Clinical translation of silica nanoparticles

The safety profile of silica nanoparticles in humans is evident from 11 clinical trials and 2 clinical studies (Fig. 1). Orally delivered silica nanoparticles have shown good tolerability with no serious adverse effects, while improving the pharmacokinetic profile of hydrophobic drugs^3,4. In one of the first human studies, a silica–lipid hybrid formulation was used to orally deliver ibuprofen to 16 healthy adults, demonstrating an increase in bioavailability by 1.95 times³. In a clinical trial that included 12 adults, lipoceramic hybrid silica nanoparticles were used to improve simvastatin pharmacokinetics, showing a 3.5-fold increase in bioavailability compared with the commercially available simvastatin formulation Sandoz (ACTRN12618001929291)⁵. In another clinical study, in which 12 healthy adults participated, oral delivery of mesoporous silica nanoparticles improved the bioavailability of fenofibrate by 54%, compared with the commercially available fenofibrate formulation Lipanthyl⁴.

The timeline shows different types of silica nanoparticle in clinical trials. cRGDY, cyclic arginyl-glycyl-aspartic acid-tyrosine; PEG, polyethylene glycol.

In addition to drug delivery, silica nanoparticles have been applied for plasmonic resonance therapy to treat cardiovascular diseases, to detect difficult-to-treat tumours and to thermally ablate tumours^6,7. Compared with organic nanoparticles (polymeric and lipidic), silica nanoparticles can be easily modified with iron oxide and gold, which can be exploited for localized plasmonic and thermal ablation therapy^6,7. Results from a completed phase I clinical trial showed that plasmonic resonance therapy using Fe₃O₄ ferromagnetic core-shell silica–gold nanoparticles (diameter 90–150 nm) significantly reduced coronary atherosclerosis (NCT01270139). Moreover, compared with conventional stent implantation, patients treated with hybrid silica nanoparticles had reduced risk of atherosclerosis and cardiovascular disease-related death, with an acceptable level of safety^6,7.

Further studies were conducted using silica nanoparticles with a gold shell (Aurolase and Auroshell) for the initiation of photothermal ablation of malignant cancer located in the head, neck (NCT00848042) and prostate (NCT04240639, NCT02680535 and NCT04656678)⁸. These gold shell–silica nanoparticles were designed to convert near-infrared light signals into heat for tumour ablation⁸. In these clinical trials, a 4.8 mg ml⁻¹ solution of gold shell–silica nanoparticles was intravenously injected at a dose of 7.5 ml kg⁻¹; the nanoparticles preferentially accumulated in the tumour via the enhanced permeation and retention effect⁸. Although the results from some clinical trials using these particles to treat prostate cancer are still pending (NCT04240639, NCT02680535 and NCT04656678), a pilot clinical study with 16 individuals with prostate cancer demonstrated successful photothermal ablation using gold shell–silica nanoparticles⁸. The main advantage of gold shell–silica nanoparticles is that they accumulate at the tumour site, allowing accurate and predictable ablation therapy for prostate cancer, with less side effects than conventional focal ablation⁸.

Cornell dots are ultrasmall silica nanoparticles with a diameter of 6–10 nm. Cornell dots can be applied as tracers for tumours, such as melanoma or malignant brain tumours (NCT03465618, NCT01266096 and NCT02106598). The size of Cornell dots is below the 10 nm renal clearance threshold, and they are thus cleared by the kidneys, addressing concerns of silica nanoparticle accumulation in the body. Cornell dots can be functionalized with tumour-homing arginyl-glycyl-aspartic acid-tyrosine (RGDY) peptide and fluorescent dye Cy5.5 to serve as an imaging agent^9,10. The first-in-human clinical trial of Cornell dots labelled with ¹²⁴I demonstrated their application as a hybrid system for positron emission tomography imaging and fluorescent-based detection for the diagnosis and staging of tumours, such as melanoma and malignant brain cancer (NCT01266096)¹⁰. The preliminary results of this trial demonstrate that Cornell dots are stable, preferentially taken up by the tumour, well tolerated, without any significant side effects, and renally cleared, with an 8.7-hour half-life in plasma¹⁰. The same Cornell dots were also tested for their ability to detect and localize sentinel lymph nodes in patients with head or neck melanoma to allow visualization during biopsy (NCT02106598)⁹. Clinically used radio-guided sentinel lymph node imaging suffers from low sensitivity, which makes visualization of lymph nodes difficult and therefore surgical biopsy risky⁹. Encapsulating Cy5.5 in silica nanoparticles has been shown to further increase their fluorescent intensity and photostability⁹. Based on these clinical trials, silica nanoparticle-based imaging holds great promise for detecting, staging and biopsy of tumours with high accuracy and low procedural risk.