Endosomal Escape: Mechanism and Improved Drug Delivery

• Název práce v češtině: Endosomal Escape: Mechanism and Improved Drug Delivery
• Název v anglickém jazyce: Endosomal Escape: Mechanism and Improved Drug Delivery
• Akademický rok vypsání: 2024/2025
• Typ práce: disertační práce
• Ústav: Ústav fyzikální chemie J. Heyrovského AV ČR, v.v.i. (32-UFCHAV)
• Vedoucí / školitel: Mgr. Marek Cebecauer, Ph.D.
• Konzultanti: Christoph Allolio, Ph.D.

Zásady pro vypracování

To be specified. More information: [e-mail]

Seznam odborné literatury

[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)

Předběžná náplň práce

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.

Předběžná náplň práce v anglickém jazyce

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.