A dual-targeted hyaluronic acid-gold nanorod platform with triple-stimuli responsiveness for photodynamic/photothermal therapy of breast cancer

Acta Biomater. 2019 Jan 1;83:400-413. doi: 10.1016/j.actbio.2018.11.026. Epub 2018 Nov 19.

Abstract

Multi-stimuli-responsive theranostic nanoplatform integrating functions of both imaging and multimodal therapeutics holds great promise for improving diagnosis and therapeutic efficacy. In this study, we reported a pH, glutathione (GSH) and hyaluronidase (HAase) triple-responsive nanoplatform for HER2 and CD44 dual-targeted and fluorescence imaging-guided PDT/PTT dual-therapy against HER2-overexpressed breast cancer. The nanoplatform was fabricated by functionalizing gold nanorods (GNRs) with hyaluronic acid (HA) bearing pendant hydrazide and thiol groups via Au-S bonds, and subsequently chemically conjugating 5-aminolevulinic acid (ALA), Cy7.5 and anti-HER2 antibody onto HA moiety for PDT, fluorescence imaging and active targeting, respectively. The resulting versatile nanoplatform GNR-HA-ALA/Cy7.5-HER2 had uniform sizes, favorable dispersibility, as well as pH, GSH and HAase triple-responsive drug release manner. In vitro studies demonstrated that HER2 and CD44 receptor-mediated dual-targeting strategy could significantly enhance the cellular uptake of GNR-HA-ALA/Cy7.5-HER2. Under near-infrared (NIR) irradiation, MCF-7 cells could efficiently generate reactive oxygen species (ROS) and heat, and be more efficiently killed by a combination of PDT and PTT as compared with individual therapy. Pharmacokinetic and biodistribution studies showed that the nanoplatform possessed a circulation half-life of 1.9 h and could be specifically delivered to tumor tissues with an accumulation ratio of 12.8%. Upon the fluorescence imaging-guided PDT/PTT treatments, the tumors were completely eliminated without obvious side effects. The results suggest that the GNR-HA-ALA/Cy7.5-HER2 holds great potential for breast cancer therapy. STATEMENT OF SIGNIFICANCE: A combination of photodynamic therapy (PDT) and photothermal therapy (PTT) is emerging as a promising cancer treatment strategy. However, its therapeutic efficacy is compromised by the nonspecific delivery and unintended release of photo-responsive agents. Herein, we developed a multifunctional theranostic nanoplatform GNR-HA-ALA/Cy7.5-HER2 with pH, glutathione and hyaluronidase triple-responsive drug release for HER2 and CD44 dual-targeted and fluorescence imaging-guided PDT/PTT therapy against breast cancer. We demonstrated that HER2 and CD44 receptors-mediated dual-targeting strategy significantly enhanced the cellular uptake of GNR-HA-ALA/Cy7.5-HER2. We also demonstrated that the combined PDT/PTT treatment had significantly superior antitumor effect than PDT or PTT alone both in vitro and in vivo. Therefore, GNR-HA-ALA/Cy7.5-HER2 could serve as a promising nanoplatform for HER2-positive breast cancer therapy.

Keywords: Gold nanorod; Hyaluronic acid; Photodynamic and photothermal dual-therapy; Targeted delivery; Triple-responsive drug release.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminolevulinic Acid / chemistry
  • Aminolevulinic Acid / pharmacokinetics
  • Aminolevulinic Acid / pharmacology
  • Animals
  • Antineoplastic Agents, Immunological / chemistry
  • Antineoplastic Agents, Immunological / pharmacokinetics
  • Antineoplastic Agents, Immunological / pharmacology
  • Breast Neoplasms* / metabolism
  • Breast Neoplasms* / pathology
  • Breast Neoplasms* / therapy
  • Female
  • Gold* / chemistry
  • Gold* / pharmacokinetics
  • Gold* / pharmacology
  • Humans
  • Hyaluronic Acid* / chemistry
  • Hyaluronic Acid* / pharmacokinetics
  • Hyaluronic Acid* / pharmacology
  • Hyperthermia, Induced*
  • MCF-7 Cells
  • Metal Nanoparticles* / chemistry
  • Metal Nanoparticles* / therapeutic use
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Nanotubes / chemistry*
  • Photochemotherapy*
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents, Immunological
  • Gold
  • Aminolevulinic Acid
  • Hyaluronic Acid