Construction and evaluation of Fe₃O₄-based PLGA nanoparticles carrying rtPA used in the detection of thrombosis and in targeted thrombolysis.
Thrombotic disease is extremely harmful to human health, but early detection and treatment can help improve prognoses and reduce mortality. To date, few studies have used MR molecular imaging in the early detection of thrombi and in the dynamic monitoring of the thrombolytic efficiency. In this article, we construct Fe3O4-based poly(lactic-co-glycolic acid) (PLGA) nanoparticles to use in the detection of thrombi and in targeted thrombolysis using MRI monitoring. Cyclic arginine-glycine-aspartic peptide (cRGD) was grafted onto the chitosan (CS) surface to synthesize a CS-cRGD film using carbodiimide-mediated amide bond formation. A double emulsion solvent evaporation method (water in oil in water [W/O/W]) was used to construct Fe3O4-based PLGA nanoparticles carrying recombinant tissue plasminogen activator (rtPA) (Fe3O4-PLGA-rtPA/CS-cRGD). Fe3O4-PLGA, Fe3O4-PLGA-rtPA, and Fe3O4-PLGA-rtPA/CS nanoparticles were constructed using the same W/O/W method. The results showed that the Fe3O4-based nanoparticles were constructed successfully and have a regular shape, a relatively uniform size, a high carrier rate of Fe3O4 and encapsulation efficiency of rtPA, and a relatively high activity of released rtPA. Transmission electron microscope (TEM) images revealed that the iron oxide particles were relatively uniformly distributed in the nano-spherical shell. The Fe3O4-based nanoparticles could be imaged using a clinical MRI scanner, and there were no significant differences in the transverse relaxation rate (R2*) or in the signal-to-noise ratio (SNR) values between the Fe3O4-based nanoparticles and an Fe3O4 solution with the same concentration of Fe3O4. In vitro and in vivo experiments confirmed that the Fe3O4-PLGA-rtPA/CS-cRGD nanoparticles specifically accumulated on the edge of the thrombus and that they had a significant effect on the thrombolysis compared with the Fe3O4-PLGA, Fe3O4-PLGA-rtPA, and Fe3O4-PLGA-rtPA/CS nanoparticles and with free rtPA solution. These results suggest the potential of the Fe3O4-PLGA-rtPA/CS-cRGD nanoparticles as a dual-function tool in the early detection of a thrombus and in the dynamic monitoring of the thrombolytic efficiency using MRI.
Department of Radiology, and ‡Institute of Ultrasound Imaging, Department of Ultrasound, Second Affiliated Hospital of Chongqing Medical University , No. 74 Linjiang Rd, Yuzhong District, 400010 Chongqing, China.
Jun
J
Zhou
Dajing
D
Guo
Yu
Y
Zhang
Wei
W
Wu
Haitao
H
Ran
Zhigang
Z
Wang
D000818:Animals; D048271:Chitosan / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000295:instrumentation / Q000379:methods*; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000737:chemistry; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry*; D008279:Magnetic Resonance Imaging; D058185:Magnetite Nanoparticles / Q000737:chemistry*; D010456:Peptides, Cyclic / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D051381:Rats; D017207:Rats, Sprague-Dawley; D013927:Thrombosis / Q000175:diagnosis* / Q000188:drug therapy*; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage* / Q000737:chemistry / Q000235:genetics
D004337:Drug Carriers; D005343:Fibrinolytic Agents; D058185:Magnetite Nanoparticles; D010456:Peptides, Cyclic; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D048271:Chitosan; D010959:Tissue Plasminogen Activator