Abstract 1311: PET-MRI microdosing can determine the delivery of the experimental cancer therapeutic, MN-anti-miR10b, to metastatic lesions in a murine model of breast cancer
Marianne Le Fur, Byunghee Yoo, Nicholas Rotile, Pamela Pantazopoulos, Alana Ross, Iris Zhou, Peter Caravan, Zdravka Medarova
Cancer Research July 1, 2021 DOI: 10.1158/1538-7445.am2021-1311 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study (abstract) Peer reviewed |
|---|---|
| Population | Murine models of metastatic breast cancer (mice bearing luciferase-expressing metastatic breast adenocarcinoma) |
| Dose | microdose of 64Cu-MN-anti-miR10b; non-carrier added microdose; standard therapeutic dose (exact amounts not stated) |
| Measures | positron emission tomography-magnetic resonance imaging (PET-MRI), bioluminescence imaging (BLI), scintigraphy |
| Topics | Microdosing |
| Key points | A microdose of 64Cu-labeled MN-anti-miR10b accumulated in metastatic breast cancer lesions in mice, as shown by PET-MRI, ex vivo imaging, and scintigraphy, with uptake significantly higher in metastatic organs than in the same organs without detectable lesions. Microdose biodistribution was comparable to that of a standard therapeutic dose, which the authors propose supports using PET-MRI microdosing in humans to assess drug delivery and guide patient selection. |
Abstract
Abstract: Conventional therapies, which are effective against primary cancer, oftentimes are not successful at treating metastatic cancer. In our earlier work, we identified miRNA-10b as a master regulator of the viability of metastatic tumor cells. This knowledge allowed us to design a miR-10b inhibitor, termed MN-anti-miR10b, capable of delivery to metastatic sites via intravenous injection. In mouse models of breast cancer, we demonstrated that MN-anti-miR10b, when combined with a low-dose cytostatic, caused lifelong complete regressions of established metastases with no evidence of systemic toxicity. As a first step towards translating MN-anti-miR10b for the treatment of metastatic breast cancer, we needed to determine if MN-anti-miR10b, which is so effective in mice, will also accumulate in human metastases. Towards that goal, we developed a method to radiolabel MN-anti-miR10b with Cu-64, inject a microdose of the radiolabeled MN-anti-miR10b into murine models of metastatic breast cancer, and determine the uptake of the therapeutic by the metastatic lesions using positron emission tomography-magnetic resonance imaging (PET-MRI). Specifically, we injected a microdose of 64Cu-MN-anti-miR10b into mice bearing luciferase-expressing metastatic breast adenocarcinoma and performed in vivo bioluminescence (BLI) and PET-MRI to assess uptake by the metastatic lesions. The lesions were identified by BLI, based on their luciferase expression. PET-MRI clearly demonstrated uptake of 64Cu-MN-anti-miR10b, measurable at a microdose. Ex vivo PET-MRI confirmed that the activity was associated with the metastatic lesions, as identified at necropsy. Uptake by metastatic organs was also demonstrated by scintigraphy and shown to be significantly higher than in the same organs devoid of BLI-detectable metastatic lesions. Finally, 64Cu-MN-anti-miR10b injected as a non-carrier added microdose had comparable biodistribution to that injected at a standard therapeutic dose. The value of the current study is in setting the stage for clinical PET-MRI microdosing, which would be able to answer a key question on the path to drug development without the associated cost to do a full clinical trial – the question of delivery to the target organ sites. Since the PET technique is sensitive enough to determine the concentration of radiolabeled drug with sensitivity approaching the sub-picomolar range, as little as a microgram of the radiolabeled drug is sufficient to perform a PET-MRI study in humans. In addition to proving delivery, the microdosing studies will reveal the pharmacokinetic behavior of MN-anti-miR10b which will allow one to establish dosing during therapy. Finally, in clinical trials, one can use microdosing PET-MRI to select patients for treatment, based on which patients' metastases accumulate the therapeutic. Citation Format: Marianne Le Fur, Byunghee Yoo, Nicholas Rotile, Pamela Pantazopoulos, Alana Ross, Iris Zhou, Peter Caravan, Zdravka Medarova. PET-MRI microdosing can determine the delivery of the experimental cancer therapeutic, MN-anti-miR10b, to metastatic lesions in a murine model of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1311.
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 |