Targeted melanoma radiotherapy using ultrasmall (177)Lu-labeled α-melanocyte stimulating hormone-functionalized core-shell silica nanoparticles Journal Article
| Authors: | Zhang, X.; Chen, F.; Turker, M. Z.; Ma, K.; Zanzonico, P.; Gallazzi, F.; Shah, M. A.; Prater, A. R.; Wiesner, U.; Bradbury, M. S.; McDevitt, M. R.; Quinn, T. P. |
| Article Title: | Targeted melanoma radiotherapy using ultrasmall (177)Lu-labeled α-melanocyte stimulating hormone-functionalized core-shell silica nanoparticles |
| Abstract: | Lutetium-177 (177Lu) radiolabeled ultrasmall (~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 (αMSH) cyclic peptide analogs for targeting the melanocortin-1 receptor (MC1-R) over-expressed on melanoma tumor cells. The 177Lu-DOTA-αMSH-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 177Lu-DOTA-αMSH-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 radiotherapeutic, 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. © 2020 Elsevier Ltd |
| Keywords: | cancer survival; controlled study; human tissue; human cell; histopathology; drug efficacy; nonhuman; cancer radiotherapy; binding affinity; animal cell; mouse; melanoma; tumor volume; embryo; radiotherapy; animal experiment; animal model; protein binding; cohort analysis; oncology; drug distribution; tumors; dosimetry; radioactivity; peptides; drug clearance; nanoparticles; silica; binding energy; ex vivo study; dermatology; thin layer chromatography; internalization; dose limiting toxicity; single photon emission computed tomography; biological properties; alpha intermedin; lutetium 177; radionuclide therapy; tetraxetan; pharmacokinetic properties; surface chemistry; targeted radiotherapy; human; priority journal; article; gel permeation chromatography; silica nanoparticle; silica nanoparticles; core-shell silica nanoparticles; ultrasmall silica nanoparticle; shells (structures); ultra-small; α-melanocyte stimulating hormone |
| Journal Title: | Biomaterials |
| Volume: | 241 |
| ISSN: | 0142-9612 |
| Publisher: | Elsevier |
| Date Published: | 2020-05-01 |
| Start Page: | 119858 |
| Language: | English |
| DOI: | 10.1016/j.biomaterials.2020.119858 |
| PUBMED: | 32120314 |
| PROVIDER: | scopus |
| PMCID: | PMC7171978 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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