PhD grants "Delivery of therapeutic drugs by sonoporation in a mouse model of liver metastases of colorectal cancer" (SSBCV)

• 36 months doctoral funding (October 2021 to September 2024)
• Keywords

Sonoporation, liver metastases, colorectal cancer, imaging, therapy

• Profile and skills required

Mandatory skills:

- Scientific and technical skills in cell biology, animal physiology and oncology;

- Knowledge of statistical tools (R, Prism);

- Ability to synthesize and write;

- Fluency in English (spoken and written);

- Participation to the collective life of the team and the laboratory (Seminars, Méridiennes), and to public outreach activities (Science festival, Brain Awareness Week).

Optional skills:

- Knowledge in acoustics;

- Animal experimentation training - Designer level.

• Project description

Background - Ultrasound contrast agents, consisting of gas microbubbles, are used in diagnosis during contrast-enhanced ultrasound imaging. In recent years, new promising new methods for the local delivery of anticancer drugs based on the use of these microbubbles have been proposed. This possibility, in combination with ultrasound (i.e., sonoporation), provides unprecedented alternatives for effective and non-invasive therapeutic action. The term “sonoporation” denotes a process by which the activation of microbubbles by ultrasound near blood-tumor barrier transiently increases its permeability and thus allows extravasation and penetration of therapeutic molecules into the tumor tissues without deleterious effects. By virtue of this extravasation, the bioavailability of these molecules in the tumor is increased, thus improving the therapeutic index. The effectiveness of sonoporation-mediated drug delivery relies on the design and optimization of an ultrasound probe, microbubbles, ultrasound sequences, and treatment regimen.

Issue - Nowadays, major protocols for delivering therapeutic molecules by sonoporation are optimized and validated on subcutaneous tumor mouse models, which do not reflect clinical reality. Therefore, these protocols are not suitable for orthotopic and metastatic models of cancer.

Objectives - In this context, we have developed a mouse model of human colorectal cancer liver metastases by a surgical approach. As part of this thesis project, we therefore propose (1) to optimize and characterize this model and (2) to validate therapeutic ultrasound probes and therapeutic schemes for the treatment of these metastases.

Methodology - To achieve these objectives, we will optimize the protocol for the induction of liver metastases from colorectal cancer in mouse. Imaging approaches (contrast-enhanced ultrasound imaging, photoacoustic imaging, CT-scan, PET imaging) will allow us to characterize the growth of liver metastases, their perfusion and their oxygenation. Histopathological analysis of the tissues will complete this characterization. This model will then be used to design and validate therapeutic ultrasound probes and delivery schemes for therapeutic molecules (irinotecan, HSV-tk gene) by sonoporation.

• References

Escoffre JM et al., (2020) Ultrason. Sonochem., 64 :104998 ;

Espitalier F et al., (2020) Front. Pharmacol., 10 :1562 ;

Bressand D et al., (2019) Mol. Pharm., 16 :3814-3822 ;

Escoffre JM et al., (2013) Mol. Pharm.,10 :2667-75.

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