title: Intravenous delivery of camptothecin-loaded PLGA nanoparticles for the treatment of intracranial glioma.
abstract: Effective treatment of glioblastoma multiforme remains a major clinical challenge, due in part to the difficulty of delivering chemotherapeutics across the blood-brain barrier. Systemically administered drugs are often poorly bioavailable in the brain, and drug efficacy within the central nervous system can be limited by peripheral toxicity. Here, we investigate the ability of systemically administered poly (lactic-co-glycolic acid) nanoparticles (PLGA NPs) to deliver hydrophobic payloads to intracranial glioma. Hydrophobic payload encapsulated within PLGA NPs accumulated at ∼10× higher levels in tumor compared to healthy brain. Tolerability of the chemotherapeutic camptothecin (CPT) was improved by encapsulation, enabling safe administration of up to 20mg/kg drug when encapsulated within NPs. Immunohistochemistry staining for γ-H2AFX, a marker for double-strand breaks, demonstrated higher levels of drug activity in tumors treated with CPT-loaded NPs compared to free drug. CPT-loaded NPs were effective in slowing the growth of intracranial GL261 tumors in immune competent C57 albino mice, providing a significant survival benefit compared to mice receiving saline, free CPT or low dose CPT NPs (median survival of 36.5 days compared to 28, 32, 33.5 days respectively). In sum, these data demonstrate the feasibility of treating intracranial glioma with systemically administered nanoparticles loaded with the otherwise ineffective chemotherapeutic CPT.
authors.affiliation: Barrow Brain Tumor Research Center, Barrow Neurological Institute, 350 W. Thomas Rd., Phoenix, AZ 85013, USA; School of Biological and Health Systems Engineering, Ira A. Fulton Schools of Engineering, Arizona State University, P.O. Box 879709, Tempe, AZ 85287, USA.
authors.forename: Kyle T
authors.initials: KT
authors.lastname: Householder
authors.affiliation: Barrow Brain Tumor Research Center, Barrow Neurological Institute, 350 W. Thomas Rd., Phoenix, AZ 85013, USA.
authors.forename: Danielle M
authors.initials: DM
authors.lastname: DiPerna
authors.affiliation: Barrow Brain Tumor Research Center, Barrow Neurological Institute, 350 W. Thomas Rd., Phoenix, AZ 85013, USA; School of Biological and Health Systems Engineering, Ira A. Fulton Schools of Engineering, Arizona State University, P.O. Box 879709, Tempe, AZ 85287, USA.
authors.forename: Eugene P
authors.initials: EP
authors.lastname: Chung
authors.affiliation: Barrow Brain Tumor Research Center, Barrow Neurological Institute, 350 W. Thomas Rd., Phoenix, AZ 85013, USA; School of Biological and Health Systems Engineering, Ira A. Fulton Schools of Engineering, Arizona State University, P.O. Box 879709, Tempe, AZ 85287, USA.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Wohlleb
authors.affiliation: Cancer and Cell Biology Division, Translational Genomics Research Institute, 455 N. Fifth St., Phoenix, AZ 85004, USA.
authors.forename: Harshil D
authors.initials: HD
authors.lastname: Dhruv
authors.affiliation: Cancer and Cell Biology Division, Translational Genomics Research Institute, 455 N. Fifth St., Phoenix, AZ 85004, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Berens
authors.affiliation: Barrow Brain Tumor Research Center, Barrow Neurological Institute, 350 W. Thomas Rd., Phoenix, AZ 85013, USA; School of Biological and Health Systems Engineering, Ira A. Fulton Schools of Engineering, Arizona State University, P.O. Box 879709, Tempe, AZ 85287, USA. Electronic address: rachael.sirianni@dignityhealth.org.
authors.forename: Rachael W
authors.initials: RW
authors.lastname: Sirianni
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D001812:Blood-Brain Barrier / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002166:Camptothecin / Q000008:administration & dosage* / Q000494:pharmacology / Q000633:toxicity; D004337:Drug Carriers / Q000737:chemistry; D005240:Feasibility Studies; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D057927:Hydrophobic and Hydrophilic Interactions; D007275:Injections, Intravenous; D019344:Lactic Acid / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D015996:Survival Rate; D013997:Time Factors
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D002166:Camptothecin
keywords: Camptothecin; GL261; Glioblastoma; Intracranial; Nanoparticles; PLGA