Biomedical Engineering – From Theory to Applications

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212 Biomedical Engineering – From Theory to Applications Fig. 5. Examination of sensitivity of in vivo tumor imaging. (A) uPAR-targeted MRI of an orthotopic pancreatic cancer. Tumor is marked as pink dotted circle. Prussian blue staining revealed the presence of IO nanoparticles in the tumor lesion with strong staining in tumor stromal areas. (B) NIR optical imaging and (C) MRI of injected labeled cells and nonlabeled cells in mouse pancreas. Reproduced with permission from Yang, L., H. Mao, et al. (2009). "Molecular imaging of pancreatic cancer in an animal model using targeted multifunctional nanoparticles." Gastroenterology 136(5): 1514-25.
Targeted Magnetic Iron Oxide Nanoparticles for Tumor Imaging and Therapy 213 In contrast, cost effective but high affinity small molecule targeting moities are not widely available or well tested. One exception is folic acid (FA), which targets the folate receptor, which is overexpressed on the surface of many human tumor cells and can thus be used as a target for tumor imaging. The vitamin FA has low molecular weight and has been widely studied as a targeting ligand. There are many advantages of using FA as a targeting ligand for synthesizing IO nanoparticles, 1) high binding affinity for its receptor (Kd = 10 −10 M), 2) low cost and easily obtained, 3) easy to be conjugated with the imaging agents, 4) lack of immunogenicity (Low, Henne et al. 2008). Sun et al constructed the FA-IO-nanoparticles, the in vitro experiments showed that FR-positive HeLa cells could uptake1.410 pg iron per cell after incubated with FR-targeted IO nanoparticles for 4 hrs, which was 12-fold higher than those cultured with non-targeted IO nanoparticles, and the increased internalization could be inhibited by increasing free FA concentration, and such targeting specificity of the FRtargeted IO nanoparticles could be further demonstrated by using FR-negative Human osteosarcoma MG-63 cells. The T2-weighted MR phantom images of HeLa cells cultured with FR-targeted IO nanoparticles showed significantly lower T2 values (23.5–14.2 ms) than those incubated with non-targeted IO nanoparticles (80.2–49.3 ms)(Sun, Sze et al. 2006). Another study also showed FA-targeted IO nanoparticles could selectively accumulate in human nasopharyngeal epidermoid carcinoma (KB) cells both in vitro and in vivo, which resulted in significant MRI signal changes (Chen, Gu et al. 2007). Given the concerns regarding the delivery of fairly large nanoparticle constructs directly into the tumor, targeted imaging and drug delivery into the tumor vasculture, which is often associated with tumor angiogenesis, appears to be a feasible approach. Angiogenesis is essential for the development of tumors. As a marker of angiogenesis, the v3 integrin locates on the surface of the tumor vessels and can be directly targeted via blood. The Arg- Gly-Asp (RGD) peptide, which can bind to the αvβ3 integrin receptor, has been well studied as a tumor vessel-targeted ligand. One study using RGD-USPIO nanoparticles for tumor vessel imaging showed that RGD-USPIO nanoparticles could target to the tumor vessels and resulted in a change in T2 relaxation detected at the field strength of 1.5 T with a clinical MRI scanner, and the signal changes were correlated to the αvβ3 integrin expression level (Zhang, Jugold et al. 2007). On the other hand, targeted delivery of biomarker-specific nanoparticle constructs to brain tumors needs to overcome the challenge of penatrating the intrinsic blood-brain barrier. Efforts have been made to identify the appropriate design of nanoparticle constructs for targeting brain tumors. It has been reported that matrix metalloproteinase-2 (MMP-2) is overexpressed in gliomas and other related cancers, and facilitates cancer invasion (Soroceanu, Gillespie et al. 1998; Deshane, Garner et al. 2003; Veiseh, Gabikian et al. 2007). The chlorotoxin (Cltx) is a small peptide (36-amino acid) which can recognize and bind to the MMP-2 endopeptidase, one study showed that Cltx-conjugated IO nanoparticles could be taken up in 9L glioma cells at significantly higher concentrations than that of their nontargeted counterpart, which further resulted in a significant difference in R2(1/T2) relaxivity between Cltx-targeted IO nanoparticle- (5.20 mm -1s -1) and non-targeted IO nanoparticle- (0.22 mm -1s -1 ) treated tumor cells, and such R2 change was also observed by MRI in vivo (Sun, Veiseh et al. 2008). One alternative and potential solution for overcoming the bloodbrain barrier to deliver therapeutic IO nanoparticles is the use of conventional enhanced delivery, in which a magnetic IO nanoparticle suspension can be slowly infused into the
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BIOMEDICAL ENGINEERING - FROM THEOR
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free online editions of InTech Book
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VI Contents Chapter 9 Targeted Magn
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X Preface stand-alone and readers c
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2 Biomedical Engineering - From The
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4 Fig. 2. Process for retrieval inf
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6 Biomedical search engine Scientif
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12 Bireme http://regional.bv salud.
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100 Biomedical Engineering - From T
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108 Method (Detection) CIEF-tITP-CZ
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110 Method (Detection) Analyte Matr
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120 6. Conclusion Biomedical Engine
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150 5. Conclusions Biomedical Engin
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300 2. Nanoparticles in biomedical
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454 In this case, the eigenvalues a
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456 where Biomedical Engineering -
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472 Nb b b l l1 Biomedical Engineer
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