Mesoporous silica nanoparticles (MSNs) are considered as one of the most promising nanovectors for controlled drug delivery. For the design of ideal drug nanocarriers, several factors have to be taken into account, such as size and surface chemistry. Here, we report how MSNs surface functionalization and particle size critically affect the drug release performances and therapeutic capabilities. We illustrate the size effect of these functionalized MSNs on in vitro, intracellular, and in vivo drug release efficiency, as well as on nanoparticle and drug diffusion into the targeted tissues (tumor). For this, dispersible MSNs with different particle sizes (from 500 down to 45 nm), similar physicochemical properties (e.g., structural and textural properties), and high colloidal stability (even in saline conditions), were synthesized. Their surface was specifically functionalized with a phosphonate-silane according to a novel postgrafting strategy, for better control over loading and release of positively charged drugs. An efficient particle-size-dependent and pH-dependent release of the loaded drug (i.e., doxorubicin) was achieved in physiological conditions with phosphonated-MSNs compared to pure-MSNs. The cellular uptake efficiency is much higher with the smallest phosphonated-nanoparticles (45 nm). Furthermore, doxorubicin is efficiently released from the nanoparticles into the intracellular compartments, and the drug reaches the nucleus in a time- and particle size-dependent manner. Intratumoral diffusion of the developed nanoparticles, as well as the drug release and its diffusion into the tumor matrix, is clearly enhanced with the smallest phosphonated-nanoparticles (45 nm), leading ultimately to a superior cell and tumor growth inhibition.
Mesoporous silica nanoparticles (MSNs) have emerged as promising biomaterials for drug delivery and cell tracking applications, for which MRI is the medical imaging modality of choice. In this contribution, MRI contrast agents (DTPA‐Gd) and polyethylene glycol (PEG) are grafted selectively at the surface of MSNs, in order to achieve optimal relaxometric and drug loading performances. In fact, DTPA and PEG grafting procedures reported until now, have resulted in significant pore obstruction, which is detrimental to the drug delivery function of MSNs. This usually induces a dramatic decrease in surface area and pore volume, thus limiting drug loading capacity. Therefore, these molecules must be selectively grafted at the outer surface of MSNs. In this study, 3D pore network MSNs (MCM‐48‐type) are synthesized and functionalized with a straightforward and efficient grafting procedure in which DTPA and PEG are selectively grafted at the outer surface of MSNs. No pore blocking is observed, and more than 90% of surface area, pore volume and pore diameter are retained. The thus‐treated particles are colloidally stable in SBF and cell culture media, they are not cytotoxic and they have high drug loading capacity. Upon labeling with Gd, the nanoparticle suspensions have strong relaxometric properties (r2/r1 = 1.47, r1 = 23.97 mM−1 s−1), which confers a remarkable positive contrast enhancement potential to the compound. The particles could serve as efficient drug carriers, as demonstrated with a model of daunorubicin submitted to physiological conditions. The selective nanoparticle surface grafting procedures described in the present article represent a significant advance in the design of high colloidal stability silica‐based vectors with high drug loading capacity, which could provide novel theranostic nanocompounds.
We report here on the adsorption and deposition of L-glutamic acid (Glu) on an amorphous silica and its subsequent thermal transformations. When adsorbed from aqueous solutions, Glu only has a low affinity for the silica surface but at high concentrations the adsorbed molecules serve as nuclei for the formation of small glutamic acid crystallites. As long as the Glu loading remains inferior to a saturation limit (about 0.5 molecule nm À2 ), the thermal behavior of adsorbed Glu is significantly different from that of bulk glutamic acid. Two successive condensation steps are observed upon mild thermal activation, and their products have been identified by a combination of techniques including thermogravimetry, in situ IR, solid-state NMR, and ESI-MS. The first step at about 120 °C is a lactam ring closure quantitatively yielding pyroglutamic acid in a first-order reaction. The second step, at 150 °C, probably results in the formation of a highly activated tricyclic imide, PyroGluDKP, and is easily reversible in the presence of water. These reactions have implications for prebiotic peptide formation and for synthetic chemistry.
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