Endosomal Escape: Mechanism and Improved Drug Delivery
| Thesis title in Czech: | Endosomal Escape: Mechanism and Improved Drug Delivery |
|---|---|
| Thesis title in English: | Endosomal Escape: Mechanism and Improved Drug Delivery |
| Academic year of topic announcement: | 2024/2025 |
| Thesis type: | dissertation |
| Thesis language: | |
| Department: | Ústav fyzikální chemie J. Heyrovského AV ČR, v.v.i. (32-UFCHAV) |
| Supervisor: | Mgr. Marek Cebecauer, Ph.D. |
| Author: | |
| Advisors: | Christoph Allolio, Ph.D. |
| Guidelines |
| To be specified. More information: allolio@karlin.mff.cuni.cz |
| References |
| [1] C. Allolio, A. Magarkar, P. Jurkiewicz, K. Baxova, P. E. Mason, R.
Šachl, M. Cebecauer, M. Hof, D. Horinek, V. Heinz, R. Rachel, C. Ziegler, A. Schrofel, P. Jungwirth Proc. Natl. Acad. Sci. U.S.A., 115, 11923-11928 (2018) [2] A. Sahni, Z. Qian, and D. Pei ACS Chem. Biol. 15, 9, 2485–2492 (2020) [3] C. Allolio, D. Harries ACS Nano 15 (8), 12880-12887 (2021) |
| Preliminary scope of work |
| After endocytosis many bioconjugate drugs remain trapped in endosomes,
consequently they cannot reach their targets in the cytosol. Cell penetrating peptides can - at high concentrations remodel the endosomal lipid membrane, in a mechanism that might allow endosomal escape via budding. Some of the details of this mechanism are visible in superresolution microscopy. We have access to custom-made endosomal escape agents from the IMC of the CAS, which show some promise in improving efficacy of endosomal escape. We aim to systematically probe the mechanism and efficacy of these agents. From a theoretical point of view, membrane deformations, including budding and fission, can be modeled using the Helfrich-Hamm-Kozlov (HHK) theory of curvature elasticity. Recent advances allow to extract the parameters of this theory from molecular dynamics simulations. The PI has prepared a solver to deal with challenging deformations. This PhD thesis is a joint theoretical and experimental effort to understand the mechanism of endosomal escape and use our insights to improve drug delivery. |
| Preliminary scope of work in English |
| After endocytosis many bioconjugate drugs remain trapped in endosomes,
consequently they cannot reach their targets in the cytosol. Cell penetrating peptides can - at high concentrations remodel the endosomal lipid membrane, in a mechanism that might allow endosomal escape via budding. Some of the details of this mechanism are visible in superresolution microscopy. We have access to custom-made endosomal escape agents from the IMC of the CAS, which show some promise in improving efficacy of endosomal escape. We aim to systematically probe the mechanism and efficacy of these agents. From a theoretical point of view, membrane deformations, including budding and fission, can be modeled using the Helfrich-Hamm-Kozlov (HHK) theory of curvature elasticity. Recent advances allow to extract the parameters of this theory from molecular dynamics simulations. The PI has prepared a solver to deal with challenging deformations. This PhD thesis is a joint theoretical and experimental effort to understand the mechanism of endosomal escape and use our insights to improve drug delivery. |