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PhD Discussions: Zhendong Xie and Júlia Alcàcer
Friday, December 15, 2023 @ 10:00 am–11:00 am
Integrating phenotypic targeting in physiologically-based pharmacokinetics modeling.
Zhendong Xie, Molecular Bionics group
Selective drugging, also known as the “magic bullet,” is the concept that drugs can target specific molecules, cells, or targets while minimising interactions with other parts of the body. Nanoparticles (NPs) with functioned ligands target cells with a certain range of receptors due to the multivalent effect. To develop precision drugs, it is crucial to understand how NPs are distributed in different organs and interact with different cell types in vivo. Our focus is on investigating the distribution of poly(2-(methacryloyloxy)ethylphosphorylcholine)-poly(2-(diisopropyl-amino)ethyl methacrylate) (PMPC-PDPA) polymersome. We use the PMPC polymersome’s interactions with different receptors to target specific cell groups based on phenotypic association theory (PAT), a statistical model based on the description between nanocarriers and cell phenotype (receptor density and glycocalyx).
We integrate phenotypic targeting in physiologically-based pharmacokinetics modeling (PBPK) to mimic the distribution of NPs in organs in silico to identify the most selective combination of parameters for precision drugs. The PBPK is built based on the circulation system, anatomy data, and cell protein atlas to predict the distribution of NPs among different organs, considering the advection among various biological fluids, diffusion of NPs in different organs, and NPs’ interaction with different cells. A non-Langmiur differential rate equation (NLDRE) is applied to extrapolate the PMPC-cell interaction kinetics based on single-cell level uptake experiments. The association constant/affinity kA/j is derived from the PAT to reveal the selectivity of NPs to different cells. We propose that the difference in kA/j results in a larger distribution and cell targeting discrimination.
Through experiments in vivo, we obtained information about drug distribution among different organs, the selectivity of NPs to different cells, and some undetectable parameters such as glycocalyx density. Based on these parameters, we change the injected dose, the NP radius, and the polymerization of the PMPC ligand to simulate the distribution of PMPC in silico and develop a better administration strategy.
Exploring host-pathogen interactions: Unraveling the dynamics of Pseudomonas aeruginosa and Burkholderia cenocepacia infection in Galleria mellonella
Júlia Alcàcer, Bacterial infections: antimicrobial therapies group
Pseudomonas aeruginosa and Burkholderia cenocepacia are two multidrug-resistant opportunistic pathogens often isolated from the lungs of cystic fibrosis patients. It is known that the presence of more than one species in an infection promotes the appearance of a network of interactions that can lead to an increase in their antimicrobial tolerance or to the evasion of the host immune system. Galleria mellonella has been used as an animal model throughout this study, as its immune system is comparable to that of mammals, and it presents practical advantages such as their easy maintenance. With the aim of understanding bacterial and host behaviors after infection, the survival rate of Galleria mellonella after a P. aeruginosa and B. cenocepacia single and dual-species infection was monitored, as well as the efficacy of antibiotic treatment to such infections. In order to characterize the infection evolution, the tissue-specific infection dissemination and hemocyte phagocytosis were evaluated through confocal microscopy.
