Development of a hybrid nanocarrier-recognizing tumor vasculature and penetrating the BBB for glioblastoma multi-targeting therapy.

Abstract

The success of glioma chemotherapy is hampered by poor drug penetration ability across the blood-brain barrier (BBB) and low intratumoral drug concentration. Novel tumor-targeted delivery systems are useful in specifically accumulating in the tumor foci and penetrating into the glioma core after entering into the brain. Here we show that a multi-targeting hybrid nanocarrier (Pep-MLHA HNPs) system based on hyaluronic acid (HA)-modified polymer and a functional peptide possesses multi-target capability and stronger penetration ability into the core of three-dimensional tumor spheroids, could migrate efficiently across the BBB in vitro. The intensity of the Pep-MLHA HNPs after transporting across the BBB was 5.2-fold and 5.6-fold higher than that of ML NPs in C6 and U87 cells, respectively. More interestingly, this multi-targeting hybrid system displayed high colloidal stability in PBS solution, and weak negative zeta potential (-1.99 ± 0.655 mV) minimizing nonspecific interactions with plasma proteins and promoting long-term circulation in vivo. Additionally, the multi-targeting hybrid system induced enhanced tumor localization in U87 in situ-bearing nude mice and xenograft-bearing nude mice after systemic administration. Furthermore, docetaxel (DTX)-loaded Pep-MLHA HNPs showed negligible systemic toxicity and enhanced therapeutic efficacy, with significantly improved survival rates in intracranial C6 glioma-bearing rats. The 50% survival rate of DTX/Pep-MLHA HNPs-treated rats (40 days) was significantly longer than that of rats treated with NS (22 days), Taxotere® (25 days), DTX/ML NPs (25 days), DTX/Pep NPs (32 days) and DTX/MLHA NPs (29 days). All the results suggested that the multi-targeting hybrid nanocarrier system is promising for glioma treatment.

• Authors: Rangrang Fan , Di Chuan , Huan Hou , Haifeng Chen , Bo Han , Xiaoning Zhang , Liangxue Zhou , Aiping Tong , Jianguo Xu , Gang Guo
• Journal: Nanoscale (Nanoscale) Vol. 11 Issue 23 Pg. 11285-11304 (Jun 13 2019) ISSN: 2040-3372 [Electronic] England
• PMID: 31165845 (Publication Type: Journal Article)

Chemical References

• Drug Carriers
• Peptides
• Docetaxel
• Hyaluronic Acid

Topics

• Animals
• Blood-Brain Barrier (metabolism, pathology)
• Brain Neoplasms (blood supply, drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Docetaxel (chemistry, pharmacokinetics, pharmacology)
• Drug Carriers (pharmacokinetics, pharmacology)
• Glioblastoma (blood supply, drug therapy, metabolism, pathology)
• Hyaluronic Acid (chemistry, pharmacokinetics, pharmacology)
• Male
• Mice
• Mice, Nude
• NIH 3T3 Cells
• Nanoparticles (chemistry, therapeutic use)
• Peptides (chemistry, pharmacokinetics, pharmacology)
• Rats
• Rats, Sprague-Dawley
• Xenograft Model Antitumor Assays