A first-in-human clinical trial of ultrasmall inorganic hybrid nanoparticles, “C dots” (Cornell dots), in patients with metastatic melanoma is described for the imaging of cancer. These renally excreted silica particles were labeled with ¹²⁴I for positron emission tomography (PET) imaging and modified with cRGDY peptides for molecular targeting. ¹²⁴I-cRGDY–PEG–C dot particles are inherently fluorescent, containing the dye, Cy5, so they may be used as hybrid PET-optical imaging agents for lesion detection, cancer staging, and treatment management in humans. However, the clinical translation of nanoparticle probes, including quantum dots, has not kept pace with the accelerated growth in minimally invasive surgical tools that rely on optical imaging agents. The safety, pharmacokinetics, clearance properties, and radiation dosimetry of ¹²⁴I-cRGDY–PEG–C dots were assessed by serial PET and computerized tomography after intravenous administration in patients. Metabolic profiles and laboratory tests of blood and urine specimens, obtained before and after particle injection, were monitored over a 2-week interval. Findings are consistent with a well-tolerated inorganic particle tracer exhibiting in vivo stability and distinct, reproducible pharmacokinetic signatures defined by renal excretion. No toxic or adverse events attributable to the particles were observed. Coupled with preferential uptake and localization of the probe at sites of disease, these first-in-human results suggest safe use of these particles in human cancer diagnostics.

Nanoparticle-based materials, such as drug delivery vehicles and diagnostic probes, currently under evaluation in oncology clinical trials are largely not tumor selective. To be clinically successful, the next generation of nanoparticle agents should be tumor selective, nontoxic, and exhibit favorable targeting and clearance profiles. Developing probes meeting these criteria is challenging, requiring comprehensive in vivo evaluations. Here, we describe our full characterization of an approximately 7-nm diameter multimodal silica nanoparticle, exhibiting what we believe to be a unique combination of structural, optical, and biological properties. This ultrasmall cancer-selective silica particle was recently approved for a first-in-human clinical trial. Optimized for efficient renal clearance, it concurrently achieved specific tumor targeting. Dye-encapsulating particles, surface functionalized with cyclic arginine–glycine–aspartic acid peptide ligands and radioiodine, exhibited high-affinity/avidity binding, favorable tumor-to-blood residence time ratios, and enhanced tumor-selective accumulation in α_vβ₃ integrin–expressing melanoma xenografts in mice. Further, the sensitive, real-time detection and imaging of lymphatic drainage patterns, particle clearance rates, nodal metastases, and differential tumor burden in a large-animal model of melanoma highlighted the distinct potential advantage of this multimodal platform for staging metastatic disease in the clinical setting.

The design of cancer-targeting particles with precisely tuned physicochemical properties may enhance the delivery of therapeutics and access to pharmacological targets. However, a molecular-level understanding of the interactions driving the fate of nanomedicine in biological systems remains elusive. Here, we show that ultrasmall (<10 nm in diameter) poly(ethylene glycol)-coated silica nanoparticles, functionalized with melanoma-targeting peptides, can induce a form of programmed cell death known as ferroptosis in starved cancer cells and cancer-bearing mice. Tumour xenografts in mice intravenously injected with nanoparticles using a high-dose multiple injection scheme exhibit reduced growth or regression, in a manner that is reversed by the pharmacological inhibitor of ferroptosis, liproxstatin-1. These data demonstrate that ferroptosis can be targeted by ultrasmall silica nanoparticles and may have therapeutic potential.