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Computational Nanomedicine Group

The main focus of our research program involves using molecular modelling to study the properties of the protective polymer polyethylene glycol (PEG) in drug delivery;  both on the surface of PEGylated liposomes (DDL), and also in the direct interaction between PEG and drugs — either as a dissolution aid or as a protective sheath as a covalent drug-PEG conjugate.

Since the diameter of the DDL is large with respect to the membrane width, the surface structure can be effectively modelled through a simulation of a segment of membrane with periodic boundary conditions. We have simulated both PEGylated (1) and nonPEGylated (2) liposome membranes at physiological salt concentrations in both the gel and liquid crystalline phase. Our simulations suggest that the PEG polymer is completely outside the membrane in the gel state. However, in the liquid crystalline state, a subset of the PEG polymers are found within the lipid core (alkyl chain region) of the membrane. This is a result of its solubility in both polar and nonpolar solvents. Since the area per lipid is greater and since some of the PEG polymers locate to the membrane interior, the PEG layer in the liquid crystalline membrane is considerably less dense compared to gel membrane. We also observe a strong association between PEG and Na+ ions, and we identified an important new effect. In the less dense PEG layer of the liquid crystalline membrane, when the molar density of PEGylated lipids is reduced from 10% to 5%, Cl ions (with their water shells) are able to sit within the PEG layer. However, they are excluded from the more dense PEG layer of the gel membrane at 10% PEGylated lipid. It is thought that an important factor in the protective role of the PEG corona is reduction in the liposome surface charge. Our results indicate that  PEG lowers the surface charge of the liposome up to a certain concentration. However, beyond a certain concentration the PEG corona becomes charged again, possibly explaining the experimental result that 5% molar density of PEG is optimal. We the simulated the interaction of the PEGylated liposome surface with K+ and Ca2+ ions (5). The simulations suggest that the PEG interaction with K+ ions is weaker than for Na+ ions, with no observed interaction with Ca2+ ions. These results suggest a mechanism for the experimentally observed result of PEGylation inhibiting calcium induced fusion. Since effects on surface charge and interaction with different salt ions in the bloodstream are keys to the protective properties of the polymer corona of a nanovector, our simulations have provided key insights that will allow a rational design approach in developing superior alternatives to PEG.
We also apply our simulation techniques to understanding targeting efficacy of liposomes with various targeting moieties (active targeting). We have performed a molecular dynamics simulation of a PEGylated membrane with two different targeting ligands attached: the hydrophilic RGD peptide that has already been shown to be effective, and a new more hydrophobic AETP ligand (4). Doxorubicin-carrying liposomes containging the AETP ligand were prepared and tested in vitro and in vivo (Prof. Arto Urtti), but these liposomes do not demonstrate specific targeting efficacy. Our molecular dynamics simulations suggest that the targeting failure is due to increased coverage of the hydrophobic AETP ligand by the PEG polymer. Molecular simulation allows us to propose a possible solution by replacing PEG with an alternate polymer that does not have as strong an interaction with the targeting moieties; and, this can then be tested in silico.
We have also simulated direct PEG-drug interactions (3) in three drugs with which PEG has been used in drug delivery: paclitaxel and piroxicam (where PEG is used as a dissolution aid) and hematoporphyrin (where PEG is covalently bound to form a protective sheath). Our simulations suggest no specific interaction between PEG and paclitaxel or piroxicam. However, our data suggest a strong attractive interaction between PEG and the hydrophobic center of the porphin ring of hematoporphyrin; and, this interaction is strengthened by the presence of salt in the solution. This result has subsequently been confirmed experimentally by using absorption spectroscopy experiments (research group of Prof. Mariusz Kepczynski of Jagiellonian University).

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Dr. Bunker has served as group leader in the Centre for Drug Research (CDR) since 2005 where he leads the Computational Nanomedicine Group.

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