Abstract
An α particle-emitting nanodrug that is a potent and specific antitumor agent and also prompts significant remodeling of local immunity in the tumor microenvironment (TME) has been developed and may impact the treatment of melanoma. Biocompatible ultrasmall fluorescent core–shell silica nanoparticles (C′ dots, diameter ∼6.0 nm) have been engineered to target the melanocortin-1 receptor expressed on melanoma through α melanocyte-stimulating hormone peptides attached to the C′ dot surface. Actinium-225 is also bound to the nanoparticle to deliver a densely ionizing dose of high-energy α particles to cancer. Nanodrug pharmacokinetic properties are optimal for targeted radionuclide therapy as they exhibit rapid blood clearance, tumor-specific accumulation, minimal off-target localization, and renal elimination. Potent and specific tumor control, arising from the α particles, was observed in a syngeneic animal model of melanoma. Surprisingly, the C′ dot component of this drug initiates a favorable pseudopathogenic response in the TME generating distinct changes in the fractions of naive and activated CD8 T cells, Th1 and regulatory T cells, immature dendritic cells, monocytes, MΦ and M1 macrophages, and activated natural killer cells. Concomitant upregulation of the inflammatory cytokine genome and adaptive immune pathways each describes a macrophage-initiated pseudoresponse to a viral-shaped pathogen. This study suggests that therapeutic α-particle irradiation of melanoma using ultrasmall functionalized core–shell silica nanoparticles potently kills tumor cells, and at the same time initiates a distinct immune response in the TME.
Highlights
Biocompatible ultrasmall fluorescent core–shell silica nanoparticles (C¢ dots, diameter *6.0 nm) have been engineered to target the melanocortin-1 receptor expressed on melanoma through a melanocyte-stimulating hormone peptides attached to the C¢ dot surface
This study describes downstream effects on tumor microenvironment (TME) immune cell populations, cytokine expression, and inflammatory pathways arising from an a particle-emitting ultrasmall fluorescent core–shell silica nanoparticle and explores the unique combination of a particles and targeted C¢ dot-based adjuvant immunotherapeutic approaches to eliminate melanoma
The inflammatory milieu is hypothesized to result from a pseudopathogenic response of macrophages to the C¢ dot
Summary
First-generation ultrasmall fluorescent core–shell silica nanoparticles (Cornell dots [C dots]) and their next-generation analogs (Cornell prime dots [C¢ dots]) have hydrodynamic diameters below 10 nm and silica core-encapsulated nearinfrared-emitting dyes.[1,2,3,4,5,6,7,8,9,10,11] These innovative nanoscale materials have been engineered to target cancer and deliver therapeutic payloads in vivo as well as image tissue distribution and clearance.[1,2,3,4,5,6,7,8,9,10,11] C¢ dots that do not target disease are readily eliminated through renal filtration due to their ultrasmall particle dimensions.[9,10] These novel particulate materials have a performance advantage that has been demonstrated in animal models and accelerated their translation into humans. Particle design has been advanced beyond the firstgeneration nanomaterials by appending of a melanocytestimulating hormone (aMSH) analog peptide sequences designed to target the melanocortin-1 receptor (MC1R) expressed on melanoma.[8,12] Additional synthetic modifications include covalent attachment of chelating agents preloaded with the a particle-emitting actinium-225 (225Ac) radionuclide to deliver a cytotoxic dose of radiation to the tumor.[13,14] MC1R targeting of metastatic melanoma in humans using a small-molecule aMSH peptide has been reported and demonstrates the clinical relevance of MC1R.15
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