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

Excerpt

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.