Enhancing Glioblastoma-Specific Penetration by Functionalization of Nanoparticles with an Iron-Mimic Peptide Targeting Transferrin/Transferrin Receptor Complex.

Abstract

Treatment of glioblastoma (GBM) remains to be the most formidable challenge because of the hindrance of the blood-brain barrier (BBB) along with the poor drug penetration into the glioma parenchyma. Nanoparticulate drug delivery systems (DDS) utilizing transferrin (Tf) as the targeting ligand to target the glioma-associated transferrin receptor (TfR) had met the problem of loss of specificity in biological environment due to the high level of endogenous Tf. Here we conjugated CRT peptide, an iron-mimicry moiety targeting the whole complex of Tf/TfR, to poly(ethylene glycol)-poly(l-lactic-co-glycolic acid) nanoparticles (CRT-NP), to open a new route to overcome such obstacle. High cellular associations, advanced transport ability through the BBB model, and penetration in 3-dimensional C6 glioma spheroids in vitro had preliminarily proved the advantages of CRT-NP over Tf-nanoparticle conjugates (Tf-NP). Compared with Tf-NP, NP, and Taxol, paclitaxel-loaded CRT-NP (CRT-NP-PTX) displayed a superior antiproliferation effect on C6 glioma cells and stronger inhibitory effect on glioma spheroids. Favored pharmacokinetics behavior and enhanced accumulation in glioma foci was observed, together with a much deeper distribution pattern in glioma parenchyma compared with unmodified nanoparticles and Tf-NP. Eventually, mice treated with CRT-NP-PTX showed a remarkably prolonged median survival compared to those treated with Taxol, NP, or Tf-NP. In conclusion, the modification of CRT to nanoparticles holds great promise for enhancement of antiglioma therapy.

• Authors: Ting Kang, Mengyin Jiang, Di Jiang, Xingye Feng, Jianhui Yao, Qingxiang Song, Hongzhuan Chen, Xiaoling Gao, Jun Chen
• Journal: Molecular pharmaceutics (Mol Pharm) Vol. 12 Issue 8 Pg. 2947-61 (Aug 03 2015) ISSN: 1543-8392 [Electronic] United States
• PMID: 26149889 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, CD
• CD71 antigen
• Peptide Fragments
• Receptors, Transferrin
• Transferrin
• Polyethylene Glycols
• Iron
• Paclitaxel

Topics

• Animals
• Antigens, CD (metabolism)
• Apoptosis (drug effects)
• Blood-Brain Barrier (drug effects, metabolism)
• Brain (cytology, drug effects, metabolism)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Drug Delivery Systems
• Glioblastoma (drug therapy, metabolism, pathology)
• Iron (pharmacology)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Nanoparticles (administration & dosage, chemistry)
• Paclitaxel (administration & dosage)
• Peptide Fragments (pharmacology)
• Photoelectron Spectroscopy
• Polyethylene Glycols (chemistry)
• Rats
• Rats, Sprague-Dawley
• Receptors, Transferrin (antagonists & inhibitors, metabolism)
• Tissue Distribution
• Transferrin (antagonists & inhibitors, metabolism)