While basic and clinical science have revealed and identified multiple problems that cause a reduction of therapeutic efficacy of systemic chemo and immunotherapy for breast cancer, numerous new nanotechnology-based drug delivery platforms have been tested to address these unmet clinical problems. Though nanomedicine holds great promise, there are still multiple challenges in order to bring this novel technology to the clinic. In particular, controlling the biodistribution of nanoparticulates in vivo and the avoidance of biological barriers are two of the most important challenges. The third generation of particulate systems can help in addressing these challenges. The main advantage of these over the previous generations relies on their modularity: each stage is dedicated to a specific function and can be rationally designed to execute that specific function with superior performances. For a multi-stage third generation particulate, the 1st stage particulate is designed to navigate into the circulatory system, avoid or limit the recognition from the cells of the immune system and accumulate with higher percentage in the organs of interest; whereas the 2nd stage particulates, loaded within the 1st stage, are designed to diffuse within the organ of interest, interact specifically with the target cells and release their payload. Clearly the functions of the two particulates are different and their geometrical and physico-chemical properties should be different so that the 1st stage could be optimally designed for vascular targeting, whereas the 2nd stage would be optimally designed for extravascular targeting. Obviously the whole delivery process can be broken down into more steps (specific functions), meaning more stages, leading to fully multiple stage particulate systems.
The work of Decuzzi and Ferrari over the past years has shown how the behavior of particulate systems can be fine tuned not only by tailoring their surface physico-chemical properties (decoration with ligand molecules; polymeric coating with PEG) but also controlling their geometrical properties, as size and shape. These three engineering parameters (size, shape and physico-chemistry) play a crucial role in particulate (i) transport within the circulation and in the tissue; (ii) recognition of vascular and extravascular targets; (iii) interaction with target cells and cells of the immune system; and can be tailored during the fabrication and synthesis process with great accuracy. Particles with nonspherical shapes have been shown to drift laterally towards the vessel walls in capillary flows, mimicking the behavior of platelets, and by doing so the likelihood of recognition of specific biological targets in the vasculature can be significantly increased. Non-spherical particles have been shown to adhere more strongly to the vessel walls under flow, and in particular for oblate spheroidal particles it has been estimated an increased of about 50 times in the deliverable payload compared to classical spherical particles with the same strength of adhesion. Nonspherical particles have been also shown to resist more internalization, so that can adhere to cells of the vessel wall without being internalized while releasing their payloads.
