Therapeutic management of pregnancy disorders provides unique challenges, as the needs of the mother and foetus can differ. Targeted delivery of drugs to the maternal placenta offers a safer and more effective method of addressing related disorders in pregnancy, like pre-eclampsia and fetal growth restriction.
Targeted drug delivery is when nanoparticles are designed to be complementary to a specific cell that the drug is to be delivered to. Along with monoclonal antibodies and aptamers (well known for targeted use on macular degeneration), homing peptides have been shown to selectively deliver drugs to tumours. Homing peptides are short, randomly occurring peptide sequences that can bind to unique receptors on the surface of cells of interest, including cancer cells.
To target tumours, the homing peptides are coupled with nanoparticles containing chemotherapeutics in a process referred to as internalisation of homing peptides. Internalisation occurs via endocytosis pathways. Recently, a new pathway, the CendR pathway has been described for two tumor homing peptides: CGKRK and iRGD. Through screening experiments of these homing peptides, a new homing peptide sequence was identified, RSGVAKS (RSG). Similar to CGKRK and iRGD, it binds to uteroplacental blood systems and placental cells but, prior to this experiment, was not known to bind to tumour cells.
This experiment focused on the homing peptide CGKRK, known to target both tumour and placental cells, and the novel homing peptide RSG to determine its ability to bind to tumour cells. The experiment used model membranes that mimic the lipid compositions of cancer and placental cell membranes, taking an innovative approach that provided insight on peptide efficacy as well as their mechanisms of interactions with cell membranes.
Their major finding was that, like CGKRK, RSG can also bind to cancer cells, suggesting there is potential for RSG to be used as a tumour homing peptide. Further to this, interactions of both peptides with the cancer model membrane were more pronounced and faster than the placental membrane, likely due to electrostatic interactions with its negatively charged lipid components. Neutron reflectometry performed on the INTER instrument was used to examine the structures of model membranes, when exposed to the homing peptides to determine the details of their interaction. Comparison of the data revealed RSG causes more lipid loss than CGKRK, as it penetrates deeper and thus causes more disruption to the membrane.
Both peptides were seen to exhibit cell penetrating behavior. This means they can bind to and translocate into membranes in an energy and receptor independent manner. CGKRK associates more superficially, binding only to the head groups of the lipid bilayer whereas RSG bound to the lipid chains as well as the heads.
The researchers hope that the approach used here to study homing peptide-membrane interactions can be exploited to predict peptide behaviour and inform the design of targeted nanoparticle formulations. With increasing recognition of the need for nanomedicines in pregnancy, there is potential to apply the placental targeting behaviours of homing peptides like these. They also hope the ability to observe the method of membrane penetration can be used as a screening method to select the optimal cell penetrating peptide for the cell/tissue of interest, eventually optimising drug targeting techniques.
