Tumor-Targeted Drug and CpG Delivery System for Phototherapy and Docetaxel-Enhanced Immunotherapy With Polarization Toward M1-Type Macrophages on Triple Negative Breast Cancers

Adv Mater. 2019 Dec;31(52):e1904997. doi: 10.1002/adma.201904997. Epub 2019 Nov 13.

Abstract

Cancer immunotherapy has achieved promising clinical responses in recent years owing to the potential of controlling metastatic disease. However, there is a limited research to prove the superior therapeutic efficacy of immunotherapy on breast cancer compared with melanoma and non-small-cell lung cancer because of its limited expression of PD-L1, low infiltration of cytotoxic T lymphocytes (CTLs), and high level of myeloid-derived suppressor cells (MDSCs). Herein, a multifunctional nanoplatform (FA-CuS/DTX@PEI-PpIX-CpG nanocomposites, denoted as FA-CD@PP-CpG) for synergistic phototherapy (photodynamic therapy (PDT), photothermal therapy (PTT) included) and docetaxel (DTX)-enhanced immunotherapy is successfully developed. The nanocomposites exhibit excellent PDT efficacy and photothermal conversion capability under 650 and 808 nm irradiation, respectively. More significantly, FA-CD@PP-CpG with no obvious side effects can remarkably inhibit the tumor growth in vivo based on a 4T1-tumor-bearing mice modal. A low dosage of loaded DTX in FA-CD@PP-CpG can promote infiltration of CTLs to improve efficacy of anti-PD-L1 antibody (aPD-L1), suppress MDSCs, and effectively polarize MDSCs toward M1 phenotype to reduce tumor burden, further to enhance the antitumor efficacy. Taken together, FA-CD@PP-CpG nanocomposites offer an efficient synergistic therapeutic modality in docetaxel-enhanced immunotherapy for clinical application of breast cancer.

Keywords: CpG; PD-L1/anti PD-L1; docetaxel; immunotherapy; phototherapy.

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Humanized / chemistry
  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Copper / chemistry
  • Docetaxel / chemistry*
  • Docetaxel / pharmacology
  • Docetaxel / therapeutic use
  • Drug Carriers / chemistry
  • Folic Acid / chemistry
  • Humans
  • Immunotherapy
  • Lasers
  • Mice
  • Nanocomposites / chemistry
  • Oligonucleotides / chemistry*
  • Phototherapy
  • Polyethyleneimine / chemistry
  • Protoporphyrins / chemistry
  • Reactive Oxygen Species / metabolism
  • T-Lymphocytes, Cytotoxic / cytology
  • T-Lymphocytes, Cytotoxic / immunology*
  • T-Lymphocytes, Cytotoxic / metabolism
  • Triple Negative Breast Neoplasms / metabolism
  • Triple Negative Breast Neoplasms / pathology
  • Triple Negative Breast Neoplasms / therapy

Substances

  • Antibodies, Monoclonal, Humanized
  • Drug Carriers
  • Oligonucleotides
  • Protoporphyrins
  • Reactive Oxygen Species
  • Docetaxel
  • atezolizumab
  • Copper
  • Polyethyleneimine
  • Folic Acid
  • protoporphyrin IX
  • cupric sulfide