Peptide-functionalized and high drug loaded novel nanoparticles as dual-targeting drug delivery system for modulated and controlled release of paclitaxel to brain glioma

Int J Pharm. 2018 Dec 20;553(1-2):169-185. doi: 10.1016/j.ijpharm.2018.10.022. Epub 2018 Oct 12.


A dual-targeting drug delivery system for paclitaxel (PTX) was developed by functionalizing novel polyester-based nanoparticles (NPs) with peptides possessing special affinity for low-density lipoprotein receptor (LDLR), overcoming the limitations of the current chemotherapeutics, to transport drug from blood to brain, and then target glioma cells. Employing novel biodegradable block co-polymers (P and 2P), PTX loaded and peptide-functionalized nanoparticles were prepared by a modified nano-co-precipitation method, carried out in one step only without emulsifier, allowing to obtain spherical nanometric (<200 nm), monodisperse (PDI ∼ 0.1), Poly (Ethylene Glycol) (PEG)-coated and high PTX loaded NPs with a slow and controlled release rate for a prolonged period of time. Peptide functionalization, confirmed by fluorimetric assay and HPLC amino acids analysis, enhanced the cellular uptake of functionalized-PTX-NPs by human primary glioblastoma cell line (U-87 MG) and Bovine Brain Endothelial Cells (BBMVECs), compared with non-functionalized-PTX-NPs. To confirm dual-targeting effect, transendothelial transport experiments in an in vitro BBB model and in vitro anti-tumoral activity against U-87 MG revealed that peptide-functionalized-PTX-NPs significantly increased the transport ratio of PTX across the BBB along with an improved anti-proliferative efficiency. Pharmacokinetics and biodistribution studies in rats, carried out by in vivo experiments with 125I radiolabelled dual-targeting PTX-NPs, confirmed the stealthy behavior of NPs and indicated slightly lower levels of penetration into brain tissue in comparison with peptides known to be able to cross the BBB. These promising results suggested that the dual-targeting drug delivery system might have great potential for glioma therapy in clinical applications.

Keywords: Blood-brain barrier; Brain glioma; Controlled release; Dual targeting; Nanoparticles; Paclitaxel.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / administration & dosage
  • Antineoplastic Agents, Phytogenic / pharmacokinetics
  • Antineoplastic Agents, Phytogenic / pharmacology
  • Blood-Brain Barrier
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / pathology
  • Cattle
  • Cell Line, Tumor
  • Cells, Cultured
  • Delayed-Action Preparations
  • Drug Delivery Systems*
  • Endothelial Cells / metabolism
  • Glioblastoma / drug therapy*
  • Glioblastoma / pathology
  • Glioma / drug therapy
  • Glioma / pathology
  • Humans
  • Nanoparticles
  • Paclitaxel / administration & dosage*
  • Paclitaxel / pharmacokinetics
  • Paclitaxel / pharmacology
  • Peptides / chemistry
  • Polymers / chemistry
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, LDL / metabolism
  • Tissue Distribution


  • Antineoplastic Agents, Phytogenic
  • Delayed-Action Preparations
  • Peptides
  • Polymers
  • Receptors, LDL
  • Paclitaxel