Intratarget Microdosing for Deep Phenotyping of Multiple Drug Effects in the Live Brain
Jennifer Kim, Sebastian W. Ahn, Kyle Deans, Devon Thompson, Benjamin Ferland, Prajan Divakar, Christine Dominas, Oliver Jonas
Frontiers in Bioengineering and Biotechnology March 18, 2022 DOI: 10.3389/fbioe.2022.855755 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical in vivo study Peer reviewed |
|---|---|
| Population | Murine models of Alzheimer’s disease (AD) and hMAPT AD mice |
| Interventions | various approved and investigational CNS drugs drugs affecting metabolism |
| Dose | microdoses |
| Topics | Microdosing |
| Keywords | Microdevice Polymer formulation Alzheimer’s disease Drug sensitivity In vivo High-throughput screen |
| Key points | Microdoses of various approved and investigational CNS drugs released from the IMD within a local brain region exhibit in situ phenotypes indicative of therapeutic responses in murine models of Alzheimer’s disease. |
Abstract
A main impediment to effective development of new therapeutics for central nervous system disorders, and for the in vivo testing of biological hypotheses in the brain, is the ability to rapidly measure the effect of novel agents and treatment combinations on the pathophysiology of native brain tissue. We have developed a miniaturized implantable microdevice (IMD) platform, optimized for direct stereotactic insertion into the brain, which enables the simultaneous measurement of multiple drug effects on the native brain tissue in situ. The IMD contains individual reservoirs which release microdoses of single agents or combinations into confined regions of the brain, with subsequent spatial analysis of phenotypic, transcriptomic or metabolomic effects. Using murine models of Alzheimer’s disease (AD), we demonstrate that microdoses of various approved and investigational CNS drugs released from the IMD within a local brain region exhibit in situ phenotypes indicative of therapeutic responses, such as neuroprotection, reduction of hyperphosphorylation, immune cell modulation, and anti-inflammatory effects. We also show that local treatments with drugs affecting metabolism provide evidence for regulation of metabolite profiles and immune cell function in hMAPT AD mice. The platform should prove useful in facilitating the rapid testing of pharmacological or biological treatment hypotheses directly within native brain tissues (of various animal models and in patients) and help to confirm on-target effects, in situ pharmacodynamics and drug-induced microenvironment remodeling, much more efficiently than currently feasible.
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 |