Targeted Delivery of Tissue Plasminogen Activator by Binding to Silica-coated Magnetic Nanoparticle

Overview

Journal Int J Nanomedicine

Publisher Dove Medical Press

Specialty Biotechnology

Date 2012 Oct 12

PMID 23055726

Citations 33

Authors

Jyh-Ping Chen

Pei-Ching Yang

Yunn-Hwa Ma

Su-Ju Tu

Yu-Jen Lu

Affiliations

Soon will be listed here.

Abstract

Background And Methods: Silica-coated magnetic nanoparticle (SiO(2)-MNP) prepared by the sol-gel method was studied as a nanocarrier for targeted delivery of tissue plasminogen activator (tPA). The nanocarrier consists of a superparamagnetic iron oxide core and an SiO(2) shell and is characterized by transmission electron microscopy, Fourier transform infrared spectroscopy, X-ray diffraction, superconducting quantum interference device, and thermogravimetric analysis. An amine-terminated surface silanizing agent (3-aminopropyltrimethoxysilane) was used to functionalize the SiO(2) surface, which provides abundant -NH(2) functional groups for conjugating with tPA.

Results: The optimum drug loading is reached when 0.5 mg/mL tPA is conjugated with 5 mg SiO(2)-MNP where 94% tPA is attached to the carrier with 86% retention of amidolytic activity and full retention of fibrinolytic activity. In vitro biocompatibility determined by lactate dehydrogenase release and cell proliferation indicated that SiO(2)-MNP does not elicit cytotoxicity. Hematological analysis of blood samples withdrawn from mice after venous administration indicates that tPA-conjugated SiO(2)-MNP (SiO(2)-MNP-tPA) did not alter blood component concentrations. After conjugating to SiO(2)-MNP, tPA showed enhanced storage stability in buffer and operation stability in whole blood up to 9.5 and 2.8-fold, respectively. Effective thrombolysis with SiO(2)-MNP-tPA under magnetic guidance is demonstrated in an ex vivo thrombolysis model where 34% and 40% reductions in blood clot lysis time were observed compared with runs without magnetic targeting and with free tPA, respectively, using the same drug dosage. Enhanced penetration of SiO(2)-MNP-tPA into blood clots under magnetic guidance was confirmed from microcomputed tomography analysis.

Conclusion: Biocompatible SiO(2)-MNP developed in this study will be useful as a magnetic targeting drug carrier to improve clinical thrombolytic therapy.

Citing Articles

Nanoparticles for Thrombolytic Therapy in Ischemic Stroke: A Systematic Review and Meta-Analysis of Preclinical Studies.

Prego-Dominguez J, Laso-Garcia F, Palomar-Alonso N, Perez-Mato M, Lopez-Arias E, Dopico-Lopez A Pharmaceutics. 2025; 17(2).

PMID: 40006575 PMC: 11859612. DOI: 10.3390/pharmaceutics17020208.

Harnessing micrometer-scale tPA beads for high plasmin generation and accelerated fibrinolysis.

Osmond M, Dabertrand F, Quillinan N, Su E, Lawrence D, Marr D bioRxiv. 2024; .

PMID: 39574757 PMC: 11580863. DOI: 10.1101/2024.11.06.621942.

Nanomaterials for stroke diagnosis and treatment.

Liu Y, Li J, Guo H, Fang C, Yang Q, Qin W iScience. 2024; 27(11):111112.

PMID: 39502285 PMC: 11536039. DOI: 10.1016/j.isci.2024.111112.

Advances in Nano-Functional Materials in Targeted Thrombolytic Drug Delivery.

Ren T, Mi Y, Wei J, Han X, Zhang X, Zhu Q Molecules. 2024; 29(10).

PMID: 38792186 PMC: 11123875. DOI: 10.3390/molecules29102325.

Magnetic Nanoparticles Mediated Thrombolysis-A Review.

Zhang B, Jiang X IEEE Open J Nanotechnol. 2023; 4:109-132.

PMID: 38111792 PMC: 10727495. DOI: 10.1109/ojnano.2023.3273921.

References

Yi D, Selvan S, Lee S, Papaefthymiou G, Kundaliya D, Ying J . Silica-coated nanocomposites of magnetic nanoparticles and quantum dots. J Am Chem Soc. 2005; 127(14):4990-1. DOI: 10.1021/ja0428863. View

Fang C, Zhang M . Multifunctional Magnetic Nanoparticles for Medical Imaging Applications. J Mater Chem. 2010; 19:6258-6266. PMC: 2893338. DOI: 10.1039/b902182e. View

Diamond S . Engineering design of optimal strategies for blood clot dissolution. Annu Rev Biomed Eng. 2001; 1:427-62. DOI: 10.1146/annurev.bioeng.1.1.427. View

Segal J, Eng J, Tamariz L, Bass E . Review of the evidence on diagnosis of deep venous thrombosis and pulmonary embolism. Ann Fam Med. 2007; 5(1):63-73. PMC: 1783914. DOI: 10.1370/afm.648. View

Kohler N, Fryxell G, Zhang M . A bifunctional poly(ethylene glycol) silane immobilized on metallic oxide-based nanoparticles for conjugation with cell targeting agents. J Am Chem Soc. 2004; 126(23):7206-11. DOI: 10.1021/ja049195r. View

Girgis E, Wahsh M, Othman A, Bandhu L, Rao K . Synthesis, magnetic and optical properties of core/shell Co1-xZnxFe2O4/SiO2 nanoparticles. Nanoscale Res Lett. 2011; 6(1):460. PMC: 3211881. DOI: 10.1186/1556-276X-6-460. View

Sun S, Ma M, Qiu N, Huang X, Cai Z, Huang Q . Affinity adsorption and separation behaviors of avidin on biofunctional magnetic nanoparticles binding to iminobiotin. Colloids Surf B Biointerfaces. 2011; 88(1):246-53. DOI: 10.1016/j.colsurfb.2011.06.039. View

Goissis G, Marcantonio Jr E, Marcantonio R, LIA R, Cancian D, de Carvalho W . Biocompatibility studies of anionic collagen membranes with different degree of glutaraldehyde cross-linking. Biomaterials. 1999; 20(1):27-34. DOI: 10.1016/s0142-9612(97)00198-1. View

Chen F, Gao Q, Ni J . The grafting and release behavior of doxorubincin from Fe(3)O(4)@SiO(2) core-shell structure nanoparticles via an acid cleaving amide bond: the potential for magnetic targeting drug delivery. Nanotechnology. 2011; 19(16):165103. DOI: 10.1088/0957-4484/19/16/165103. View

10.

Anderson H, Willerson J . Thrombolysis in acute myocardial infarction. N Engl J Med. 1993; 329(10):703-9. DOI: 10.1056/NEJM199309023291006. View

11.

Gupta A, Gupta M . Synthesis and surface engineering of iron oxide nanoparticles for biomedical applications. Biomaterials. 2005; 26(18):3995-4021. DOI: 10.1016/j.biomaterials.2004.10.012. View

12.

Madison E, Goldsmith E, Gerard R, Gething M, Sambrook J . Amino acid residues that affect interaction of tissue-type plasminogen activator with plasminogen activator inhibitor 1. Proc Natl Acad Sci U S A. 1990; 87(9):3530-3. PMC: 53935. DOI: 10.1073/pnas.87.9.3530. View

13.

Sun J, Zhou S, Hou P, Yang Y, Weng J, Li X . Synthesis and characterization of biocompatible Fe3O4 nanoparticles. J Biomed Mater Res A. 2006; 80(2):333-41. DOI: 10.1002/jbm.a.30909. View

14.

Ganguly K, Murciano J, Westrick R, Leferovich J, Cines D, Muzykantov V . The glycocalyx protects erythrocyte-bound tissue-type plasminogen activator from enzymatic inhibition. J Pharmacol Exp Ther. 2007; 321(1):158-64. DOI: 10.1124/jpet.106.114405. View

15.

Kaminski M, Xie Y, Mertz C, Finck M, Chen H, Rosengart A . Encapsulation and release of plasminogen activator from biodegradable magnetic microcarriers. Eur J Pharm Sci. 2008; 35(1-2):96-103. DOI: 10.1016/j.ejps.2008.06.012. View

16.

Mahmoudi M, Sant S, Wang B, Laurent S, Sen T . Superparamagnetic iron oxide nanoparticles (SPIONs): development, surface modification and applications in chemotherapy. Adv Drug Deliv Rev. 2010; 63(1-2):24-46. DOI: 10.1016/j.addr.2010.05.006. View

17.

Lovlien M, Johansson I, Hole T, Schei B . Early warning signs of an acute myocardial infarction and their influence on symptoms during the acute phase, with comparisons by gender. Gend Med. 2009; 6(3):444-53. DOI: 10.1016/j.genm.2009.09.009. View

18.

Bennett W, Paoni N, Keyt B, Botstein D, Jones A, Presta L . High resolution analysis of functional determinants on human tissue-type plasminogen activator. J Biol Chem. 1991; 266(8):5191-201. View

19.

van der Worp H, van Gijn J . Clinical practice. Acute ischemic stroke. N Engl J Med. 2007; 357(6):572-9. DOI: 10.1056/NEJMcp072057. View

20.

Li C, Ma C, Wang F, Xil Z, Wang Z, Deng Y . Preparation and biomedical applications of core-shell silica/magnetic nanoparticle composites. J Nanosci Nanotechnol. 2012; 12(4):2964-72. DOI: 10.1166/jnn.2012.6428. View