## Magnetic Nanoparticles in the Imaging of Tumor Angiogenesis  
**[PERSON] 1,* and [PERSON] 1,2**  
proteases, plasmin) are secreted into the intersititium. This leads to degradation of basal membrane surrounding the pre-existing vasculature, along with proliferation and migration of smooth muscle and endothelial cells. All these events lead to the alignment and organization of endothelial cells to form new vessels and a vascular network within the tumor [2; 3; 4]. Tumor angiogenesis is not simply the production of an increased number of blood vessels to serve a growing tumor mass. Although the main purpose of tumor angiogenesis can be considered to maintain a cancer's blood supply, the process occurs in an unmitigated fashion, and the resultant vascular network is highly abnormal [1]. This profoundly aberrant vasculature dramatically alters the tumor microenvironment and influences heavily the ways in which cancers grow and progress, escape the host's immune system, metastasize, and respond to anticancer therapies [5]. The heterogeneity in vessel distribution and haphazard anatomical arrangement of the vasculature cause spatial and temporal heterogeneity in blood flow, with areas of hypervasularity adjacent to hypovascular ones [6]. Also, the structural abnormalities of the tumor vasculature lead to a marked increase in vessel leakiness. As a consequence, there is a protein and fluid build-up in the tumor interstitium. This excess extravasation of protein increases the extravascular oncotic pressure, dragging further fluid into the interstitial space [6; 7]. Furthermore, there is an absence of functional intratumoral lymphatic vessels, resulting in the impaired clearance of extracellular fluid and hence interstitial hypertension within tumors. The raised intratumoral interstitial fluid pressure (IFP) reduces the hydrostatic pressure gradient between the intravascular and extravascular compartments such that the two essentially equilibrate, which reduces transvascular flow. Moreover, the mechanical stress from the solid mass of proliferating cancer cells and the matrix is able to collapse tumor vessels, closing the lumen through compressive forces [8]. This combination of regional poor perfusion, raised IFP, and areas of vascular collapse produces regional hypoxia and acidosis within tumors [9], with major implications for tumor sensitivity to therapy. Hypoxia is a well-known mediator of cancer cell resistance to conventional radiotherapy and cytotoxics [10; 11]. Moreover, the poor blood supply and raised intratumoral IFP (leading to a reduction in transvascular flow) impair the delivery of systemically administered therapies, such as conventional cytotoxics and monoclonal antibodies, to tumors [6; 12]. With the discovery of vascular endothelial growth factor (VEGF) as a major driver of tumor angiogenesis, efforts were focused on novel therapeutics aimed at inhibiting VEGF activity, with the goal of regressing tumors by starvation. Unfortunately, clinical trials of anti-VEGF monotherapy in patients with solid tumors have been largely negative [13]. Intriguingly, the combination of anti-VEGF therapy with conventional chemotherapy has improved survival in cancer patients compared with chemotherapy alone [14; 15]. In 2001, a \"vascular normalization\" hypothesis was proposed to explain this paradox [16]. The normalization hypothesis suggests that by correcting the abnormalities in structure and function of tumor vessels (rather than destroying vessels completely) a normalization of the tumor microenvironment and ultimately control tumor progression can be achieved due to improved response to intravenous as well as radiation therapy [5]. In clinical practice, angiogenesis is assessed in terms of microvessel density as determined on surgical biopsy specimens [17]. Whereas biopsies provide information only from particular regions within the tumor, the vasculature of high-grade tumors is highly heterogeneous [4].