As we discussed in class, one way that cells recognize biomaterials is through the proteins that are coated on them. For nanoparticles, proteins surround the particle forming something called the protein corona. This allows cells to recognize and interact with the particle.
Image 1: Cartoon showing the formation of the protein corona of a nanoparticle.
“Nanotechnology for Maternal Foetal Medicine” discusses the importance of characterizing nanoparticles in the medium they will be used, i.e. amniotic fluid. Although many studies using nanoparticles show promise as fetal therapies, some essential safety questions remain unanswered, which hinders clinical translation. Nanoparticle stability and distribution within placental and fetal environments needs to be better characterized to overcome these hurdles. Many of these factors are influenced by the composition of the protein corona of nanoparticles, so a better understanding and improved characterization of the protein corona is essential for eventual translation to clinic.
The composition of the protein corona can be very important for nanoparticle biocompatibility and stability. Nanoparticle toxicity is influenced by protein corona composition1. Furthermore, biodistribution of particles is highly influenced by the composition of the protein corona1.
The composition of the protein corona alters what proteins cells are interacting with. This can modulate what cells will preferentially take up particles. For example, adsorption of immunoglobins or complement proteins to the nanoparticle’s surface can encourage phagocytosis by macrophages whereas particular ligands can encourage clathrin-mediated endocytosis by most cells in the body. Therefore, the protein corona influences how nanoparticles are seen and processed by the body, as well as can influence the efficacy of the drug dose inside the nanoparticle (i.e. if it is not being delivered to the correct cell type, it is likely not an efficacious treatment).
Nanoparticles can also be stabilized (or destabilized) by the protein corona. For example, a PLGA nanoparticle that is not very stable in saline may exhibit greater stability in blood1. Therefore, testing the stability and release of a nanoparticle in the medium it will be applied to is important. The varying protein compositions may lead to differing protein coronas which can significantly influence nanoparticle behavior.
Therefore, if we want to use nanoparticles for fetal therapy, we need to understand how they will perform in the media they will be used in. If nanoparticles are being systemically injected to fetal circulation, then this is already known, since it is well researched how nanoparticles perform when injected systemically. However, little is known about the protein corona and nanoparticle stability in amniotic fluid. A PLGA nanoparticle may exhibit great stability in the blood, but, due to the different protein corona it will form, be very unstable in amniotic fluid.
Understanding the protein corona of nanoparticles in amniotic fluid is important as many fetal therapies may want to explore administration to the amniotic fluid. Maternal-fetal medicine doctors and fetal surgeons can access the amniotic cavity (for amniocentesis) safely with a very low risk of fetal loss as early as 13 weeks of gestation. At the 10th to 11th week of gestation, the fetus also begins to breathe and swallow amniotic fluid to help lung development. Therefore, a gene therapy designed to target a genetic disorder primarily affecting the respiratory or GI systems may want to take advantage of nanoparticle delivery through the amniotic fluid.
Image 2: Diagram describing process of amniocentesis.
“Nanotechnology for Maternal Foetal Medicine” makes an important point about the need for more research in the field of cell-biomaterial interactions, specifically looking at how the protein corona of nanoparticles influences behavior in different media. Since many potential fetal therapies may involve delivery to amniotic fluid, research in maternal-fetal medicine needs to gain a better understanding of nanoparticle protein coronas in amniotic fluid. If we want more nanoparticle-based therapies to make it to clinic, this could be essential.
Reference: Casals, et. al. “Nanotechnology for Maternal Foetal Medicine.” International Journal of Pediatrics and Neonatal Health (2018). 2:5, 57-66.
Image 1 reproduced from: Riviere, et. al. “Computational approaches and metrics required for formulating biologically realistic nanomaterial pharmacokinetic models.” Computational Science & Discovery (2013). 6(1):014005.
Image 2 reproduced from: “Amniocentesis.” Mayo Clinic. https://www.mayoclinic.org/tests-procedures/amniocentesis/about/pac-20392914