There are a wide variety of silica nanoformulations being investigated for biomedical applications. Silica nanoparticles can be produced using a wide variety of synthetic techniques with precise control over their physical and chemical characteristics. Inorganic nanoformulations are often criticized or neglected for their poor tolerance; however, extensive studies into silica nanoparticle biodistributions and toxicology have shown that silica nanoparticles may be well tolerated, and in some case are excreted or are biodegradable. Robust synthetic techniques have allowed silica nanoparticles to be developed for applications such as biomedical imaging contrast agents, ablative therapy sensitizers, and drug delivery vehicles. This review explores the synthetic techniques used to create and modify an assortment of silica nanoformulations, as well as several of the diagnostic and therapeutic applications.

Diagnosing tumors at an early stage when they are easily curable and may not require systemic chemotherapy remains a challenge to clinicians. In order to improve early cancer detection, gas filled hollow boron-doped silica particles have been developed, which can be used for ultrasound-guided breast conservation therapy. The particles are synthesized using a polystyrene template and subsequently calcinated to create hollow, rigid nanoporous microspheres. The microshells are filled with perfluoropentane vapor. Studies were performed in phantoms to optimize particle concentration, injection dose, and the ultrasound settings such as pulse frequency and mechanical index. In vitro studies have shown that these particles can be continuously imaged by US up to 48 min and their signal lifetime persisted for 5 days. These particles could potentially be given by intravenous injection and, in conjunction with contrast-enhanced ultrasound, be utilized as a screening tool to detect smaller breast cancers before they are detectible by traditional mammography.

Silica nanoparticles are being investigated for a number of medical applications; however, its use in vivo has been questioned because of the potential for bioaccumulation. To obviate this problem, silica nanoshells were tested for enhanced biodegradability by doping iron(III) into the nanoshells. Exposure of the doped silica to small molecule chelators and mammalian serum was explored to test whether the removal of iron(III) from the silica nanoshell structure would facilitate its degradation. Iron chelators such as EDTA, desferrioxamine, and deferiprone were found to cause the nanoshells to degrade on the removal of iron(III) within several days at 80 °C. When the iron(III)-doped, silica nanoshells were submerged in fetal bovine serum (FBS) and human serum (HS) at physiological temperature, they also degrade via removal of the iron by serum proteins, such as transferrin, over a period of several weeks.

Perfluoropentane gas filled iron-silica nanoshells have been developed as stationary ultrasound contrast agents for marking tumors to guide surgical resection. It is critical to establish their long term imaging efficacy, as well as biodistribution. This work shows that 500 nm Fe-SiO2 nanoshells can be imaged by color Doppler ultrasound over the course of 10 days in Py8119 tumor bearing mice. The 500 nm non-biodegradable SiO2 and biodegradable Fe-SiO2 nanoshells were functionalized with diethylenetriamine pentaacetic acid (DTPA) ligand and radiolabeled with 111In3+ for biodistribution studies in nu/nu mice. The majority of radioactivity was detected in the liver and kidneys following intravenous (IV) administration of nanoshells to healthy animals. By contrast, after nanoshells were injected intratumorally, most of the radioactivity remained at the injection site; however, some nanoshells escaped into circulation and were distributed similarly as those given intravenously. For intratumoral delivery of nanoshells and IV delivery to healthy animals, little difference was seen between the biodistribution of SiO2 and biodegradable Fe-SiO2 nanoshells. However, when nanoshells were administered IV to tumor bearing mice, a significant increase was observed in liver accumulation of SiO2 nanoshells relative to biodegradable Fe-SiO2 nanoshells. Both SiO2 and Fe-SiO2 nanoshells accumulate passively in proportion to tumor mass, during intravenous delivery of nanoshells. This is the first report of the biodistribution following intratumoral injection of any biodegradable silica particle, as well as the first report demonstrating the utility of DTPA-111In labeling for studying silica nanoparticle biodistributions.

Perfluoropentane (PFP) gas filled biodegradable iron-doped silica nanoshells have been demonstrated as long-lived ultrasound contrast agents. Nanoshells are synthesized by a sol-gel process with tetramethyl orthosilicate (TMOS) and iron ethoxide. Substituting a fraction of the TMOS with R-substituted trialkoxysilanes produces ultrathin nanoshells with varying shell thicknesses and morphologies composed of fused nanoflakes. The ultrathin nanoshells had continuous ultrasound Doppler imaging lifetimes exceeding 3 hours, were twice as bright using contrast specific imaging, and had decreased pressure thresholds compared to control nanoshells synthesized with just TMOS. Transmission electron microscopy (TEM) showed that the R-group substituted trialkoxysilanes could reduce the mechanically critical nanoshell layer to 1.4 nm. These ultrathin nanoshells have the mechanical behavior of weakly linked nanoflakes but the chemical stability of silica. The synthesis can be adapted for general fabrication of three-dimensional nanostructures composed of nanoflakes, which have thicknesses from 1.4–3.8 nm and diameters from 2–23 nm.