A novel targeted co-delivery nanosystem for enhanced ovarian cancer treatment via multidrug resistance reversion and mTOR-mediated signaling pathway

J Nanobiotechnology. 2021 Dec 23;19(1):444. doi: 10.1186/s12951-021-01139-1.

Abstract

Background: Multidrug resistance (MDR) is the main challenge of successful chemotherapy for ovarian cancer patients, with 50% to 75% of ovarian cancer patients eventually relapsed due to it. One of the effective strategies for treating MDR and improving therapeutic efficiency of ovarian cancer is to use nanotechnology-based targeted drug delivery systems. In this study, a novel nano targeted co-delivery system modified by hyaluronic acid (HA) was developed by using gold nanorods coated with functionalized mesoporous silica nanoparticles (HA-PTX/let-7a-GNR@MSN) for combined delivery of hydrophobic chemotherapy drug Paclitaxel (PTX) and lethal-7a (let-7a), a microRNA (miR), to overcome MDR in ovarian cancer. Furthermore, we also analyzed the molecular mechanism of this nanotherapeutic system in the treatment of ovarian cancer.

Results: HA-modified nanocomplexes can specifically bind to the CD44 receptor, which is highly expressed in SKOV3/SKOV3TR cells, achieving effective cell uptake and 150% enhancement of tumor site permeability. The nanosystem realized the stable combination and protective transportation of PTX and miRs. Analysis of drug-resistant SKOV3TR cells and an SKOV3TR xenograft model in BALB/c-nude mice showed significant downregulation of P-glycoprotein in heterogeneous tumor sites, PTX release, and subsequent induction of apoptosis. More importantly, this nanosystem could synergistically inhibit the growth of ovarian tumors. Further studies suggest that mTOR-mediated signaling pathways play an important role in reversing drug resistance and inducing apoptosis.

Conclusions: To sum up, these data provide a model for overcoming PTX resistance in ovarian cancer.

Keywords: Co-delivery nanosystem; Multidrug resistance; Ovarian cancer; PTX, miR let-7a.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Animals
  • Antineoplastic Agents, Phytogenic / chemistry
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Antineoplastic Agents, Phytogenic / therapeutic use
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / drug effects*
  • Female
  • Gold / chemistry
  • Humans
  • Mice
  • Mice, Nude
  • MicroRNAs / chemistry
  • Nanoparticles / chemistry
  • Nanostructures / chemistry*
  • Nanotubes / chemistry
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / pathology
  • Paclitaxel / chemistry
  • Paclitaxel / pharmacology*
  • Paclitaxel / therapeutic use
  • Signal Transduction / drug effects*
  • Silicon Dioxide / chemistry
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antineoplastic Agents, Phytogenic
  • MicroRNAs
  • Gold
  • Silicon Dioxide
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Paclitaxel