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Anti-vascular endothelial growth factor polylactic acid-polyethylene glycol-poly-L-Lys/gadolinium-diethylenetriamine pentaacetic acid nanoparticles

Anti-VEGF PLA-PEG-PLL-DTPA-Gd NPs
, PhD
National Center for Biotechnology Information, NLM, NIH
Corresponding author.

Created: ; Last Update: July 19, 2012.

Chemical name:Anti-vascular endothelial growth factor polylactic acid-polyethylene glycol-poly-L-Lys/gadolinium-diethylenetriamine pentaacetic acid nanoparticles
Abbreviated name:Anti-VEGF PLA-PEG-PLL-DTPA-Gd NPs, anti-VEGF PLA-PEG-PLL-Gd NPs
Synonym:
Agent category:Antibody
Target:Vascular endothelial growth factor (VEGF)
Target category:Protein
Method of detection:Magnetic resonance imaging (MRI)
Source of signal:Gadolinium (Gd)
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
No structure is available in PubChem.

Background

[PubMed]

Magnetic resonance imaging (MRI) maps information about tissues spatially and functionally. Protons (hydrogen nuclei) are widely used to create images because of their abundance in water molecules, which comprise >80% of most soft tissues. The contrast of proton MRI images depends mainly on the density of nuclear proton spins, the relaxation times of the nuclear magnetization (T1, longitudinal; T2, transverse), the magnetic environment of the tissues, and the blood flow to the tissues. However, insufficient contrast between normal and diseased tissues requires the use of contrast agents. Most contrast agents affect the T1 and T2 relaxation times of the surrounding nuclei, mainly the protons of water. T2* is the spin–spin relaxation time composed of variations from molecular interactions and intrinsic magnetic heterogeneities of tissues in the magnetic field (1). Cross-linked iron oxide and other iron oxide formulations affect T2 primarily and lead to a decreased signal. On the other hand, paramagnetic T1 agents such as gadolinium (Gd3+) and manganese (Mn2+) accelerate T1 relaxation and lead to brighter contrast images.

Vascular endothelial growth factor (VEGF) consists of at least six isoforms of various numbers of amino acids (121, 145, 165, 183, 189, and 206 amino acids) produced through alternative splicing (2). VEGF121, VEGF165, and VEGF189 are the forms secreted by most cell types and are active as homodimers linked by disulfide bonds. VEGF121 does not bind to heparin like the other VEGF species (3). VEGF is a potent angiogenic factor that induces proliferation, sprouting, migration, and tube formation of endothelial cells. There are three high-affinity tyrosine kinase VEGF receptors (VEGFR-1, Flt-1; VEGFR-2, KDR/Flt-1; and VEGFR-3, Flt-4) on endothelial cells. Several types of non-endothelial cells such as hematopoietic stem cells, melanoma cells, monocytes, osteoblasts, and pancreatic β cells also express VEGF receptors (2).

VEGF is overexpressed in various tumor cells and tumor-associated endothelial cells (4). Inhibition of VEGF receptor function has been shown to inhibit pathological angiogenesis as well as tumor growth and metastasis (5, 6). Radiolabeled VEGF has been developed as a single-photon emission computed tomography tracer for imaging solid tumors and angiogenesis in humans (7-9). However, several studies have shown that cancer treatments (photodynamic therapy, radiotherapy, and chemotherapy) can lead to increased tumor VEGF expression and subsequently to more aggressive disease. Therefore, it is important to measure VEGF levels in the tumors for designing better anti-cancer treatment protocols. Bevacizumab is a humanized antibody against VEGF-A. It binds to all VEGF isoforms. Bevacizumab is approved for clinical use in metastatic colon carcinoma and non-small cell lung cancer. Nagengast et al. (10) prepared 89Zr-N-succinyldesferrioxamine-bevacizumab (89Zr-bevacizumab) for imaging VEGF expression in nude mice bearing SKOV-3 human ovarian tumor xenografts.

VEGF has been demonstrated to be overexpressed in hepatocellular carcinoma (HCC) compared with normal tissue, even in early stages of HCC (11). Liu et al. (12) used polylactic acid-polyethylene glycol-poly-L-Lys as a multifunctional encapsulating agent composed of gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) and anti-VEGF monoclonal antibody (anti-VEGF PLA-PEG-PLL-DTPA-Gd NPs) for use in MRI to target VEGF expression in HCC.

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Synthesis

[PubMed]

PLA-PEG-PLL-DTPA-Gd NPs were prepared with a solvent diffusion method as described by Liu et al. (12). A mixture of PLA-PEG-PLL-DTPA (40 mg) and PLA-PEG-PLL (20 mg) was dissolved in 2 mL dimethylformamide (DMF). The organic polymer solution was added into 40 mL aqueous solution at 12 mL/h at room temperature and stirred for 2 h. DMF was removed by dialyzed against deionized water for 72 h. PLA-PEG-PLL-DTPA-Gd NPs were concentrated by centrifugation. Anti-VEGF monoclonal antibody (clone not specified) was linked on the glutaraldehyde-activated amino group of PLL on the surface of PLA-PEG-PLL-DTPA-Gd NPs after incubation for 12 h at 4°C. Anti-VEGF PLA-PEG-PLL-DTPA-Gd NPs were washed three times to removed unbound antibody. For flow cytometry studies, fluorescein-labeled NPs (PLA-PEG-PLL-FITC NPs and anti-VEGF PLA-PEG-PLL-FITC NPs) were also prepared. The average numbers of PLA-PEG and PLA-PEG-PLL groups per NP were 9,500 and 12,800, respectively. The mean diameters of PLA-PEG-PLL-DTPA-Gd NPs, anti-VEGF PLA-PEG-PLL-DTPA-Gd NPs, and anti-VEGF PLA-PEG-PLL-FITC NPs (n = 3/group) as determined with photon correlation spectroscopy were 69.8 ± 5.3 nm, 85.8 ± 7.2 nm, and 85.2 ± 5.8 nm, respectively. The larger diameters of anti-VEGF NPs indicate that the antibody is successfully linked to the NPs. The zeta potential values for PLA-PEG-PLL-DTPA-Gd NPs, anti-VEGF PLA-PEG-PLL-DTPA-Gd NPs, and anti-VEGF PLA-PEG-PLL-FITC NPs were 23.03 ± 4.6 mv, 21.63 ± 2.4 mv, and 22.77 ± 2.5 mv, respectively. The similar zeta potential values of the three NPs suggest that the antibody linkage has little effect on their surface charge. No aggregation of these NPs was observed with transmission electronic microscopy in blood plasma after up to 4 h of incubation. The number of antibody moieties and Gd3+ ions per NP were not reported.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

T1- and T2-Weighted MRI of anti-VEGF PLA-PEG-PLL-DTPA-Gd NPs (Gd = 0.6–12.0 µM) and DTPA-Gd ([Gd] = 40 µM) were performed at 3.0 T at room temperature (12). For T1-weighted imaging, the signal of 8 µM anti-VEGF PLA-PEG-PLL-DTPA-Gd NPs was similar to that of 40 µM DTPA-Gd. The r1 and r2 relaxivity values of anti-VEGF PLA-PEG-PLL-DTPA-Gd NPs were 18.39 mM–1s–1 and 24.86 mM–1s–1, respectively.

Human HCC HepG2 cells exhibited dose- and time-dependent accumulation of anti-VEGF PLA-PEG-PLL-FITC NPs (0.25–0.75 mg/ml NPs) at 37°C as determined with flow cytometry analysis, whereas PLA-PEG-PLL-FITC NPs showed only minimal accumulation (12). DTPA-Gd, PLA-PEG-PLL-DTPA-Gd NPs, anti-VEGF PLA-PEG-PLL-DTPA-Gd NPs, and anti-VEGF PLA-PEG-PLL-FITC showed no cytotoxic effect at 40 µM for 24 h at 37°C.

Animal Studies

Rodents

[PubMed]

Liu et al. (12) performed quantitative T1 MRI at 3.0 T in mice bearing mouse hepatocarcinoma HC22 xenografts at various time points after intravenous injection of 40 µmol/kg DTPA-Gd, PLA-PEG-PLL-DTPA-Gd NPs, or anti-VEGF PLA-PEG-PLL-DTPA-Gd NPs. DTPA-Gd distributed all over the body shortly after injection and returned to normal at 1 h after injection. The signal intensity reached the maximum in the tumor at 10 min and then declined rapidly. The maximum signal intensity of the kidney was higher than those of the tumor, liver, heart, and muscle at 10 min and declined relatively slowly. PLA-PEG-PLL-DTPA-Gd NPs showed a slight signal enhancement in the tumor at 1 h and reached a maximum at 3 h. The tumor boundary was clearly visualized. This represents non-specific binding. The signal intensity of the heart reached a maximum at ~1 min and declined slowly. At 12 h, the signal intensities of the tumor and normal tissues all returned to the background levels. Anti-VEGF PLA-PEG-PLL-DTPA-Gd NPs showed maximum signal intensity in the tumor at 2 h and declined slowly. The tumor signal intensity was still visualized at 12 h and returned to background level at 24 h. The signal intensities of the heart, liver, and muscle showed similar enhancement curves compared with PLA-PEG-PLL-DTPA-Gd NPs. Both NPs showed significant target enhancements to the tumor, liver, heart, and muscle compared with DTPA-Gd (P < 0.01). Anti-VEGF PLA-PEG-PLL-DTPA-Gd NPs showed significantly higher tumor enhancement (P < 0.01) compared with PLA-PEG-PLL-DTPA-Gd NPs, which in turn showed significantly higher tumor enhancement (P < 0.01) compared with DTPA-Gd. Blocking studies were not performed with the anti-VEGF antibody, though DTPA-Gd and PLA-PEG-PLL-DTPA-Gd NPs were used as controls.

Other Non-Primate Mammals

[PubMed]

No publication is currently available.

Non-Human Primates

[PubMed]

No publication is currently available.

Human Studies

[PubMed]

No publication is currently available.

References

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Wang Y.X., Hussain S.M., Krestin G.P. Superparamagnetic iron oxide contrast agents: physicochemical characteristics and applications in MR imaging. Eur Radiol. 2001;11(11):2319–31. [PubMed: 11702180]
2.
Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev. 2004;25(4):581–611. [PubMed: 15294883]
3.
Cohen T., Gitay-Goren H., Sharon R., Shibuya M., Halaban R., Levi B.Z., Neufeld G. VEGF121, a vascular endothelial growth factor (VEGF) isoform lacking heparin binding ability, requires cell-surface heparan sulfates for efficient binding to the VEGF receptors of human melanoma cells. J Biol Chem. 1995;270(19):11322–6. [PubMed: 7744769]
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Soria J.C., Fayette J., Armand J.P. Molecular targeting: targeting angiogenesis in solid tumors. Ann Oncol. 2004;15 Suppl 4:iv223–7. [PubMed: 15477311]
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Ferrara N. Vascular endothelial growth factor as a target for anticancer therapy. Oncologist. 2004;9 Suppl 1:2–10. [PubMed: 15178810]
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8.
Li S., Peck-Radosavljevic M., Kienast O., Preitfellner J., Hamilton G., Kurtaran A., Pirich C., Angelberger P., Dudczak R. Imaging gastrointestinal tumours using vascular endothelial growth factor-165 (VEGF165) receptor scintigraphy. Ann Oncol. 2003;14(8):1274–7. [PubMed: 12881392]
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Li S., Peck-Radosavljevic M., Kienast O., Preitfellner J., Havlik E., Schima W., Traub-Weidinger T., Graf S., Beheshti M., Schmid M., Angelberger P., Dudczak R. Iodine-123-vascular endothelial growth factor-165 (123I-VEGF165). Biodistribution, safety and radiation dosimetry in patients with pancreatic carcinoma. Q J Nucl Med Mol Imaging. 2004;48(3):198–206. [PubMed: 15499293]
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Nagengast W.B., de Vries E.G., Hospers G.A., Mulder N.H., de Jong J.R., Hollema H., Brouwers A.H., van Dongen G.A., Perk L.R., Lub-de Hooge M.N. In vivo VEGF imaging with radiolabeled bevacizumab in a human ovarian tumor xenograft. J Nucl Med. 2007;48(8):1313–9. [PubMed: 17631557]
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Finn R.S., Zhu A.X. Targeting angiogenesis in hepatocellular carcinoma: focus on VEGF and bevacizumab. Expert Rev Anticancer Ther. 2009;9(4):503–9. [PubMed: 19374603]
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Liu Y., Chen Z., Liu C., Yu D., Lu Z., Zhang N. Gadolinium-loaded polymeric nanoparticles modified with Anti-VEGF as multifunctional MRI contrast agents for the diagnosis of liver cancer. Biomaterials. 2011;32(22):5167–76. [PubMed: 21521627]

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