Mechanism of erosion of nanostructured porous silicon drug carriers in neoplastic tissues.

Nanostructured porous silicon (PSi) is emerging as a promising platform for drug delivery owing to its biocompatibility, degradability and high surface area available for drug loading. The ability to control PSi structure, size and porosity enables programming its in vivo retention, providing tight control over embedded drug release kinetics. In this work, the relationship between the in vitro and in vivo degradation of PSi under (pre)clinically relevant conditions, using breast cancer mouse model, is defined. We show that PSi undergoes enhanced degradation in diseased environment compared with healthy state, owing to the upregulation of reactive oxygen species (ROS) in the tumour vicinity that oxidize the silicon scaffold and catalyse its degradation. We further show that PSi degradation in vitro and in vivo correlates in healthy and diseased states when ROS-free or ROS-containing media are used, respectively. Our work demonstrates that understanding the governing mechanisms associated with specific tissue microenvironment permits predictive material performance.

Bombarding cancer: biolistic delivery of therapeutics using porous Si carriers.

A new paradigm for an effective delivery of therapeutics into cancer cells is presented. Degradable porous silicon carriers, which are tailored to carry and release a model anti-cancer drug, are biolistically bombarded into in-vitro cancerous targets. We demonstrate the ability to launch these highly porous microparticles by a pneumatic capillary gene gun, which is conventionally used to deliver cargos by heavy metal carriers. By optimizing the gun parameters e.g., the accelerating gas pressure, we have successfully delivered the porous carriers, to reach deep targets and to cross a skin barrier in a highly spatial resolution. Our study reveals significant cytotoxicity towards the target human breast carcinoma cells following the delivery of drug-loaded carriers, while administrating empty particles results in no effect on cell viability. The unique combination of biolistics with the temporal control of payload release from porous carriers presents a powerful and non-conventional platform for designing new therapeutic strategies.

Mathematical modeling of drug release from nanostructured porous Si: combining carrier erosion and hindered drug diffusion for predicting release kinetics.

A novel, empirical, macroscopic model is developed to describe the release of a model anticancer drug, Mitoxantrone, from native and chemically modified porous Si (PSi) thin films. Drug release from these carriers results from a combination of two mechanisms, i.e. out-diffusion of the drug molecules and erosion of the Si scaffold. Thus, the proposed mathematical model adapts the Crank model to lump the effects of temporal changes in molecular interactions and carrier scaffold erosion into a comprehensive model of hindered drug diffusion from nanoscale porous systems. Careful characterization of pore size, porosity, surface area, drug loading, as well as Si scaffold degradation profiles, measured over the same time-scale as drug release, are incorporated into the model parameter estimation. A comparison of the experimental and model results shows accurate representation of the data, emphasizing the reliability of the model. The proposed model shows that drug diffusivity values significantly vary with time for the two studied carriers, which are ascribed to the distinctive role of the prevailing physical mechanisms in each system. Finally, secondary validation of the proposed model is demonstrated by showing adequate fit to published data of the release of dexamethasone from similar mesoporous Si carriers.

Engineering porous silicon nanostructures as tunable carriers for mitoxantrone dihydrochloride.

Nanostructured porous silicon (PSi) thin films, fabricated by the electrochemical anodization of single crystalline Si wafers, are studied as delivery systems for the anticancer drug mitoxantrone dihydrochloride (MTX). The surface chemistry of the PSi carriers was tailored by surface alkylation using thermal hydrosilylation of 1-dodecene and undecylenic acid, followed by physical adsorption or covalent attachment of MTX to the Si scaffold. The nanostructure and the physiochemical properties of the different carriers were characterized by attenuated total reflectance Fourier transform infrared spectroscopy, nitrogen adsorption-desorption and contact angle measurements, demonstrating that surface alkylation results in a pronounced effect on the hydrophobicity/hydrophilicity of the scaffolds and a volumetric gain in pore wall, which in turn results in a decrease in pore diameter (>23%) and available porous volume (>40%). The effect of these key parameters on MTX loading efficacy, release profile, Si scaffold erosion kinetics and in vitro cytotoxicity on human breast carcinoma (MDA-MB-231) cells was studied and compared to the behavior of neat PSi carriers. We show that the chemically modified PSi carriers exhibit sustained release for several days to weeks with minimal to no burst effect, while for the native PSi MTX release was completed within 5h with a substantial burst release of ~40%. Moreover, our in vitro cytotoxicity experiments have clearly demonstrated that the MTX released from all PSi carriers maintained its cytotoxic effect towards MDA-MB-231 cells, in comparison to the low toxicity of the PSi carriers.