3.4.1. General Design of Cancer Nanomedicines

Concerning the general design of a given nanomedicine, the function, characteristics, materials, and method of synthesis are the four factors that must be taken into account. Once clearly established, the defined function is then used to specify the essential characteristics

of the nanomedicine. Then, the materials used to build the object and its manufacturing method have a significant impact on its ability to exhibit the desired properties [14]. Thus, the physicochemical properties obtained from a rational design will have a major influence on the biodistribution and pharmacokinetics of a nanomedicine. The major physicochemical properties of a given nanomedicine are the size, the shape, the surface charge, and chemistry. The size of nanomedicines is a major feature dictating their overall biodistribution and cell internalization. As previously mentioned, the suitable diameter for nanomedicines targeting cancers ranges from 10 to 100 nm, making it possible to passively target tumors through the EPR effect.

The surface charge, expressed through zeta potential (i.e., the surface charge of an NP in colloidal suspension), is also a major parameter related to nanomedicine biodistribution due to electrostatic interactions between the NPs and various biological molecules. Unlike negatively charged NPs, positively charged NPs are more prone to be uptaken by cells that may induce side effects (non-targeted cells), decrease a drug delivery process to targeted cells, and shorten the circulation time. Zeta potential may also affect the loading capacity of SPIONs according to the charge of the payload drug. The surface chemistry of nanomedicines aims also to significantly improve their targeting properties. This goal can be achieved through various functionalizations with targeting ligands enhancing the affinity of nanomedicines to significantly increase the uptake within the targeted tissues. These functionalizations can also rely on surface modification with various polymers (e.g., polyethylene glycol, PEG, *vide infra*) to protect the nanomedicines from rapid clearance, subsequently making them stealthy. The clearance phenomenon may also be increased through renal elimination. This can be observed with small NPs (approximately 6 nm), positively charged NPs (through the negative glomerular basement membrane), and rodshaped NPs [14].
