Feasibility of implantable microdosing devices to perform in vivo pharmacotyping in pancreatic cancer.
Lyudmyla Demyan, Oliver Standring, Taemoon Chung, Emma Gazzara, Scott P. Lyons, Matthew John Weiss, Youngkyu Park, Oliver Jonas, David A. Tuveson, Daniel King
Journal of Clinical Oncology February 1, 2023 DOI: 10.1200/jco.2023.41.4_suppl.742 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study (proof-of-principle) Peer reviewed |
|---|---|
| Sample size | 15 |
| Population | Mice xenotransplanted with human pancreatic cancer organoids (hM1A and hM1E) |
| Interventions | gemcitabine SN-38 paclitaxel oxaliplatin doxorubicin |
| Duration | Devices retrieved at 4h, 8h, and 24h post-implantation |
| Measures | Doxorubicin fluorescence diffusion distance and concentration profiles, co-immunohistochemistry for cleaved caspase-3 (CC3), gamma H2AX, and human mitochondria |
| Topics | Microdosing |
| Key points | Implantable microdevice pharmacotyping proved feasible in a mouse xenotransplant model of pancreatic cancer: all 15 animals survived, all devices were retrieved, and drug diffusion and differential drug responses were detectable as early as 4 hours. The authors propose this approach could inform personalized drug-sensitivity testing, with further work needed to extend it to other drugs and biomarkers. |
Abstract
742
Background: Current biomarkers offer modest predictive capacity for drug sensitivity testing in pancreatic cancer. Patient-specific pharmacotyping offers the potential for a more direct, personalized prediction model. Recently, an implantable microdevice was developed to facilitate in situ multi-agent pharmacotyping and has since entered clinical trials in multiple cancer types, but had not yet been tested in pancreatic cancer. Here we evaluated the use of a microdosing device (microdevice) in a mouse xenotransplant model of pancreatic cancer as proof of principle to inform future translation to the clinic.
Methods: A microdevice consists of a cylindrical frame and 18 wells embedded with standard chemotherapy agents (5 FU, gemcitabine, SN 38, paclitaxel, oxaliplatin), a non-toxic polyethylene glycol (PEG) matrix as control, and doxorubicin, the auto-fluorescent properties of which allow us to determine the distance of drug diffusion for each tumor. Devices were implanted into murine xenotransplanted human organoids (hM1A and hM1E Table 1). Microdevices retrieved at 4h, 8h, and 24h post-implantation together with tumors were fixed in 10% formalin. The tissue was embedded in paraffin and sectioned parallel to the device. A distance-dependent drug diffusion rate and concentration profiles with doxorubicin were evaluated. Co-immunohistochemistry (IHC) for cleaved caspase-3 (CC3), gamma H2AX (apoptosis markers), and human mitochondria (human cancer cell marker) was performed in the area of drug diffusion to determine the cytotoxic effects of chemotherapy.
Results: 15 animals were enrolled in the experiment with 100% postoperative survival. One device per animal was placed, and all devices were successfully retrieved. Microdevice insertion and exposure to PEG had no effect on tumor integrity. At 250-350µm from the well, we observed intensity from doxorubicin, suggesting drug diffusion. The signal on differential response to drugs was detected as early as 4 hours.
Conclusions: Utilization of implantable microdevice to predictcancer drug sensitivity is feasible in organoid transplantation animal models of pancreatic cancer. Future work is needed to expand this model to other cancer drugs and biomarkers to evaluate the cancer drug sensitivity and to test the feasibility of this model to study the effects of chemotherapy on the tumor microenvironment. [Table: see text]
Comparable studies
Other preclinical and animal studies on microdosing, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocin and ketamine microdosing: effects of subchronic intermittent microdoses in the elevated plus-maze in male Wistar rats Wistar rats | 2018 | Experimental study | n = 40 |
| Repeated low doses of psilocybin increase resilience to stress, lower compulsive actions, and strengthen cortical connections to the paraventricular thalamic nucleus in rats. Rats | 2023 | Experimental study | |
| Repeated microdoses of LSD do not alter anxiety or boldness in zebrafish. Zebrafish (Danio rerio) | 2024 | Experimental study | |
| Application of microarray patches for the transdermal administration of psychedelic drugs in micro-doses. Excised neonatal porcine skin and rats | 2025 | Experimental study | |
| Toward Predicting Acute Myeloid Leukemia Patient Response to 7 + 3 Induction Chemotherapy via Diagnostic Microdosing Paired sensitive and resistant cancer cell lines, AML cell lines, and 10 viably... | 2018 | Preclinical cell line study with a pilot retrospective analysis of primary patient samples | n = 10 |