In Vivo Toxicity Study of Engineered Lipid Microbubbles in Rodents

Gaio Paradossi, Letizia Oddo, Barbara Cerroni, Carmit Ben-Harush, Eti Ariel, Francesco Di Meco, Zvi Ram, Rachel Grossman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Real-time intraoperative imaging for brain tumor surgery is crucial for achieving complete resection. We are developing novel lipid-based microbubbles (MBs), engineered with specific ligands, which are able to interact with the integrins overexpressed in the endothelium of the brain tumor vasculature. These MBs are designed to visualize the tumor and to carry therapeutic molecules into the tumor tissue, preserving the ultrasound acoustic properties of the starting plain lipid MBs. The potential toxicity of this novel technology was assessed in rats by intravenous injections of two doses of plain MBs and MBs engineered for targeting and near-infrared fluorescence visualization at two time-points, 10 min and 7 days, for potential acute and chronic responses in rats [(1) MB, (2) MB-ICG, (3) MB-RGD, and (4) MB-ICG-RGD]. No mortality occurred during the 7-day study period in any of the dosing groups. All animals demonstrated a body weight gain during the study period. Minor, mostly reversible changes in hematological and biochemical analysis were observed in some of the treated animals. All changes were reversible by the 7-day time-point. Histopathology examination in the high-dose animals showed development of foreign body granulomatous inflammation. We concluded that the low-dose tested items appear to be safe. The results allow for proceeding to clinical testing of the product.

Original languageEnglish
Pages (from-to)5526-5533
Number of pages8
JournalACS Omega
Issue number3
StatePublished - 19 Mar 2019


FundersFunder number
Seventh Framework Programme602923
Seventh Framework Programme


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