Targeted Nanoparticle for Co-delivery of HER2 siRNA and a Taxane to Mirror the Standard Treatment of HER2+ Breast Cancer: Efficacy in Breast Tumor and Brain Metastasis

Worapol Ngamcherdtrakul, Daniel S. Bejan, William Cruz-Muñoz, Moataz Reda, Husam Y. Zaidan, Natnaree Siriwon, Suphalak Marshall, Ruijie Wang, Molly A. Nelson, Justin P.C. Rehwaldt, Joe W. Gray, Kullervo Hynynen, Wassana Yantasee

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

The first-line treatment of advanced and metastatic human epidermal growth factor receptor type 2 (HER2+) breast cancer requires two HER2-targeting antibodies (trastuzumab and pertuzumab) and a taxane (docetaxel or paclitaxel). The three-drug regimen costs over $320,000 per treatment course, requires a 4 h infusion time, and has many adverse side effects, while achieving only 18 months of progression-free survival. To replace this regimen, reduce infusion time, and enhance efficacy, a single therapeutic is developed based on trastuzumab-conjugated nanoparticles for co-delivering docetaxel and siRNA against HER2 (siHER2). The optimal nanoconstruct has a hydrodynamic size of 100 nm and specifically treats HER2+ breast cancer cells over organ-derived normal cells. In a drug-resistant orthotopic HER2+ HCC1954 tumor mouse model, the nanoconstruct inhibits tumor growth more effectively than the docetaxel and trastuzumab combination. When coupled with microbubble-assisted focused ultrasound that transiently disrupts the blood brain barrier, the nanoconstruct inhibits the growth of trastuzumab-resistant HER2+ BT474 tumors residing in the brains of mice. The nanoconstruct has a favorable safety profile in cells and in mice. Combination therapies have become the cornerstone of cancer treatment and this versatile nanoparticle platform can co-deliver multiple therapeutic types to ensure that they reach the target cells at the same time to realize their synergy.

Original languageEnglish (US)
Article number2107550
JournalSmall
Volume18
Issue number11
DOIs
StatePublished - Mar 17 2022

Keywords

  • HER2+
  • breast cancer
  • nanoparticles
  • siRNAs
  • taxane

ASJC Scopus subject areas

  • Biotechnology
  • Chemistry(all)
  • Biomaterials
  • Materials Science(all)

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