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要旨:
Motivated by the selective adsorption of functionalised drug carrier particles to certain
cell types for medical applications this thesis investigates fundamental heteroaggregation
phenomena under special consideration of the dynamic behaviour in physical
and biological model systems. The adsorption of antibodies as possible functional
moieties to receptors on cell surfaces represents an essential first step in a series
of further transport limitations for the cellular uptake of functionalised drug carrier
particles. To establish suitable scientific methods for the analysis of selective and
competitive heteroaggregation processes, the specific interaction and heteroaggregation
of multiple colloid constituents was studied in physical particle systems first.
Experimental methods primarily include flow cytometry and diverse microscopic
techniques, while simulations are based on population balance equations with kernel
models rooting in classical colloid science. Both approaches were transferred to
biological systems to achieve a more rigorous description of drug delivery dynamics
and efficiency. This could prove valuable for future optimisation efforts.
Flow cytometry was established as a very powerful and convenient tool to characterise
cluster composition and its dynamics in heteroaggregation processes. It enables
an independent and very detailed resolution of multidimensional distributions
by a reliably automated single particle analysis. Investigations in binary and ternary
particle mixtures focus on electrostatic de- and restabilisation phenomena, that can
be tailored by the choice of suitable particle species and their mixing ratio. Experimental
results were reconstructed by multivariate population balance simulations in
which the internal coordinates represent the particle number of the respective species
inside an aggregate. The physically discrete property state space was adaptively
reduced by a semi-heuristic approach, so that only property coordinates featuring
high aggregate concentrations were considered in the model. The applied aggregation
kernels are based on deterministic models from colloid science, in particular
DLVO theory, and connect interactions on the single-particle level with the macroscopic
behaviour of multiple particle populations. The methods established for particle
systems were successfully transferred to a systematic, model-based investigation
of preferential aggregation processes in a ternary system of antibodies and two human
tumour cell lines (KARPAS-299 and U-937). Despite the assumed instantaneous
aggregation following receptor-ligand collisions, the low receptor expression on cellular
surfaces causes a rate limited aggregation process (RLCA). Population balance
simulations with kernels that consider the strong surface heterogeneities of the aggregating
species (patchy particles) confirm the experimental results. The targeted
administration of pharmaceutical compounds by functionalised carrier particles to
specific cells under minimisation of adverse effects represents a potential area of application
of these results.
