title: Poly(lactide-co-glycolide) microspheres for MRI-monitored transcatheter delivery of sorafenib to liver tumors.
abstract: The multi-kinase inhibitor (MKI) sorafenib can be an effective palliative therapy for patients with hepatocellular carcinoma (HCC). However, patient tolerance is often poor due to common systemic side effects following oral administration. Local transcatheter delivery of sorafenib to liver tumors has the potential to reduce systemic toxicities while increasing the dose delivered to targeted tumors. We developed sorafenib-eluting PLG microspheres for delivery by intra-hepatic transcatheter infusion in an orthotropic rodent HCC model. The particles also encapsulated iron-oxide nanoparticles permitting magnetic resonance imaging (MRI) of intra-hepatic biodistributions. The PLG microspheres (diameter≈1μm) were loaded with 18.6% (w/w) sorafenib and 0.54% (w/w) ferrofluid and 65.2% of the sorafenib was released within 72h of media exposure. In vitro studies demonstrated significant reductions in HCC cell proliferation with increasing doses of the sorafenib-eluting microspheres, where the estimated IC50 was a 29μg/mL dose of microspheres. During in vivo studies, MRI permitted intra-procedural visualization of intra-hepatic microsphere delivery. At 72h after microsphere infusion, microvessel density was significantly reduced in tumors treated with the sorafenib-eluting microspheres compared to both sham control tumors (by 35%) and controls (by 30%). These PLG microspheres offer the potential to increase the efficacy of molecularly targeted MKI therapies while reducing systemic exposures via selective catheter-directed delivery to HCC.
authors.affiliation: Department of Chemical & Biological Engineering, Northwestern University, Evanston, IL, USA; Department of Radiology, Northwestern University, Chicago, IL, USA.
authors.forename: Jeane
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Radiology, Northwestern University, Chicago, IL, USA.
authors.forename: Alexander Y
authors.initials: AY
authors.lastname: Sheu
authors.affiliation: Department of Radiology, Northwestern University, Chicago, IL, USA.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Radiology, Northwestern University, Chicago, IL, USA; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.
authors.forename: Zhuoli
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Radiology, Northwestern University, Chicago, IL, USA.
authors.forename: Dong-Hyun
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Department of Radiology, Northwestern University, Chicago, IL, USA; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lewandowski
authors.affiliation: Department of Radiology, Northwestern University, Chicago, IL, USA; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA; Department of Biomedical Engineering, Northwestern University, Chicago, IL, USA.
authors.forename: Reed A
authors.initials: RA
authors.lastname: Omary
authors.affiliation: Department of Chemical & Biological Engineering, Northwestern University, Evanston, IL, USA; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.
authors.forename: Lonnie D
authors.initials: LD
authors.lastname: Shea
authors.affiliation: Department of Radiology, Northwestern University, Chicago, IL, USA; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA; Department of Biomedical Engineering, Northwestern University, Chicago, IL, USA; Department of Electrical Engineering and Computer Science, Evanston, IL, USA. Electronic address: a-larson@northwestern.edu.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Larson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000473:pathology; D002404:Catheterization; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004337:Drug Carriers / Q000008:administration & dosage*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D008863:Microspheres; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D010671:Phenylurea Compounds / Q000008:administration & dosage*; D011098:Polyglactin 910; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077157:Sorafenib
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D011098:Polyglactin 910; D000077157:Sorafenib
keywords: Hepatocellular carcinoma; Magnetic resonance imaging; Poly(lactide-co-glycolide); Sorafenib
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