Imaging the delivery of brain-penetrating PLGA nanoparticles in the brain using magnetic resonance.
Current therapy for glioblastoma multiforme (GBM) is largely ineffective, with nearly universal tumor recurrence. The failure of current therapy is primarily due to the lack of approaches for the efficient delivery of therapeutics to diffuse tumors in the brain. In our prior study, we developed brain-penetrating nanoparticles that are capable of penetrating brain tissue and distribute over clinically relevant volumes when administered via convection-enhanced delivery (CED). We demonstrated that these particles are capable of efficient delivery of chemotherapeutics to diffuse tumors in the brain, indicating that they may serve as a groundbreaking approach for the treatment of GBM. In the original study, nanoparticles in the brain were imaged using positron emission tomography (PET). However, clinical translation of this delivery platform can be enabled by engineering a non-invasive detection modality using magnetic resonance imaging (MRI). For this purpose, we developed chemistry to incorporate superparamagnetic iron oxide (SPIO) into the brain-penetrating nanoparticles. We demonstrated that SPIO-loaded nanoparticles, which retain the same morphology as nanoparticles without SPIO, have an excellent transverse (T(2)) relaxivity. After CED, the distribution of nanoparticles in the brain (i.e., in the vicinity of injection site) can be detected using MRI and the long-lasting signal attenuation of SPIO-loaded brain-penetrating nanoparticles lasted over a one-month timecourse. Development of these nanoparticles is significant as, in future clinical applications, co-administration of SPIO-loaded nanoparticles will allow for intraoperative monitoring of particle distribution in the brain to ensure drug-loaded nanoparticles reach tumors as well as for monitoring the therapeutic benefit with time and to evaluate tumor relapse patterns.
Department of Biomedical Engineering, Yale University, New Haven, CT, 06511, USA.
Garth
G
Strohbehn
Daniel
D
Coman
Liang
L
Han
Ragy R T
RR
Ragheb
Tarek M
TM
Fahmy
Anita J
AJ
Huttner
Fahmeed
F
Hyder
Joseph M
JM
Piepmeier
W Mark
WM
Saltzman
Jiangbing
J
Zhou
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001932:Brain Neoplasms / Q000188:drug therapy; D018481:Convection; D016503:Drug Delivery Systems / Q000379:methods*; D005290:Ferric Compounds; D005909:Glioblastoma / Q000188:drug therapy; D006801:Humans; D007091:Image Processing, Computer-Assisted; D019344:Lactic Acid / Q000008:administration & dosage*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D059906:Neuroimaging / Q000379:methods*; D011100:Polyglycolic Acid / Q000008:administration & dosage*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D051381:Rats; D017207:Rats, Sprague-Dawley
D000970:Antineoplastic Agents; D005290:Ferric Compounds; C000499:ferric oxide; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid