Albumin-based nanostructures for uveal melanoma treatment

Nanomedicine. 2021 Jul:35:102391. doi: 10.1016/j.nano.2021.102391. Epub 2021 Mar 29.

Abstract

Uveal melanoma (UM) is an intraocular tumor which is almost lethal at the metastatic stage due to the lack of effective treatments. In this regard, we have developed an albumin-based nanostructure (ABN) containing AZD8055 (ABN-AZD), which is a potent mTOR kinase inhibitor, for its efficient delivery to the tumors. The drug has been conjugated to ABN using tailored linkers that have a disulfide moiety, allowing its release selectively and effectively in the presence of an elevated concentration of glutathione, such as inside the tumoral cells. Our therapeutic approach induced significant cellular toxicity in uveal melanoma cells, but not in non-tumoral keratinocytes, highlighting the excellent selectivity of the system. In addition, these nanostructures showed excellent activity in vivo, decreasing the tumor surface compared to the free AZD8055 in mice models. Remarkably, the results obtained were achieved employing a dose 23 times lower than those used in previous reports.

Keywords: AZD8055; Albumin-based nanostructures; Controlled-release; Nanomedicine; Uveal melanoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Feeder Cells
  • Humans
  • Melanoma / drug therapy*
  • Melanoma / enzymology
  • Mice
  • Mice, Nude
  • Morpholines* / chemistry
  • Morpholines* / pharmacology
  • Nanostructures* / chemistry
  • Nanostructures* / therapeutic use
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / metabolism
  • Serum Albumin, Human* / chemistry
  • Serum Albumin, Human* / pharmacology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism
  • Uveal Neoplasms / drug therapy*
  • Uveal Neoplasms / enzymology
  • Xenograft Model Antitumor Assays

Substances

  • Morpholines
  • Neoplasm Proteins
  • (5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Serum Albumin, Human

Supplementary concepts

  • Uveal melanoma