A targeted combinatorial therapy for Ewing's sarcoma

Nanomedicine. 2021 Oct:37:102446. doi: 10.1016/j.nano.2021.102446. Epub 2021 Jul 23.

Abstract

Ewing's sarcoma (EwS) is the second most common bone cancer in children and adolescents. Current chemotherapy regimens are mainly ineffective in patients with relapsed disease and cause long-term effects in survivors. Therefore, we have developed a combinatorial therapy based on a novel drug candidate named ML111 that exhibits selective activity against EwS cells and synergizes with vincristine. To increase the aqueous solubility of hydrophobic ML111, polymeric nanoparticles (ML111-NP) were developed. In vitro data revealed that ML111-NP compromise viability of EwS cells without affecting non-malignant cells. Furthermore, ML111-NP exhibit strong synergistic effects in a combination with vincristine on EwS cells, while this drug pair exhibits antagonistic effects towards normal cells. Finally, animal studies validated that ML111-NP efficiently accumulate in orthotopic EwS xenografts after intravenous injection and provide superior therapeutic outcomes in a combination with vincristine without evident toxicity. These results support the potential of the ML111-based combinatorial therapy for EwS.

Keywords: Chemotherapy; Combinatorial therapy; Ewing's sarcoma; ML111; Nanoparticle.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Cell Line, Tumor
  • Drug Synergism*
  • Humans
  • Mice
  • Nanoparticles / chemistry
  • Sarcoma, Ewing* / drug therapy
  • Sarcoma, Ewing* / genetics
  • Sarcoma, Ewing* / pathology
  • Vincristine* / pharmacology
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Vincristine
  • ML111