Intracellular drug delivery by laser-induced photoporation: molecular modeling of photothermally heated nanoparticles near biological membranes

  1. Intracellular drug delivery by laser-induced photoporation: molecular modeling of photothermally heated nanoparticles near biological membranes

    19MODEV01 / Model and software development
    Promotor(en): A. Ghysels, K. Braeckmans / Begeleider(s): A. Ghysels, K. Braeckmans

    Delivering foreign materials, such as nucleic acids or imaging contrast agents, into living biological cells is an important aspect both in fundamental cell studies and in biomedical applications. Many of those foreign molecules or nanoparticles are too large to enter spontaneously into living cells which are protected by their outer cell membrane. Numerous methodologies have, therefore, been developed to deliver exogenous materials across the cell membrane into cells, which can be broadly classified as biological, chemical and physical methods [1]. Physical approaches are attractive because they typically can be applied to many different cell types and a broad variety of compounds. Examples of physical approaches are electroporation, sonoporation and mechanoporation, which all have in common that they use a physical force to form small pores in the cell membrane through which foreign materials can diffuse into the cell.

    One of the newest physical intracellular delivery approaches that has received increasing attention in the last decade is “laser-induced photoporation” [2]. As illustrated in Figure 1, living cells are first incubated with light-sensitive nanoparticles, e.g. gold nanoparticles, which can attach to the cell membrane. Next, the cells are irradiated with (pulsed) laser light, which causes rapid heating of the nanoparticles and a temporary permeabilization of the nearby cell membrane. Foreign compounds in the cell’s neighborhood can then diffuse across the cell membrane and reach the cell’s interior to have their therapeutic effect. Even though photoporation has been extensively experimentally investigated and validated, the process of how the laser-heated nanoparticles increase the permeability of the cell membrane is still not well understood at the molecular scale. Yet this knowledge would be of tremendous benefit in order to further enhance the efficiency of photoporation which is expected to become an increasingly valuable tool in biotechnological and biomedical applications, including the modification of cells for cell-based anti-cancer therapies.

    Goal

    The primary goal of the thesis is to unravel the membrane's response when it comes into contact with the heated NP using molecular modeling. The membrane structure and the permeability will be studied at the molecular scale using molecular dynamics (MD) simulations. In MD simulations, the trajectories of the atoms' positions over time are constructed by integrating Newton's equations of motion. MD with force fields is a well-known technique in the Center for Molecular Modeling for membranes. An essential step in photoporation is the delivery of heat by the NP. To model this delivery of heat, the student will need to develop new simulation methodologies by extending existing MD tools with a heat source that represents the heated particle. Analysis scripts will also need to be developed to track the heat waves and to detect water or drug permeation events. The overall aim of the work is to capture the essential physical aspects that are relevant in photoporation. In particular, photoporation is inherently a time-dependent phenomenon with temporarily higher permeability, increasing the modeling challenge considerably, as standard equilibrium statistical physics do not apply. Not only the amount of heat but also the heating rate will need to be taken into account, apart from other variables like the size of the NP (several nanometers) and the distance between the heated NP and membrane. It will be especially challenging to construct simulations that have a suitable simulation box size, that is both large enough to study the process and small enough to be computationally feasible. Conceptually, this concerns a spherical source near an essentially two-dimensional surface, complicated by the fact that properties are anisotropic and inhomogeneous. The thesis should result in a biophysical picture of the photoporation phenomenon by heated NP.

    This thesis will be performed in close collaboration between the Center for Molecular Modeling and the Biophotonic Research Group. Depending on the student’s interest, it is possible to perform photoporation experiments in the laboratory of prof. K. Braeckmans, to allow for a closer comparison between experiment and computational results.

    Aspects
    Master of Science in Biomedical Engineering: The modeling of the photoporation aids the design of drug delivery by nanoparticles.
    Master of Science in Engineering Physics: The physics aspect is the fundamental insight in the physical aspects of the photoporation process based on heat transfer and the understanding of the time-dependency of the process. Engineering aspect is the construction of a methodological simulation tools that model a heat source near a membrane, which aids in the design of drug delivery by nanoparticles.