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PhD in Biomedical Photoacoustic Imaging : Accumulation of Labeled Drug Nanovectors in murine model of arthritis (M/F)

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Français - Anglais

Date Limite Candidature : lundi 17 mai 2021

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General information

Reference : UMR7371-JERGAT-001
Workplace : PARIS 06
Date of publication : Monday, April 26, 2021
Scientific Responsible name : Jérôme Gateau
Type of Contract : PhD Student contract / Thesis offer
Contract Period : 36 months
Start date of the thesis : 1 October 2021
Proportion of work : Full time
Remuneration : 2 135,00 € gross monthly

Description of the thesis topic

Nanoparticles as drug nanovectors are expected to profoundly change therapeutic treatments in the next 15 years and specifically benefit highly prevalent diseases such as rheumatoid arthritis [1,2]⁠. Compared to conventional drug formulations, drug nanovectors need to overcome several biological barriers to achieve drug delivery at the site of inflammation. It has recently become increasingly evident that the heterogeneity of the NV accumulation profoundly impacts therapeutic response. Therefore, image-based selection of patients with an efficient accumulation for a given NV has been identified as a key point for improving therapeutic outcome. The objective of this thesis project is to develop new methods to image the biodistribution of labeled NVs at the site of inflammation in 3D and with high spatial resolution. The developed methods will be validated in a preclinical study in mice.

Pulse-echo ultrasound imaging yields an anatomical image that can serve as a reference, while photoacoustic imaging (PAI) provides a molecular contrast and a sensitivity to the accumulation of NVs. PAI is an emerging biomedical imaging modality [3]⁠ which combines optical excitation and ultrasound detection to map optical absorption in biological tissues. It can be optimized to enable detection of NVs with a sub-millimeter resolution and to spectrally discriminate some molecular absorbers  [4]⁠ that can label specific types of NVs. A 3D dual-modality scanner (ultrasound and PAI) will be implemented for simultaneous ultrasound and photoacoustic imaging with ~0.1mm spatial resolution and 1-2 cm penetration depth. The scanner will be designed to study the slow kinetics of the in vivo accumulation of NVs. This innovative scanner will be based on previous work on 3D ultrasound  [5]⁠ and photoacoustic  [6]⁠ tomography at the Laboratory of Biomedical Imaging (Laboratoire d'Imagerie Biomédicale, LIB). In particular, a first prototype has recently been validated in vitro but with a lower ultrasound frequency than needed for this doctoral project. 3D imaging is obtained by scanning an ultrasound array in translation and rotation and yields unique contrast and resolution.

Several types of NVs are promising in terms of drug encapsulation for rheumatoid arthritis thanks to their biocompatibility, biodegradability and low toxicity. Three such types of NVs, whose formulation is well mastered at the Institut Galien Paris-Saclay (IGPS) in the team of N. Tsapis, will be synthesized within the framework of this project: polymer nanospheres, liposomes and solid lipid nanoparticles [7]⁠. Each of these NVs has different chemical, structural and mechanical properties that can influence their accumulation at the site of inflammation. Moreover, they can be formulated within a range of sizes (50 nm to 500nm). The synthesized NVs will be labeled with a molecular absorber with an absorption spectrum different from the hemoglobin to optimize the detectability with PAI.

The 3D in vivo imaging methods will be applied to detect the signals from the labeled nanovectors to obtain a better understanding of the relationship between the volumetric distribution of the accumulation at the site of inflammation and the structural and mechanical properties of the NVs. A series of detection and accumulation measurements will be conducted using murine models of arthritis.

This highly interdisciplinary project is at the interface between the instrumentation for biomedical imaging (LIB) and the physical chemistry of drug nanovectors (IGPS). The doctoral student will join the two research groups (the LIB and the IGPS) and will perform the experimental work and data analysis to attain the goal for sensitive, 3D detection of the biodistribution of NVs effectively delivered to treat an inflammation. More precisely, she/he will label and formulate NVs according to methods developed at the IGPS. She/he will characterize the labeled NVs with standard methods for the characterization of nanoparticles and will further measure their photoacoustic properties. The doctoral student will also implement the high frequency 3D scanner at the LIB. She/he will be in charge of optimizing the imaging sequence, the image reconstruction and the image analysis based on methods already developed at the LIB. Finally, she/he will perform the in vivo experimental study on murine models.



The indicative timetable for this doctoral project is :
• 0 to 12 months : development of the high frequency in vivo imaging scanner and its validation. Formulation and characterization of one type of labeled NVs.
• 12 to 24 months: imaging of the accumulation of labeled NVs at the site of inflammation. Synthesis of several types of labeled NVs.
• 24 to 36 months: comparison of the accumulation of different labeled NVs. Analysis of the structural and mechanical properties of the NVs influencing their accumulation. Analysis of the quality and spatial resolution of the assessment of PAI-based assessment of the NVs.

Bibliography
1. 2016-2030 SRIA, Nanomedicine Strategic Research & Innovation Agenda 2016–2030: Creating Junctions for Healthcare (2016).
2. Q. Wang and X. Sun, "Recent advances in nanomedicines for the treatment of rheumatoid arthritis," Biomater. Sci. 5, 1407–1420 (2017).
3. P. Beard, "Biomedical photoacoustic imaging.," Interface Focus 1, 602–31 (2011).
4. J. Weber, P. C. Beard, and S. E. Bohndiek, "Contrast agents for molecular photoacoustic imaging.," Nat. Methods 13, 639–50 (2016).
5. T. Lucas, I. Quidu, S. L. Bridal, and J. Gateau, "High-Contrast and -Resolution 3-D Ultrasonography with a Clinical Linear Transducer Array Scanned in a Rotate-Translate Geometry," Appl. Sci. 11, 493 (2021).
6. J. Gateau, M. Gesnik, J.-M. J.-M. Chassot, and E. Bossy, "Single-side access, isotropic resolution, and multispectral three-dimensional photoacoustic imaging with rotate-translate scanning of ultrasonic detector array," J. Biomed. Opt. 20, 056004 (2015).
7. M. Lorscheider, N. Tsapis, M. ur-Rehman, F. Gaudin, I. Stolfa, S. Abreu, S. Mura, P. Chaminade, M. Espeli, and E. Fattal, "Dexamethasone palmitate nanoparticles: An efficient treatment for rheumatoid arthritis," J. Control. Release 296, 179–189 (2019).

Profile and skills expected:
- Master 2 (or equivalent) with knowledge of wave physics, instrumentation and a taste for physical-chemistry
- Strong interest in experimental techniques and analysis of experimental data
- Skills in programming and signal and image processing
- Taste for interdisciplinary work : physics, chemistry and biology (involving good communication skills)
- Good interpersonal skills (enthusiasm for research), able to work independently as well as in a team, taking initiatives
- Good command of English

To apply, please send:
• A resume
• A cover letter
• A copy of the transcripts of Master 1, Master 2 and / or School of Engineering
• A description of previous work (max. 3 pages)
• Letters of recommendations, if any

Work Context

The doctoral student will be appointed by the CNRS, one of the most well-established French multidisciplinary research institute in the World. This thesis project is funded directly by the CNRS through the MITI (https://miti.cnrs.fr/) interdisciplinary program 80Prime. For this multidisciplinary project, the student will be co-supervised by two research teams working in biomedical photoacoustic imaging (Team: Imaging and targeted therapy development in cancer and inflammation, Laboratoire d'imagerie Biomedical, LIB , https://www.lib.upmc.fr/ ) and nanoparticle engineering (Team: Particle and cell engineering for therapeutic applications, Institut Galien Paris Saclay, IGPS, http://www.umr-cnrs8612.universite-paris-saclay.fr/ ), respectively. The LIB is located in the Centre de Recherche des Cordeliers (CRC, Paris). The laboratory has a strong expertise in the development of ultrasound based imaging modalities, such as pulse-echo ultrasound imaging and photoacoustic imaging. The project will benefit from state-of-the-art equipment (tunable nanosecond laser, programmable research ultrasound machine, high precision motorized stages) and from the experience gained in previous implementations of 3D imaging with this equipment. IPGS is located in the Faculty of Pharmacy of the University Paris Saclay (Châtenay-Malabry). It is a unique department focusing on the development of new drug delivery systems and contrast agents for biomedical imaging. IGPS is well equipped to synthesize formulate, characterize and study nanoparticles. In vivo experiments will be performed at the in vivo imaging platform at the Cochin Institute (Paris).
The PhD student will belong to the doctoral school « Public health - Pierre Louis: Epidemiology and Biomedical Information Science” (ED393, http://www.ed393.upmc.fr/) of Sorbonne University, for PhD formations and degree.

Constraints and risks

Laser risk. Appropriate equipment (laser googles and shields) will be provided. Training will be provided regarding the safety procedures and repect of safety procedures will be mandatory.
Work with animal models. Appropriate training will be provided in accordance with regulations.

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