Hyaluronic Acid-Targeted Stimuli-Sensitive Nanomicelles Co-Encapsulating Paclitaxel and Ritonavir to Overcome Multi-Drug Resistance in Metastatic Breast Cancer and Triple-Negative Breast Cancer Cells

Int J Mol Sci. 2021 Jan 27;22(3):1257. doi: 10.3390/ijms22031257.


Active targeting and overcoming multi-drug resistance (MDR) can be some of the important attributes of targeted therapy for metastatic breast cancer (MBC) and triple-negative breast cancer (TNBC) treatment. In this study, we constructed a hyaluronic acid (HA)-decorated mixed nanomicelles-encapsulating chemotherapeutic agent paclitaxel (PTX) and P-glycoprotein inhibitor ritonavir (RTV). HA was conjugated to poly (lactide) co-(glycolide) (PLGA) polymer by disulfide bonds (HA-ss-PLGA). HA is a natural ligand for CD44 receptors overexpressed in breast cancer cells. Disulfide bonds undergo rapid reduction in the presence of glutathione, present in breast cancer cells. The addition of RTV can inhibit the P-gp and CYP3A4-mediated metabolism of PTX, thus aiding in reversing MDR and sensitizing the cells toward PTX. An in vitro uptake and cytotoxicity study in MBC MCF-7 and TNBC MDA-MB-231 cell lines demonstrated the effective uptake of the nanomicelles and drug PTX compared to non-neoplastic breast epithelium MCF-12A cells. Interestingly, in vitro potency determination showed a reduction in mitochondrial membrane potential and reactive oxygen species in breast cancer cell lines, indicating effective apoptosis of cancer cells. Thus, stimuli-sensitive nanomicelles along with HA targeting and RTV addition can effectively serve as a chemotherapeutic drug delivery agent for MBC and TNBC.

Keywords: CD44 receptors; MCF-12A; MCF-7; MDA-MB-231; VEGF; active targeting; cellular uptake and intracellular distribution; design of experiment; disulfide bond; glutathione; mitochondrial membrane potential; stability studies.

MeSH terms

  • Apoptosis / drug effects
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Drug Delivery Systems*
  • Drug Resistance, Multiple / drug effects
  • Drug Resistance, Multiple / genetics
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Humans
  • Hyaluronic Acid / chemistry*
  • Hyaluronic Acid / pharmacology
  • MCF-7 Cells
  • Micelles
  • Nanoparticles / chemistry
  • Neoplasm Metastasis
  • Paclitaxel / chemistry
  • Paclitaxel / pharmacology*
  • Ritonavir / chemistry
  • Ritonavir / pharmacology*
  • Triple Negative Breast Neoplasms / drug therapy*
  • Triple Negative Breast Neoplasms / pathology


  • Micelles
  • Hyaluronic Acid
  • Ritonavir
  • Paclitaxel