Journal
BIOMATERIALS
Volume 241, Issue -, Pages -Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2020.119858
Keywords
Ultrasmall silica nanoparticle; alpha-melanocyte stimulating hormone; Melanoma; Radionuclide therapy
Funding
- National Institutes of Health [1R01CA161280-01A1, 1U54 CA199081-01]
- Sloan Kettering Institute [P30 CA008748CCSG]
- University of Missouri Molecular Interactions, Cell and Immunology, and Molecular Cytology cores
- The Harry Truman VA Hospital Biomolecular Imaging Center and Pharmacokinetics Core
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Lutetium-177 ((177) Lu) radiolabeled ultrasmall (similar to 6 nm dia.) fluorescent core-shell silica nanoparticles (Cornell prime dots or C' dots) were developed for improving efficacy of targeted radiotherapy in melanoma models. PEGylated C' dots were surface engineered to display 10-15 alpha melanocyte stimulating hormone (alpha MSH) cyclic peptide analogs for targeting the melanocortin-1 receptor (MC1-R) over-expressed on melanoma tumor cells. The Lu-177-DOTA-aMSH-PEG-C' dot product was radiochemically stable, biologically active, and exhibited high affinity cellular binding properties and internalization. Selective tumor uptake and favorable biodistribution properties were also demonstrated, in addition to bulk renal clearance, in syngeneic B16F10 and human M21 xenografted models. Prolonged survival was observed in the treated cohorts relative to controls. Dosimetric analysis showed no excessively high absorbed dose among normal organs. Correlative histopathology of ex vivo treated tumor specimens revealed expected necrotic changes; no acute pathologic findings were noted in the liver or kidneys. Collectively, these results demonstrated that Lu-177-DOTA-aMSH-PEG-C' dot targeted melanoma therapy overcame the unfavorable biological properties and dose-limiting toxicities associated with existing mono-molecular treatments. The unique and tunable surface chemistries of this targeted ultrasmall radio-therapeutic, coupled with its favorable pharmacokinetic properties, substantially improved treatment efficacy and demonstrated a clear survival benefit in melanoma models, which supports its further clinical translation.
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