After introduction in the bloodstream, nanoparticles are instantly surrounded by a protein coating referred to as 'protein corona' (PC). Thus, what the cell sees is the interface made of the proteins engaged from the blood that could promote the association with specific receptors of target cells.
Here we want to demonstrate that the specificity of clinically approved liposomal drug depends on the PC formed around liposome after their interaction with the blood. The second aim is the validation of a new targeted strategy of drug delivery based on the rational exploitation of PC. Starting from the receptor profile of target cells (i.e. breast cancer cells), optimal PC composition will be identified by bio-informatics and manipulated by liposome design. This will represent a truly new paradigm for designing next-generation liposomes for targeted cancer therapy.
When liposomes are injected intravenously they are immediately exposed to a plethora of biomolecules, mainly proteins, which rapidly form the protein corona. In vitro investigations showed that a protein corona formed in just 30s has a significant impact on how the nanoparticle affects cells compared with pristine nanoparticles (7). The resulting biological identity is the size and aggregation state of the liposome, along with the thickness, density and composition of the protein corona (7,8).
A huge amount of preliminary data published by our lab conceivably form the basis for understanding liposome-plasma interactions and suggest it is feasible to design novel liposomal formulations with optimal circulation profiles based on their corona-forming properties. The concept of using the "liposome-protein corona" as a natural functionalization of liposomes to target specific cells or tissues is absolutely novel and has the potential to revolutionize the field of targeted therapeutic delivery. The relationship between the synthetic and the biological identity of liposomes and the implications for clinical practice have never been investigated. As has become clear, ligand-functionalized liposome surfaces may not actually exist in nature. This notion has far-reaching implications for the use and development of targeted liposomal therapeutics. Liposome targeting properties then depend on the identity, arrangement and residence time of the (corona) proteins at the liposome surface. What is more, the liposomal formulations currently on the market may be relying on their acquired biological identity in vivo, as their protein corona may be responsible for effective drug delivery. This potential working mechanism is thus far not being considered. This project will investigate this notion specifically, by determining the synthetic and biologic identity of a set of marketed liposomal cancer therapeutics. The ability to specifically manipulate the liposome-protein corona effect for targeted drug delivery will influence the direction of future research related to the development of liposomal therapeutics. It will allow for the classification of such therapeutics in terms of their corona composition, as this mediates their interaction with the cellular machinery. This project will provide the tools to support such classification as well as the future developments. To this end, protein-liposome complexes will be studied in terms of structural properties, composition and interactions with target cells, tissues and organs. This will yield a validated methodology for the analysis of different liposome formulations and for the design of liposome formulations engineered to create the desired biological identity.
7. G. Caraccioloet al., Applied Physics Letters, 2011, 99, 033702.
8. S. Tenzer et al., ACS Nano, 2011, 5, 7155-7167.