Multimodal silica nanoparticles are effective cancer-targeted probes in a model of human melanoma

Abstract

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 v β 3 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.and comprehensively defined according to the following set of diagnostic criteria: favorable distribution and targeting kinetics (1, 5-9), efficient renal clearance (10, 11), extended circulation (blood residence) times (5, 12, 13), pronounced tissue signal amplification (5, 6, 14), and improved tumoral penetration (15).Recently reported design criteria have been proposed for advancing targeted probes to the clinic (11).These have largely been restricted to improving renal clearance properties of inorganic particles containing inherently toxic components.The relative lack of in vivo toxicology data associated with these probes has led to persistent and valid safety concerns ( 16), prompting a number of particle-design modifications (9, 17-19), including size, composition, and surface chemistry, that promote more rapid clearance through kidney (renal) or liver (hepatic) pathways (20).While such approaches may minimize toxicity, the ultimate fate and impact of residual particles in the reticuloendothelial system (RES; liver, spleen, lymph nodes, bone marrow) remains unclear, particularly if toxicity is related to prolonged organ residence times (16, 17).Accelerated particle clearance may also preclude certain clinical applications as a result of restrictions imposed upon the available imaging period.Further, while rapid particle extravasation may facilitate clearance and delivery to tumors, reduced receptor binding (5) and increased nonspecific tissue dispersal (21, 22) may also occur, increasing image background and, potentially, toxicity by prolonging retention.Only a relatively small percentage of new imaging agents undergoing comprehensive preclinical testing potentially satisfy diagnostic criteria for translation (2).Although a number of fluo-Authorship note: Miriam Benezra and Oula Penate-Medina contributed equally to this work.