Heparan sulfate targeting strategy for enhancing liposomal drug accumulation and facilitating deep distribution in tumors

Drug Deliv. 2020 Dec;27(1):542-555. doi: 10.1080/10717544.2020.1745326.

Abstract

Nanoparticles (NPs), such as liposomes, effectively evade the severe toxicity of unexpected accumulation and passively shuttle drugs into tumor tissues by enhanced permeability and retention. In the case of non-small cell lung cancer and pancreatic ductal adenocarcinoma, cancer-associated fibroblasts promote the aggregation of a gel-like extracellular matrix that forms a physical barrier in the desmoplastic stroma of the tumor. These stroma are composed of protein networks and glycosaminoglycans (GAGs) that greatly compromise tumor-penetrating performance, leading to insufficient extravasation and tissue penetration of NPs. Moreover, the presence of heparan sulfate (HS) and related proteoglycans on the cell surface and tumor extracellular matrix may serve as molecular targets for NP-mediated drug delivery. Here, a GAG-binding peptide (GBP) with high affinity for HS and high cell-penetrating activity was used to develop an HS-targeting delivery system. Specifically, liposomal doxorubicin (L-DOX) was modified by post-insertion with the GBP. We show that the in vitro uptake of L-DOX in A549 lung adenocarcinoma cells increased by GBP modification. Cellular uptake of GBP-modified L-DOX (L-DOX-GBP) was diminished in the presence of extracellular HS but not in the presence of other GAGs, indicating that the interaction with HS is critical for the cell surface binding of L-DOX-GBP. The cytotoxicity of doxorubicin positively correlated with the molecular composition of GBP. Moreover, GBP modification improved the in vivo distribution and anticancer efficiency of L-DOX, with enhanced desmoplastic targeting and extensive distribution. Taken together, GBP modification may greatly improve the tissue distribution and delivery efficiency of NPs against HS-abundant desmoplastic stroma-associated neoplasm.

Keywords: Desmoplastic stroma; drug delivery; extracellular matrix; heparan sulfate; tumor penetration.

MeSH terms

  • A549 Cells
  • Adenocarcinoma of Lung / drug therapy*
  • Adenocarcinoma of Lung / metabolism
  • Animals
  • Antibiotics, Antineoplastic / administration & dosage*
  • Antibiotics, Antineoplastic / chemistry
  • Antibiotics, Antineoplastic / pharmacokinetics*
  • Cell Line, Tumor
  • Doxorubicin / administration & dosage
  • Doxorubicin / analogs & derivatives*
  • Doxorubicin / chemistry
  • Doxorubicin / pharmacokinetics
  • Drug Delivery Systems
  • Female
  • Glycosaminoglycans / metabolism
  • Heparitin Sulfate / metabolism*
  • Humans
  • Liposomes / administration & dosage
  • Liposomes / chemical synthesis
  • Liposomes / chemistry
  • Liposomes / pharmacokinetics
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism
  • Mice
  • NIH 3T3 Cells
  • Nanoparticles / administration & dosage
  • Nanoparticles / chemistry
  • Nanoparticles / metabolism
  • Polyethylene Glycols / administration & dosage
  • Polyethylene Glycols / chemistry
  • Polyethylene Glycols / pharmacokinetics
  • Tissue Distribution / drug effects
  • Tumor Microenvironment
  • Xenograft Model Antitumor Assays

Substances

  • Antibiotics, Antineoplastic
  • Glycosaminoglycans
  • Liposomes
  • liposomal doxorubicin
  • Polyethylene Glycols
  • Doxorubicin
  • Heparitin Sulfate

Grants and funding

This work was supported by Ministry of Science and Technology (MOST), Taiwan [grant numbers 103-2622-B-007-001-CC1, 106-2321-B-007-005 and 107-2311-B-007-009] as well as Industrial Value Creation Program for Academia [107B7016V1], Program for Translational Innovation of Biopharmaceutical Development-Technology Supporting Platform Axis [107-0210-01-19-04], and MacKay Memorial Hospital-National Tsing Hua University Joint Research Grant [106J00X9J8]. This work was also financially supported by the Brain Research Center from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) and MOST in Taiwan. Ping-Hsueh Kuo was supported by Shen’s Culture & Education Foundation (Apex Biotechnology Corporation, Taiwan) and by Innopharmax Inc., Taiwan. The founders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.