Chlorotoxin modified morusin-PLGA nanoparticles for targeted glioblastoma therapy.

Abstract

Malignant brain tumors remain a major cause of concern and mortality as successful treatment is hindered due to the poor transport and low penetration of chemotherapeutics across the blood-brain barrier (BBB). In this study, a nano formulation composed of chlorotoxin (CTX)-conjugated morusin loaded PLGA nanoparticles (PLGA-MOR-CTX) was devised against Glioblastoma Multiforme (GBM) and its anti-proliferative effects were evaluated in vitro. The synthesized nanoparticles were loaded with morusin, a naturally derived chemotherapeutic drug, and surface conjugated with CTX, a peptide derived from scorpion venom, highly specific for chloride channels (CIC-3) expressed in glioma tumor cells, as well as for matrix metalloproteinase (MMP-2), which is up regulated in the tumor microenvironment. Subsequently, the anti-cancer potential of the NPs was assessed in U87 and GI-1 (human glioblastoma) cells. Antiproliferative, cell apoptosis, and other cell-based assays demonstrated that the PLGA-MOR-CTX NPs resulted in enhanced inhibitory effects on U87 and GI-1 glioma cells. Prominent cytotoxicity parameters such as ROS generation, enhanced caspase activity, cytoskeletal destabilization, and inhibition of MMP-activity were observed in glioblastoma cells upon PLGA-MOR-CTX NP treatment. The cytocompatibility observed with normal human neuronal cells (HCN-1A) and the enhanced lethal effects in glioblastoma cells highlight the potential of PLGA-MOR-CTX nanoparticles as promising therapeutic nanocarriers towards GBM.

• Authors: Srishti Agarwal, M Sheikh Mohamed, Toru Mizuki, Toru Maekawa, D Sakthi Kumar
• Journal: Journal of materials chemistry. B (J Mater Chem B) Vol. 7 Issue 39 Pg. 5896-5919 (10 09 2019) ISSN: 2050-7518 [Electronic] England
• PMID: 31423502 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Drug Carriers
• Flavonoids
• Reactive Oxygen Species
• Scorpion Venoms
• Chlorotoxin
• Polylactic Acid-Polyglycolic Acid Copolymer
• morusin
• Matrix Metalloproteinase 2
• Matrix Metalloproteinase 9

Topics

• Autophagy (drug effects)
• Biological Transport
• Brain Neoplasms (drug therapy, pathology)
• Cell Line, Tumor
• Cytoskeleton (drug effects, metabolism)
• Drug Carriers (chemistry)
• Drug Liberation
• Flavonoids (chemistry)
• Glioblastoma (drug therapy, pathology)
• Humans
• Matrix Metalloproteinase 2 (metabolism)
• Matrix Metalloproteinase 9 (metabolism)
• Molecular Targeted Therapy
• Nanoparticles (chemistry)
• Polylactic Acid-Polyglycolic Acid Copolymer (chemistry)
• Reactive Oxygen Species (metabolism)
• Scorpion Venoms (chemistry, pharmacology)