Application of nanotechnology to medical science has been emerging as a new field of interdisciplinary research among medicine, biology, toxicology, pharmacology, chemistry, material science, engineering, and mathematics, and is expected to bring a major breakthrough to address unsolved medical issues. The delivery strategy of these vectors is based on enhanced permeation and retention (EPR) effect ; the circulating vector accumulates in the tumor mass over time because it is sufficiently small (<300 nm) to extravasate by crossing passively the fenestrations in the diseased vasculature (passive targeting). In addition to liposomal doxorubicin, albumin-bound paclitaxel (Abraxane ®) is another example of an EPR based nanovector application for breast cancer chemotherapy.
Paclitaxel is highly hydrophobic and dissolved in cremophor to prevent paclitaxel precipitation. However, according to Liebmancn et al. 1993, cremophor-associated toxicities are severe (hypersensitivity reaction and neurotoxicity) and challenge the application of paclitaxel. Albumin-bound paclitaxel was developed to improve the solubility of paclitaxel. This formulation improves the toxicity profile of conventional paclitaxel therapy formulated with cremophor (Nyman et al. 2005). These vectors are not specifically targeted against any molecule expressed on the tumor cells or the endothelium and have been classified as ‘first generation’ vectors [6] . The ‘second generation’ of therapeutic nanovectors evolved to be able to recognize and target specific biological molecules on the surface of the cancer cells (active targeting). Such application will promise to improve therapeutic window to delivery higher concentration to diseased lesion, while reducing life-threatening systemic cytotoxicity. This can be achieved by chemical coupling of high affinity ligand, such as Arg–Gly–Asp (RGD), folate, prostate specific membrane antigen , on the surface of the nanoparticles, and it facilitates the interaction of nanoparticles and cancer cells, resulting in a dramatic improvement of the biodistribution of nanoparticles compared to the non-targeted first generation nanovectors. We are currently developing a ‘third generation’ of nanovectors , which relies on a multi-stage strategy and is characterized as a carrier for nanoparticles and a higher level of multi-functional integration. Biodegradable mesoporous silicon microparticles (1st stage) can be loaded with one or multiple types of nanoparticles (2nd stage) containing different types of payloads, both for therapy and imaging (Figure 2). The 1st stage particle is designed to navigate within the circulatory system and to recognize specifically the diseased endothelium through a judicious (mathematically driven) choice of its geometrical (size, shape) and surface physico-chemical properties. The 2nd stage nanoparticles within the pores of the 1st stage, are released towards the tumor mass from the site of vascular adhesion (tumor endothelium) as the 1st stage degrades over time. The 2nd stage nanoparticles are sufficiently small (<20 nm) to easily cross the inter-endothelial junctions and diffuse within the extravascular compartment. The delivery strategy of the third generation vectors does not rely on the EPR effect, in that the 1st stage particles are directed towards the vascular endothelium and the 2nd stage particles pass the fenestrations. The modularity of the third generation vectors presents a powerful tool to address multiple unmet medical issues, with a focus of development of multifunctional and multimodal therapies.
