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In Vivo Toxicity Study of Engineered Lipid Microbubbles in Rodents.

ABSTRACT: 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.

SUBMITTER: Paradossi G

PROVIDER: S-EPMC6715268 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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In Vivo Toxicity Study of Engineered Lipid Microbubbles in Rodents.

Paradossi Gaio G Oddo Letizia L Cerroni Barbara B Ben-Harush Carmit C Ariel Eti E Di Meco Francesco F Ram Zvi Z Grossman Rachel R

ACS omega 20190319 3

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 ...[more]

PMID: 31497678

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Project description:Phospholipid-coated targeted microbubbles are ultrasound contrast agents that can be used for molecular imaging and enhanced drug delivery. However, a better understanding is needed of their targeting capabilities and how they relate to microstructures in the microbubble coating. Here, we investigated the ligand distribution, lipid phase behavior, and their correlation in targeted microbubbles of clinically relevant sizes, coated with a ternary mixture of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) or 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), with PEG40-stearate and DSPE-PEG2000. To investigate the effect of lipid handling prior to microbubble production in DSPC-based microbubbles, the components were either dispersed in aqueous medium (direct method) or first dissolved and mixed in an organic solvent (indirect method). To determine the lipid-phase behavior of all components, experiments were conducted on monolayers at the air/water interface. In comparison to pure DSPC and DPPC, the ternary mixtures had an additional transition plateau around 10-12 mN/m. As confirmed by infrared reflection absorption spectroscopy (IRRAS), this plateau was due to a transition in the conformation of the PEGylated components (mushroom to brush). While the condensed phase domains had a different morphology in the ternary DPPC and DSPC monolayers on the Langmuir trough, the domain morphology was similar in the coating of both ternary DPPC and DSPC microbubbles (1.5-8 ?m diameter). The ternary DPPC microbubbles had a homogenous ligand distribution and significantly less liquid condensed (LC) phase area in their coating than the DSPC-based microbubbles. For ternary DSPC microbubbles, the ligand distribution and LC phase area in the coating depended on the lipid handling. The direct method resulted in a heterogeneous ligand distribution, less LC phase area than the indirect method, and the ligand colocalizing with the liquid expanded (LE) phase area. The indirect method resulted in a homogenous ligand distribution with the largest LC phase area. In conclusion, lipid handling prior to microbubble production is of importance for a ternary mixture of DSPC, PEG40-stearate, and DSPE-PEG2000.

Dataset Information

In Vivo Toxicity Study of Engineered Lipid Microbubbles in Rodents.

Publications

In Vivo Toxicity Study of Engineered Lipid Microbubbles in Rodents.

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