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The demand for LIB with enhanced energy densities leads to increased utilization of the space within the confinements of the battery housing or to the use of electrode material with increased intrinsic specific energy densities. Both requirements result in more stress on the battery electrodes and separator during cycling or aging. However, the effect of mechanical strain on the cell’s electrochemistry and thus the performance of batteries is rather unexplored compared to the impact of current or temperature, for example. The objective of this thesis was to give a better understanding of the electrochemical and mechanical interplay in current- and next-generation lithium based battery cells. Therefore, the thesis was structured into the investigations on SoA and next-generation LIBs. For SoA LIBs, the investigations of the interplay started at laboratory scale. Here, the expansion of various electrodes and also the impact of mechanical pressure and its distribution on the performance of the cells were
studied. The investigations at laboratory scale was followed by an examination of the electrochemical and mechanical interactions on large format commercial LIBs which are used in BEVs. Accordingly, the effect of bracing and its effect on the performance was studied in an aging and post-mortem study. To gain a deeper understanding of the mechanical changes in LIBs, an ultrasonic study was performed for pouch cells. Here, the mechanical changes were further investigated in dependence of SoC and SoH. The effects of the mechanical stress on the performance for next-generation batteries were studied at laboratory scale. In the beginning, the expansion of next-generation anode materials such as silicon and lithium was compared with today’s anode materials. Furthermore, the effect of mechanical pressure and electrolyte on the irreversible dilation and performance was investigated for lithium metal cells. Overall, it was shown that pressure has a significant effect on the performance of today’s and also future LIBs. The interplay of the electrochemical and mechanical effects inside a LIB has a considerable impact on the lifetime, capacity fading and impedance increase of the batteries.
A series of tetracationic bis-triarylborane dyes, differing in the aromatic linker connecting two dicationic triarylborane moieties, showed very high submicromolar affinities toward ds-DNA and ds-RNA. The linker strongly influenced the emissive properties of triarylborane cations and controlled the fluorimetric response of dyes. The fluorene-analog shows the most selective fluorescence response between AT-DNA, GC-DNA, and AU-RNA, the pyrene-analog’s emission is non-selectively enhanced by all DNA/RNA, and the dithienyl-diketopyrrolopyrrole analog’s emission is strongly quenched upon DNA/RNA binding. The emission properties of the biphenyl-analog were not applicable, but the compound showed specific induced circular dichroism (ICD) signals only for AT-sequence-containing ds-DNAs, whereas the pyrene-analog ICD signals were specific for AT-DNA with respect to GC-DNA, and also recognized AU-RNA by giving a different ICD pattern from that observed upon interaction with AT-DNA. The fluorene- and dithienyl-diketopyrrolopyrrole analogs were ICD-signal silent. Thus, fine-tuning of the aromatic linker properties connecting two triarylborane dications can be used for the dual sensing (fluorimetric and CD) of various ds-DNA/RNA secondary structures, depending on the steric properties of the DNA/RNA grooves.
In the last few years, fluorescence resonance energy transfer (FRET) receptor sensors have contributed to the understanding of GPCR ligand binding and functional activation. FRET sensors based on muscarinic acetylcholine receptors (mAChRs) have been employed to study dual-steric ligands, allowing for the detection of different kinetics and distinguishing between partial, full, and super agonism. Herein, we report the synthesis of the two series of bitopic ligands, 12-Cn and 13-Cn, and their pharmacological investigation at the M\(_1\), M\(_2\), M\(_4\), and M\(_5\) FRET-based receptor sensors. The hybrids were prepared by merging the pharmacophoric moieties of the M\(_1\)/M\(_4\)-preferring orthosteric agonist Xanomeline 10 and the M\(_1\)-selective positive allosteric modulator 77-LH-28-1 (1-[3-(4-butyl-1-piperidinyl)propyl]-3,4-dihydro-2(1H)-quinolinone) 11. The two pharmacophores were connected through alkylene chains of different lengths (C3, C5, C7, and C9). Analyzing the FRET responses, the tertiary amine compounds 12-C5, 12-C7, and 12-C9 evidenced a selective activation of M\(_1\) mAChRs, while the methyl tetrahydropyridinium salts 13-C5, 13-C7, and 13-C9 showed a degree of selectivity for M\(_1\) and M\(_4\) mAChRs. Moreover, whereas hybrids 12-Cn showed an almost linear response at the M\(_1\) subtype, hybrids 13-Cn evidenced a bell-shaped activation response. This different activation pattern suggests that the positive charge anchoring the compound 13-Cn to the orthosteric site ensues a degree of receptor activation depending on the linker length, which induces a graded conformational interference with the binding pocket closure. These bitopic derivatives represent novel pharmacological tools for a better understanding of ligand-receptor interactions at a molecular level.
Poor or variable oral bioavailability is of major concern regarding safety and efficacy for the treatment of patients with poorly water-soluble drugs (PWSDs). The problem statement of this work involves a pharmaceutical development perspective, the physicochemical basis of the absorption process and physiological / biopharmaceutical aspects. A methodology was developed aiming at closing the gap between drug liberation and dissolution on the one hand and the appearance of drug in the blood on the other. Considering what is out of control from a formulation development perspective, a clear differentiation between bioavailability and bioaccessibility was necessary. Focusing on the absorption process, bioaccessibility of a model compound, a poorly soluble but well permeable weak base, was characterized by means of flux across artificial biomimetic membranes. Such setups can be considered to reasonably mimic relevant oral absorption resistances in vitro in terms of diffusion through an unstirred water layer (UWL) and a lipidic barrier. Mechanistic understanding of the driving force for permeation was gained by differentiating drug species and subsequently linking them to the observed transfer rates using a bioaccessibility concept. The three key species that need to be differentiated are molecularly dissolved drug, drug associated in solution with other components (liquid reservoir) and undissolved drug (solid reservoir). An innovative approach to differentiate molecularly dissolved drug from the liquid reservoir using ultracentrifugation in combination with dynamic light scattering as control is presented. A guidance for rational formulation development of PWSDs is elaborated based on the employed model compound. It is structured into five guiding questions to help drug formulation scientists in selecting drug form, excipients and eventually the formulation principle. Overall, the relevance but also limitations of characterizing bioaccessibility were outlined with respect to practical application e.g. in early drug formulation development.
Based on previous results showing that thioether modification of gold nanoparticles (AuNPs), especially coating with a multivalent system, yielded in excellent colloidal stability, the first aim of this thesis was to prove whether functionalization of silver nanoparticles (AgNPs) with thioether also has a comparable or even enhanced stabilization efficacy compared with the gold standard of coating with thiols and, particularly, whether the multivalency of polymers leads to stable AgNPs conjugates. Herein, AgNPs coated with mono- and multivalent thiol- and thioether polymers were prepared to systematically investigate the adsorption kinetics onto the silver surface as well as the colloidal stability after exposure to different conditions relevant for biomedical application. Although the thioether-polymers showed a slower immobilization onto AgNPs, same or mostly even better stabilization was exhibited than for the thiol analogs.
As multivalent thioether-poly(glycidol) (PG) is already proven as a promising candidate for AuNP modification and stabilization, the second aim of this thesis was to examine the stealth behavior of thioether-PG, side-chain functionalized with various hydrophobic (alkyl and cholesteryl) units, to gain a deeper understanding of AuNP surface functionalization in terms of protein adsorption and their subsequent cellular uptake by human monocyte-derived macrophages. For this purpose, citrate-stabilized AuNPs were modified with the amphiphilic polymers by ligand exchange reaction, followed by incubation in human serum. The various surface amphiphilicities affected protein adsorption to a certain extent, with less hydrophobic particle layers leading to a more inhibited protein binding. Especially AuNPs functionalized with PG carrying the longest alkyl chain showed differences in the protein corona composition compared to the other polymer-coated NPs. In addition, PGylation, and especially prior serum incubation, of the NPs exhibited reduced macrophage internalization.
As the use of mammals for in vivo experiments faces various challenges including increasing regulatory hurdles and costs, the third aim of this thesis was to validate larvae of the domestic silkworm Bombyx mori as an alternative invertebrate model for preliminary in vivo research, using AuNPs with various surface chemistry (one PEG-based modification and three PG-coatings with slightly hydrophobic functionalization, as well as positively and negatively charges) for studying their biodistribution and elimination. 6 h and 24 h after intra-hemolymph injection the Au content in different organ compartments was measured with ICP-MS, showing that positively charged particles appeared to be eliminated most rapidly through the midgut, while AuNPs modified with PEG, alkyl-functionalized PG and negatively charged PG exhibited long-term bioavailability in the silkworm body.
Für Kinder und Jugendliche stellt die Blutentnahme im Rahmen des Therapeutischen Drug Monitorings (TDM) aufgrund der Invasivität häufig eine große physische sowie psychische Belastung dar. Diese Stresssituation kann durch Speichelsammlung aufgrund des nicht invasiven Prozederes vermieden und zusätzlich der Material-, Personal- und Zeitaufwand im Vergleich zu einer Blutentnahme minimiert werden. Da die therapeutischen Referenzbereiche in der AGNP Konsensus-Leitlinie zum TDM von Psychopharmaka nur für Serum und Plasma validiert sind, sind vergleichende Untersuchungen von alternativen Matrizes mit Serum oder Plasma sowie eine klinische Validierung essenziell für die Implementierung in die klinische Praxis.
Die Zielsetzung dieser Arbeit war es daher, den Zusammenhang zwischen Speichel- und Serumkonzentrationen von Amphetamin und Guanfacin zu untersuchen, um zukünftig das Prozedere der Probenahme für TDM bei Kinder und Jugendliche unter ADHS-Pharmakotherapie durch ein nicht invasives Verfahren zu erleichtern. Zur quantitativen Bestimmung wurden zwei unterschiedliche Methoden aus der Literatur weiterentwickelt. So war es möglich, aus Speichel- und Serumproben Amphetamin mittels HPLC-FL Analytik sowie Guanfacin mittels LC-MS/MS Analytik zu quantifizieren. Die chromatographischen Methoden wurden in Anlehnung an die Richtlinien der Gesellschaft für toxikologische und forensische Chemie (GTFCh) erfolgreich validiert.
Zur Untersuchung des Zusammenhangs zwischen Speichel- und Serumkonzentrationen von Amphetamin und Guanfacin bei Kinder und Jugendlichen wurde eine klinische Studie in der Klinik und Poliklinik für Kinder- und Jugendpsychiatrie, Psychosomatik und Psychotherapie des Universitätsklinikum Würzburgs initiiert. Von 34 Probanden, die mit Lisdexamphetamin und/oder Guanfacin behandelt wurden, konnte jeweils eine korrespondierende Speichel- und Serumprobe gewonnen und quantifiziert werden. Für Amphetamin wurde belegt, dass der Speichel-pH-Wert einen erheblichen Einfluss auf die Wirkstoffverteilung, den Quotienten aus Speichel- und Serumkonzentration, hat (ρ = -0,712; P < 0,001). Dadurch konnte erstmalig unter Berücksichtigung des Speichel-pH-Wertes eine Berechnung der theoretischen Serumkonzentration aus der Speichelkonzentration durchgeführt werden. Es wurde zwar gezeigt, dass sich sowohl der Mittelwert der Differenzen durch die Berechnung theoretischen Serumkonzentration von -343 auf 12 ng/mL als auch die Anzahl der Messwert innerhalb des Akzeptanzintervalls von 20 % verbessern, jedoch war auch nach der Umrechnung die Differenz der Messwerte zu groß, sodass eine klinische Validierung für Amphetamin nicht möglich war. In dieser Studie wurde auch erstmals Guanfacin im Speichel nachgewiesen und quantifiziert, die Konzentrationen lagen zwischen 0,45 und 5,55 ng/mL und waren im Mittel dreifach niedriger als im Serum (2,36 ng/mL vs. 7,47 ng/mL; t (8) = 5,94; P < 0,001).
Die Speichelguanfacinkonzentration wies einen starken Zusammenhang mit der korrespondierenden Serumkonzentration auf (r = 0,758; P = 0,018). Obwohl ein nicht signifikanter Trend für den Einfluss des Speichel-pH-Wertes auf den Quotienten aus Speichel- und Serumkonzentration zu erkennen war, scheint dieser weniger stark ausgeprägt zu sein als bei Amphetamin und anderen basischen Arzneistoffen (r = -0,574; P = 0,106).
Mit der vorliegenden Arbeit konnte zum einen gezeigt werden, dass sich die Speichelbestimmung von Amphetamin nur zum qualitativen Nachweis für TDM eignet. Zum anderen konnte gezeigt werden, dass der Speichel-pH-Wert einen geringeren Einfluss auf die Speichelkonzentration von Guanfacin zu haben scheint, als es bei Amphetamin der Fall ist, und sich Guanfacin somit potenziell für TDM in Speichel eignet. Zukünftig könnten Speichelproben zur Kontrolle der Adhärenz sowohl von Amphetamin als auch von Guanfacin verwendet werden und die Probenahme für die Patienten vereinfachen.
Most medicines are taken orally. To enter the systemic circulation, they dissolve in the intestinal fluid, cross the epithelial barrier, and pass through the liver. Intestinal absorption is driven by the unique features of the gastrointestinal tract, including the bile colloids formed in the lumen and the mucus layer covering the intestinal epithelium. Neglecting this multifaceted environment can lead to poor drug development decisions, especially for poorly water-soluble drugs that interact with bile and mucus. However, there is a lack of a rationale nexus of molecular interactions between oral medicines and gastrointestinal components with drug bioavailability. Against this background, this thesis aims to develop biopharmaceutical strategies to optimize the presentation of oral therapeutics to the intestinal epithelial barrier.
In Chapter 1, the dynamics of bile colloids upon solubilization of the poorly-water soluble drug Perphenazine was studied. Perphenazine impacted molecular arrangement, structure, binding thermodynamics, and induced a morphological transition from vesicles to worm-like micelles. Despite these dynamics, the bile colloids ensured stable relative amounts of free drug substance. The chapter was published in Langmuir.
Chapter 2 examined the impact of pharmaceutical polymeric excipients on bile-mediated drug solubilization. Perphenazine and Imatinib were introduced as model compounds interacting with bile, whereas Metoprolol did not. Some polymers altered the arrangement and geometry of bile colloids, thereby affecting the molecularly soluble amount of those drugs interacting with bile. These insights into the bile-drug-excipient interplay provide a blueprint to optimizing formulations leveraging bile solubilization. The chapter was published in Journal of Controlled Release.
Chapter 3 deals with the impact of bile on porcine intestinal mucus. Mucus exposed to bile solution changed transiently, it stiffened, and the overall diffusion rate increased. The bile-induced changes eased the transport of the bile-interacting drug substance Fluphenazine, whereas Metoprolol was unaffected. This dichotomous pattern was linked to bioavailability in rats and generalized based on two previously published data sets. The outcomes point to a bile-mucus interaction relevant to drug delivery. The chapter is submitted.
The Appendix provides a guide for biopharmaceutical characterization of drug substances by nuclear magnetic resonance spectroscopy aiming at establishing a predictive algorithm.
In summary, this thesis deciphers bile-driven mechanisms shaping intestinal drug absorption. Based on these molecular insights, pharmaceuticals can be developed along a biopharmaceutical optimization, ultimately leading to better oral drugs of tomorrow.
In this thesis, a new approach of a qNMR method has been investigated to demonstrate the reliability and importance of this method as an alternative solution for analyzing oil quality parameters, especially in RFO, which has particular characteristics (red color). This study also includes the chemometric evaluation of spectral data for authentication, visual grouping, and prediction of RFO quality based on the degree of unsaturation, FFA value, and unsaturated fatty acid content.
The analytical measurement procedure of NMR spectroscopy begins with optimization of the analytical acquisition parameters, including effect of solvent, effect of sample concentration, selection of appropriate internal standards, determination of T1, and method validation. Furthermore, the results of the method development were interpreted to RFO samples evaluation, which began with determining the assignment of signal spectra for the determination of AV, SV, EV, and IV simultaneously with: the hydrolysis approach and standard addition of palmitic acid.
Drug Discovery based on Oxidative Stress and HDAC6 for Treatment of Neurodegenerative Diseases
(2024)
Most antioxidants reported so far only achieved limited success in AD clinical trials. Growing evidences suggest that merely targeting oxidative stress will not be sufficient to fight AD. While multi-target directed ligands could synergistically modulate different steps in the neurodegenerative process, offering a promising potential for treatment of this complex disease.
Fifteen target compounds have been designed by merging melatonin and ferulic acid into the cap group of a tertiary amide HDAC6 inhibitor. Compound 10b was screened as the best hybrid molecule exhibit potent HDAC6 inhibition and potent antioxidant capacity. Compound 10b also alleviated LPS-induced microglia inflammation and led to a switch from neurotoxic M1 to the neuroprotective M2 microglial phenotype. Moreover, compound 10b show pronounced attenuation of spatial working memory and long-term memory damage in an in vivo AD mouse model. Compound 10b can be a potentially effective drug candidate for treatment of AD and its druggability worth to be further studied.
We have designed ten novel neuroprotectants by hybridizing with several common antioxidants, including ferulic acid, melatonin, lipoic acid, and trolox. The trolox hybrid compound exhibited the most potent neuroprotective effects in multiple neuroprotection assays. Besides, we identified the synergistic effects between trolox and vitamin K derivative, and our trolox hybrid compound showed comparable neuroprotection with the mixture of trolox and vitamin K derivative.
We have designed and synthesized 24 quinone derivatives based on five kinds of different quinones including ubiquinone, 2,3,5-trimethyl-1,4-benzoquinone, memoquin, thymoquinone, and anthraquinone. Trimethylbenzoquinone and thymoquinone derivatives showed more potent neuroprotection than other quinones in oxytosis assay. Therefore, trimethylbenzoquinone and thymoquinone derivatives can be used as lead compounds for further mechanism study and drug discovery for treatment of neurodegenerative disease.
We designed a series of photoswitchable HDAC inhibitors, which could be effective molecular tools due to the high spatial and temporal resolution. In total 23 target compounds were synthesized and photophysicochemically characterized. Azoquinoline-based compounds possess more thermally stable cis-isomers in buffer solution, which were further tested in enzyme-based HDAC inhibition assay. However, none of those tested compounds show significant differences in activities between trans-isomers and corresponding cis-isomers.
The bile system in vertebrates is an evolutionary conserved endogenous solubilization system for hydrophobic fats and poorly water-soluble vitamins. Bile pours out from the gallbladder through the common bile duct into the duodenum triggered by cholecystokinin. Cholecystokinin is released from enteroendocrine cells after food intake. The small intestine is also the absorption site of many orally administered drugs. Most emerging drug candidates belong to the class of poorly water-soluble drugs (PWSDs). Like hydrophobic vitamins, these PWSDs might as well be solubilized by bile. Therefore, this natural system is of high interest for drug formulation strategies. Simulated intestinal fluids containing bile salts (e.g., taurocholate TC) and phospholipids (e.g., lecithin L) have been widely applied over the last decade to approximate the behavior of PWSDs in the intestine. Solubilization by bile can enhance the oral absorption of PWSDs being at least in part responsible for the positive “food effect”. The dissolution rate of PWSDs can be also enhanced by the presence of bile. Furthermore, some PWSDs profit from supersaturation stabilization by bile salts. Some excipients solubilizing PWSDs seemed to be promising candidates for drug formulation when investigated in vitro without bile. When tested in vivo, these excipients reduced the bioavailability of drugs. However, these observations have been hardly examined on a molecular level and general links between bile interaction in vitro and bioavailability are still missing.
This thesis investigated the interplay of bile, PWSDs, and excipients on a molecular level, providing formulation scientists a blueprint for rational formulation design taking bile/PWSD/excipient/ interaction into account. The first chapter focus on an in silico 1H nuclear magnetic resonance (NMR) spectroscopy-based algorithm for bile/drug interaction prediction. Chapter II to IV report the impact of excipients on bioavailability of PWSDs interacting with bile. At last, we summarized helpful in vitro methods for drug formulation excipient choice harnessing biopharmaceutic solubilization in chapter V.
Chapter I applies 1H NMR studies with bile and drugs on a large scale for quantitative structure-property relationship analysis. 141 drugs were tested in simulated intestinal media by 1H NMR. Drug aryl-proton signal shifts were correlated to in silico calculated molecular 2D descriptors. The probability of a drug interacting with bile was dependent on its polarizability and lipophilicity, whereas interaction with lipids in simulated intestinal media components was dependent on molecular symmetry, lipophilicity, hydrogen bond acceptor capability, and aromaticity. The probability of a drug to interact with bile was predictive for a positive food effect. This algorithm might help in the future to identify a bile and lipid interacting drug a priori.
Chapter II investigates the impact of excipients on bile and free drug fraction. Three different interaction patterns for excipients were observed. The first pattern defined excipients that interacted with bile and irreversibly bound bile. Therefore, the free drug fraction of bile interacting drugs increased. The second pattern categorized excipients that formed new colloidal entities with bile which had a high affinity to bile interacting drugs. These colloids trapped the drug and decreased the free drug fraction. The last excipient pattern described excipients that formed supramolecular structures in coexistence with bile and had no impact on the free drug fraction. These effects were only observed for drugs interacting with bile (Perphenazine and Imatinib). Metoprolol’s free drug fraction, a compound not interacting with bile, was unaffected by bile or bile/excipient interaction. We hypothesized that bile/excipient interactions may reduce the bioavailability of bile interacting drugs.
Chapter III addresses the hypothesis from chapter II. A pharmacokinetic study in rats revealed that the absorption of Perphenazine was reduced by bile interacting excipients due to bile/excipient interaction. The simultaneous administration of excipient patterns I and II did not further reduce or enhance Perphenazine absorption. Conversely, the absorption of Metoprolol was not impacted by excipients. This reinforced the hypothesis, that drugs interacting with bile should not be formulated with excipients also interacting with bile.
Chapter IV further elaborates which in vitro methods using simulated intestinal fluids are predictive for a drug’s pharmacokinetic profile. The PWSD Naporafenib was analyzed in vitro with simulated intestinal fluids and in presence of excipients regarding solubility, supersaturation, and free drug fraction. Naporafenib showed a strong interaction with TC/L from simulated bile. Assays with TC/L, but not without identified one excipient as possibly bioavailability reducing, one as supersaturation destabilizing, and the last as bile not interacting and supersaturation stabilizing excipient. A pharmacokinetic study in beagle dogs outlined and confirmed the in vitro predictions.
The Appendix summarizes in vivo predictive methods as presented in chapter I to IV and rationalizes experimental design paving the way towards a biopharmaceutic excipient screening. The first presented preliminary decision tree is transformed into a step-by-step instruction. The presented decision matrix might serve as a blueprint for processes in early phase drug formulation development.
In summary, this thesis describes how a drug can be defined as bile interacting or non-interacting and gives a guide as well how to rate the impact of excipients on bile. We showed in two in vivo studies that bile/excipient interaction reduced the bioavailability of bile interacting drugs, while bile non-interacting drugs were not affected. We pointed out that the bile solubilization system must be incorporated during drug formulation design. Simulated gastrointestinal fluids offer a well-established platform studying the fate of drugs and excipients in vivo. Therefore, rational implementation of biopharmaceutic drug and excipient screening steers towards efficacy of oral PWSD formulation design.