Functional ordered mesoporous silica in nanomedicine: target and drug delivery systems.

Ordered mesoporous materials (OMMs) are characterized by high surface area (up to 1000 m2/g), high pore volume (1-3 cm3/g) and narrow pore size (2-30 nm) distribution. Recently, mesoporous silica nanoparticles (MSNs), a subclass of OMMs, have had great development as nanocarriers for drug delivery, particularly for cancer treatment. The research activity of my PhD work was aimed to study SBA-15 and MCM-41 mesoporous silica samples for biomedical applications. The texture and the structure of the synthesized materials were characterized through N2 adsorption/desorption isotherms, SAXS, and TEM. The functionalization of the mesoporous silica samples was verified by means of Fourier-transform infrared spectroscopy (FTIR) and thermogravimetric analysis (TGA). DLS and ELS were used to determinate hydrodynamic diameter and zeta potential of the studied systems under different conditions. The PhD thesis focused on different aspects of the use of OMMs, particularly MSNs, as drug nanocarriers. In the first paper how different features of OMMs (surface area, pore size and surface charge) can affect the adsorption and release of drugs was investigated. Ampicillin, a penicillin-like -lactam antibiotic was loaded on MCM-41, SBA-15, and amino-functionalized SBA-15, then its release in simulated physiological conditions was studied. This study demonstrated that to obtain a sustained drug release, the chemical nature of the matrix’s surface plays a role which is more important than its textural features. SBA-15-NH2 matrix is a suitable candidate as depot system for local sustained release of ampicillin. Common target systems have the disadvantage that the targeting molecule can be recognized by several receptors. A possible strategy to solve this issue was investigated in the second paper. The targeting molecule was hidden by preparing a double sequential targeting system. To this purpose a double target system was synthesized. Alendronate was used as a tissue target to recognize a diseased bone, and an encrypted cellular target, Arg-Gly-Asp (RGD) was used to improve the internalization in human osteosarcoma cells (collaboration with Universidad Complutense de Madrid). This preliminary study showed the efficacy of the double target systems. The next step could be the functionalization of MSNs with the previously described systems for the synthesis of a smart target systems usable as a carrier for anticancer drugs against bone cancer. In the third paper, the effect of surface charge on the internalization of MCM-41-type MSNs, functionalized with chitosan (CHIT) and hyaluronic acid (HA) biopolymers, on 3T3 mouse fibroblast cells was then investigated. The opposite surface charge of the biopolymer-functionalized MSNs (negative for MSN-HA and positive for MSN-CHIT) gave a different interaction with BSA, used as a model protein to investigate the formation of the protein corona (forth paper). Finally, in the fifth paper, MSNs were functionalized with HA samples having three different molecular weights (HAS, HAM, and HAL). The effect of HA molecular weight on the internalization of HA-MSNs particles on HeLa cells was evaluated. These last studies showed the importance of the external functionalization on the interaction between MSNs and the components of body fluids, that change their surface properties. These changes as well as the polymer’s features (i.e. the molecular weight) are able to modulate the cellular uptake. The obtained results highlight the importance of the physico-chemical phenomena occurring at the nano-biointerface for the future use of functionalized OMMs and MSNs in nanomedicine. The present findings confirm that these nanocarriers are very promising matrices for the obtainment of targeting drug delivery systems for cancer treatment.