Tumor-Induced Myeloid Cells Are Reduced by Gemcitabine-Loaded PAMAM Dendrimers Decorated with Anti-Flt1 Antibody

Mol Pharm. 2018 Apr 2;15(4):1526-1533. doi: 10.1021/acs.molpharmaceut.7b01075. Epub 2018 Mar 6.

Abstract

While reshaping their microenvironment, tumors are also capable of influencing systemic processes including myeloid cell production. Therefore, the tumor-induced myeloid cells, such as myeloid-derived suppressor cells (MDSCs), which are characterized with pro-cancer properties, became another target in order to increase the success of the therapy. This study evaluated the capacity of a novel dendrimeric drug delivery platform to eliminate tumor-induced myeloid cells. As described in a previous study by our research group, the anti-Flt1 antibody-conjugated polyethylene glycol (PEG)-cored poly(amidoamine) (PAMAM) dendrimers improved the efficacy of gemcitabine against pancreatic cancer. Here, the biodistribution studies showed that these dendrimeric structures accumulated in the compartments that became rich in myeloid cells in the pancreatic tumor-bearing mice. When gemcitabine was loaded into the dendrimer complexes, the number of myeloid cells was significantly reduced while the percentage distribution of granulocytic and monocytic myeloid cells was not always significantly altered. The CD11b+Ly6G-Ly6C+ monocytes were more severely affected by the treatments than CD11b+Ly6G+Ly6C+ granulocytes. Immune infiltration levels in the tumor tissue were also altered. Myeloid cells in the spleen and F4/80+ macrophages of the liver were protected. The compartments, such as the liver and the bone marrow, which are known to have high vascular endothelial growth factor (VEGF)-Flt1 pathway activity, were particularly targeted by gemcitabine when delivered through anti-Flt1 antibody-conjugated PAMAM dendrimers. In conclusion, chemotherapeutic agents complexed with dendrimers not only improve anticancer efficacy, but they also assist in the elimination of the tumor-induced myeloid cells.

Keywords: PAMAM; cancer; dendrimer; drug delivery; myeloid cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Dendrimers / chemistry*
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / chemistry
  • Deoxycytidine / pharmacology
  • Drug Delivery Systems
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Myeloid Cells / drug effects*
  • Pancreatic Neoplasms / metabolism*
  • Polyethylene Glycols / chemistry
  • Tissue Distribution
  • Vascular Endothelial Growth Factor Receptor-1 / metabolism*

Substances

  • Dendrimers
  • PAMAM Starburst
  • Deoxycytidine
  • Polyethylene Glycols
  • gemcitabine
  • FLT1 protein, human
  • Vascular Endothelial Growth Factor Receptor-1