatment planning, we modified several beam settings of the clinical IMPT plan, including the beam angle, beam energy, and robustness. Furthermore, we combined treatment modalities to reduce the NTCP.

We compared the results of the clinically used IMPT plan with the results obtained by the modified IMPT plans. The local redistribution of LETd leads to a decrease in NTCP up to the point when the LETd becomes uniform. The robustness did not reveal deviations in terms of the NTCP. By choosing appropriate beam angles that result in a smeared out
LETd distribution, the NTCP does not improve for small deep located tumors, improves relatively modest by 11.6% for elongated tumors, and significantly improves by 37.0% for large, superficially located tumors. The inclusion of partial transmission beams lowers the NTCP by 30-50% relative to the clinical IMPT plan while limiting the relative increase in mean brain dose by 5-16%. When comparing the IMPT plan with the photon plan used for plan comparison, the VMAT plan always results in the lowest NTCP and provides a relative improvement in NTCP by 60-75%. Meanwhile, the mean brain dose significantly increases by 50-80% compared to the clinical IMPT plan. Intermediate NTCP-Dmean(brain minus CTV) values are achieved when combining protons with the photons or by including proton transmission beams.

In general, we can conclude that the inclusion of partial proton transmission beams is more promising than choosing appropriate beam angles to lower the RBE/LETd effect. However, further optimization of transmission beams is required. Moreover, an improvement in NTCP is always at the cost of the mean dose to healthy tissue. On top, our results support further investigation to combine different modalities, like protons and photon fractionation.

Liposomes, self-assembled vesicles with a lipid-bilayer boundary similar to cell membranes, are extensively used in both fundamental and applied sciences. Manipulation of their physical properties, such as growth and division, may significantly expand their use as model systems in cellular and synthetic biology. Several approaches have been explored to controllably divide liposomes, such as shape transformation through temperature cycling, incorporation of additional lipids, and the encapsulation of protein division machinery. However, so far, these methods lacked control, exhibited low efficiency, and yielded asymmetric division in terms of volume or lipid composition. Here, we present a microfluidics-based strategy to realize mechanical division of cell-sized (∼6 μm) liposomes. We use octanol-assisted liposome assembly (OLA) to produce liposomes on chip, which are subsequently flowed against the sharp edge of a wedge-shaped splitter. Upon encountering such a Y-shaped bifurcation, the liposomes are deformed and, remarkably, are able to divide into two stable daughter liposomes in just a few milliseconds. The probability of successful division is found to critically depend on the surface area-to-volume ratio of the mother liposome, which can be tuned through osmotic pressure, and to strongly correlate to the mother liposome size for given microchannel dimensions. The division process is highly symmetric (∼3% size variation between the daughter liposomes) and is accompanied by a low leakage. This mechanical division of liposomes may constitute a valuable step to establish a growth-division cycle of synthetic cells.

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