In vivo fate and therapeutic efficacy of PF-4/CTF microspheres in an orthotopic human glioblastoma model.
The correlation between glioma grade and angiogenesis suggests that antiangiogenic therapies are potentially therapeutically effective for these tumors. However, to achieve tumor suppression, antiangiogenic therapies need to be administered daily using high systemic quantities. We designed a biodegradable polymeric device that overcomes those barriers by providing sustained local delivery of a C-terminal fragment of platelet factor 4 (PF-4/CTF), an antiangiogenic agent. Fluorescent-labeled microspheres composed of poly lactic-coglycolic acid (PLGA) were loaded with rhodamine-labeled PF-4/CTF and formulated to release their contents over time. Fluorescent labeling enabled the correlation between the in vitro to the in vivo kinetic and release studies. PF-4/CTF microspheres were injected into established intracranial human glioma tumors in nude mice. Noninvasive magnetic resonance imaging (MRI) was used to assess the therapeutic response. Tumor size, microvessel density, proliferation, and apoptosis rate were measured by histological analysis. Intracranially, the microspheres were located throughout the tumor bed and continuously released PF-4/CTF during the entire experimental period. MRI and histological studies showed that a single injection of microspheres containing PF-4/CTF caused a 65.2% and 72% reduction in tumor volume, respectively, with a significant decrease in angiogenesis and an increase in apoptosis. Our data demonstrate that polymeric microspheres are an effective therapeutic approach for delivering antiangiogenic agents that result in the inhibition of glioma tumor growth.
Benny
Ofra
O
M.M., Department of Biotechnology and Food Engineering, Technion-Israel Institute of Technology, Haifa, Israel.
Kim
Seung-Ki
SK
Gvili
Koby
K
Radzishevsky
Inna S
IS
Mor
Amram
A
Verduzco
Luis
L
Menon
Lata G
LG
Black
Peter M
PM
Machluf
Marcelle
M
Carroll
Rona S
RS
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology*; D006801:Humans; D019344:Lactic Acid; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008855:Microscopy, Electron, Scanning; D008863:Microspheres; D010316:Particle Size; D010446:Peptide Fragments / Q000494:pharmacology* / Q000627:therapeutic use*; D010978:Platelet Factor 4 / Q000494:pharmacology* / Q000627:therapeutic use*; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
D010446:Peptide Fragments; D011108:Polymers; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D010978:Platelet Factor 4