Pharmacokinetics and tissue distribution of bovine testicular hyaluronidase and vinblastine in mice: an attempt to optimize the mode of adjuvant hyaluronidase administration in cancer chemotherapy

Matrices made of glyceryl trimyristate as a bioerodible and biocompatible material were manufactured by compression in dimensions that would still allow an application via injection. Pyranine, as a low molecular hydrophilic compound with a low detection limit, and tetramethylrhodamine labeled bovine serum albumin (TAMRA-BSA), as a high molecular weight (66 kDa) protein compound, served as model drugs for release investigations. In vitro studies with pyranine revealed that release depends substantially on the gelatin content of the matrices, which proved to be a useful tool as a release modifier. The duration of the drug release period can be adjusted to a desired time interval ranging from days to weeks by choosing the right gelatin content. Moreover, results illustrated the importance of the molecular weight and the nature of the compound to be incorporated into such matrices, since investigations with TAMRA-BSA showed a more pronounced burst release and altered release profiles and periods. Experiments with hyaluronidase, which served as a model enzyme to assess the problem of protein integrity in such matrices, suggested that proteins may display sufficient stability during the manufacturing procedure of the cylinders or while in contact with the triglyceride matrices. In addition to in vitro investigations, a study in mice revealed that after 15 days of subcutaneous implantation the matrices showed a good in vivo stability. The main conclusion that could be drawn from these results was that triglycerides are a promising alternative to biodegradable polymers for the development of parenteral release systems for protein and peptide drugs.

Monolithic triglyceride matrices: a controlled-release system for proteins.

Preclinical and clinical observations suggest that the administration of hyaluronidase (Hyase) shortly before that of chemotherapy increases the access and, thus, the effectiveness of aniticancer drugs in tumors. To examine this hypothesis as well as the selectivity of such a therapeutic approach potentially beneficial in isolated limb perfusion, the Hyase-induced distribution of melphalan was measured in tumor-bearing nude mice with respect to the mode of drug administration using RP-18 ion-pair high-performance liquid chromatography (HPLC) with fluorimetric detection. Melphalan alone (50 μmol/kg) or a combination of melphalan (50 μmol/kg) and Hyase (100,000 IU/kg) was injected either i.p. or s.c. in the vicinity of the tumors. The s.c. melphalan injection caused a 4-fold rise in melphalan concentration (59 μM) in the tumors as compared with i.p. application (15 μM). Only minor effects were observed with respect to the route of melphalan application on its distribution in other tissues (ca. 13 μM in plasma, 15 μM in muscle, 30 μM in the liver, 26 μM in the kidney, and 21 μM in the testicle). Irrespective of the route of Hyase coadministration, the enzyme increased the concentration of i.p. injected melphalan in all tissues to ca. 20 μM in the tumor, 15 μM in plasma, 27 μM in muscle, 40 μM in the liver, 29 μM in the kidney, and 28 μM in the testicle. In contrast, s.c. injected melphalan was selectively accumulated by the tumors after both s.c. and i.p. Hyase administration (462 and 388 μM, respectively). Melphalan enrichment in the tumors was higher (16- to 32-fold higher than in the other tissues) after i.p. administration of Hyase since, in contrast to s.c. injection of the enzyme, its i.p. administration caused a decrease in the concentration of the cytostatic in all other tissues as compared with the s.c. administration of melphalan alone.

Hyaluronidase pretreatment produces selective melphalan enrichment in malignant melanoma implanted in nude mice.

The treatment of malignant brain tumors, especially of high-grade gliomas, poses one of the major challenges in cancer therapy. Despite seminal advancements in imaging techniques for the early diagnosis of CNS neoplasms as well as amendments in surgery and radiooncology, the prognosis of patients with glioma is very poor. The administration of temozolomide adjuvant to irradiation after resection of the tumor - the current “gold standard” in the treatment of glioblastoma - has only marginally improved median survival by ca. 3 months. Hence, there is an urgent need for novel approaches to the treatment of malignant brain tumors. To investigate the efficiency of such regimens in vivo, predictive preclinical animal models are indispensible. 

In this thesis, three subject areas were dealt with: 
- evaluation of doxorubicin-loaded poly(butylcyanoacrylate) (PBCA) nanoparticle (NP) formulations as drug-carriers, 
- modulation of the ATP-binding cassette transporter ABCG2, which is expressed in brain capillaries, by newly synthesized inhibitors, as a strategy to overcome the blood-brain barrier (BBB) with chemotherapeutics, which are substrates of this efflux pump, and 
- refinement of orthotopic glioblastoma models in nude mice to allow noninvasive optical imaging of intracerebral tumors.


Human glioblastoma cells U-87 MG, U-118 MG and U-373 MG were incubated with free doxorubicin and doxorubicin loaded onto PBCA NPs. As the glioblastoma cells do neither express ABCB1 nor ABCG2, Kb-V1 and MCF-7/Topo cells were included, to study effects on both efflux pumps. In the crystal-violet chemosensitivity assay, cytotoxicities of the doxorubicin-loaded NPs and of the dissolved cytostatic were similar against all glioblastoma cells. By contrast, a higher efficacy of the NP formulations was observed on ABCB1-overexpressing Kb-V1, but not on ABCG2-expressing MCF-7/Topo cells, indicating an interaction of the NPs with the ABCB1 efflux pump. Therefore, increased drug concentrations in the brain after administration of such drug-loaded NPs to animals, as reported in literature, might be due interactions of the NPs with ABCB1 at the BBB.

The modulation of ABC transporters at the BBB represents an attractive strategy to increase intracerebral levels of drugs, which are known to be substrates of such efflux pumps. 

For this reason, the identification of potent efflux pump inhibitors is a promising approach to improve the chemotherapy of brain tumors. A series of analogs, derived from the original ABCB1 inhibitor tariquidar, was investigated for potency against ABCG2 and selectivity vs. ABCB1. To expand methodology and to by-pass problems associated with the flow cytometric (FACS) mitoxantrone-efflux assay, two 96-well plate assays, using the fluorescent ABCG2 substrates Hoechst 33342 and pheophorbide a, were developed. Interestingly, slight structural modifications of tariquidar analogs yielded potent and selective inhibitors of ABCG2. The most potent modulator showed an IC50 value of 60 nM in the FACS assay and 65 and 126 nM in the microtiter plate assays. In view of future in vivo studies, the most potent inhibitors were investigated for stability in plasma by the means of HPLC-MS analysis. Unfortunately, these compounds are prone to rapid enzymatic cleavage at the central benzamide moiety. Therefore, compounds with improved drug-like properties are required. Since a regulation of ABCG2 by estrogens is discussed in literature, MCF-7/Topo cells were treated with estradiol and subjected to treatment with topotecan. No differences in the antiproliferative effect between estradiol-treated and non-treated controls were observed, indicating, at best, a therapeutically irrelevant regulation of the ABCG2-level by estradiol.

To investigate the therapeutic value of new concepts, e.g. the combined administration of selective inhibitors of ABC-transporters with appropriate cytostatics, the main focus of this work was the refinement of in vivo xenograft models. Indeed, orthotopic brain tumor models, allowing the monitoring of tumor progression by noninvasive optical imaging, were established in nude mice. For this purpose, human U-87 MG glioblastoma cells were transfected with the genes encoding luciferase2 (Luc2) and the recently discovered far-red fluorescent protein Katushka (Kat), respectively. Numerous clones were characterized in vitro with respect to bioluminescence / fluorescence, growth kinetics and chemosensitivity. As the transfectants were tumorigenic subcutaneously (s.c.), and Luc2 as well as Kat expression persisted in the s.c. model, the human glioblastoma variants were injected into the brains of nude mice, where reproducibly growing tumors developed. Most important is the fact that these intracerebral xenografts were accessible to both, bioluminescence and fluorescence imaging. Moreover, there was a direct correlation between the optical signals and the tumor load, confirmed by histology.

Experimental therapy and detection of glioblastoma: investigation of nanoparticles, ABCG2 modulators and optical imaging of intracerebral xenografts

Abstract The global shortage of healthcare staff has led to high workloads and subsequent risks to patient well-being. One of the professions affected is that of the scrub nurse. Robotic scrub nurse systems have the potential to reduce workload and to assist in handling surgical instruments. Existing approaches mostly use two-finger grippers or electromagnetic grippers. However, it is assumed that a granular jamming gripper is more suitable for handling various surgical instruments, regardless of material and shape. A gripping unit based on a granular jamming gripper and attached to a robotic arm is presented. For evaluation, six surgical instruments were repeatedly gripped and transported. The granular jamming gripper was found to be suitable for picking up and transferring most instruments, however, handling very flat instruments turned out to be challenging.

Robotic Scrub Nurse: Surgical Instrument Handling with a Granular Jamming Gripper

Five-Year Breeding Data, Immunology, and Tumor Take Rates of an NMRI Nude Mouse Colony

Integrating fleets of mobile service robots into the operating room wing (OR wing) has the potential to help overcome staff shortages and reduce the amount of dull or unhealthy tasks for humans. However, the OR wing has been little studied in this regard and the requirements for realizing this vision have not yet been fully identified. This includes fundamental aspects such as fleet size and composition, which we have now studied comprehensively for the first time.Using simulation, 150 different scenarios with varying fleet compositions, robot speeds and workloads were studied for a setup based on a real-life OR wing. The simulation included battery recharging cycles and queueing due to shared resources.For all simulated scenarios we report results regarding total duration of execution, average task response times and fleet utilization. The relationship between these performance measures and global scenario parameters-such as fleet size, fleet composition, robot velocity and the number of operating rooms to be served-is visualized.Our simulation-based studies have proven to be a valuable tool for individualized dimensioning of mobile robotic fleets, based on realistic workflows and environmental models. Thereby, important implications for future developments of mobile robots have been identified and a basis of decision-making regarding fleet size, fleet composition, robot capabilities and robot velocities can be provided. Due to costs, space limitations and safety requirements, these aspects must be carefully considered to successfully integrate mobile robotic technology into real-world OR wing environments. 

https://link.springer.com/content/pdf/10.1007/s11548-022-02735-8.pdf

Mobile service robots for the operating room wing: balancing cost and performance by optimizing robotic fleet size and composition

The adjustment of medical devices in the operating room is currently done by the circulating nurses. As digital interfaces for the devices are not foreseeable in the near future and to incorporate legacy devices, the robotic operation of medical devices is an open topic.We propose a teleoperated learning from demonstration process to acquire the high-level device functionality with given motion primitives. The proposed system is validated using an insufflator as an exemplary medical device.At the beginning of the proposed learning period, the teacher annotates the user interface to obtain the outline of the medical device. During the demonstrated interactions, the system observes the state change of the device to generalize logical rules describing the internal functionality. The combination of the internal logics with the interface annotations enable the robotic system to adjust the medical device autonomously. To interact with the device, a robotic manipulator with a finger-like end-effector is used while relying on haptic feedback from torque sensors.The proposed approach is a first step towards teaching a robotic system to operate medical devices. We aim at validating the system in an extensive user study with clinical personnel. The logical rule generalization and the logical rule inference based on computer vision methods will be focused in the future. 

/pdf/intuitive-teaching-of-medical-device-operation-to-clinical-2tzu9ugo.pdf

Intuitive teaching of medical device operation to clinical assistance robots

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Five-Year Breeding Data, Immunology, and Tumor Take Rates of an NMRI Nude Mouse Colony

Mobile service robots for the operating room wing: balancing cost and performance by optimizing robotic fleet size and composition

Intuitive teaching of medical device operation to clinical assistance robots