2.2.3. In Vivo Imaging of Cancer

Cancer metastasis is the final insult leading to patient mortality. The early detection of metastasis is therefore a primary concern in the field of oncology. CD-based MRI contrast agents hold promise for the imaging of metastasis. Although CD-based contrast agents have yet been clinically tested, a number of groups have demonstrated these contrast agents in mammalian models.

Zhou et al. [74] reported the enhancement of MRI of liver metastases with a zwitterionized biodegradable dendritic CD-based contrast agent. Traditionally, the sensitivity in the liver for MR imaging of metastases is low due to the accumulation of the contrast agent in the Kupffer cells and hepatocytes instead of cancer cells. Zhou et al. used a novel dendritic contrast agent with β-CD core and the net size of 9 nm. The developed dendritic contrast agent reduces background signals in the liver significantly by avoiding being uptakes by hepatocytes and Kupffer cells through the zwitterionization, while increasing the signal in tumors through the enhanced permeability and retention effect. This CD-based zwitterionized dendritic contrast agent also showed shorter Gd(III) retention in all organs and tissues, because it could degrade into small fragments.

Zhang et al. developed polyethyleneimine- β-CD (PEI-β-CD) as a novel vector for carrying ferritin gene modified by alpha-fetoprotein promoter [75] to create a highly specific endogenous T<sup>2</sup> contrast agent for hepatocellular carcinoma. In vitro T2-weighted and T<sup>2</sup> \* -weighted MRI was used to examine the effect of ferritin heavy gene transfection. Zhang et al. observed the significant T2/T<sup>2</sup> \* -induced MRI signal decay (up to 40%) from the BEL-7402 hepatocellular carcinoma cells treated with the developed PEI-β-CD/ferritin gene. Therefore, it was proposed that the ferritin gene carried by PEIβ-CD has a high potential to be used for early-stage MRI detection as an endogenous contrast agent for hepatocellular carcinoma imaging.

Gd (III) oxide NPs coated with folic acid functionalized poly (β-CD-co-pentetic acid) (Gd2O3@PCD-FA) as a biocompatible targeted nano-contrast agent was proposed by Mortezazadeh et al. [76]. Mortezazadeh et al. observed that Gd2O3@PCD-FA demonstrated significantly higher <sup>r</sup><sup>1</sup> and r<sup>2</sup> relaxivities at 3T (r<sup>1</sup> <sup>=</sup> 3.95 mM−<sup>1</sup> s −1 ; r<sup>2</sup> <sup>=</sup> 4.6 mM−<sup>1</sup> s −1 ) than Gd(III)-DOTA. On the other hand, the measured relaxivities were lower compared to the pure Gd2O<sup>3</sup> (r<sup>1</sup> <sup>=</sup> 4.86 mM−<sup>1</sup> s −1 ; <sup>r</sup><sup>2</sup> <sup>=</sup> 5.97 mM−<sup>1</sup> s −1 ) due to the reduced water accessibility to Gd2O<sup>3</sup> core in Gd2O3@PCD-FA. In order to study the performance of the developed NPs in vivo, the Gd2O3@PCD-FA contrast agent has been evaluated in the animal tumor model. Maximization of CNR was observed in 1h post-injection of the Gd2O3@PCD-FA contrast agent. Interestingly, Gd2O3@PCD-FA NPs demonstrated almost no cytotoxicity after 12 and 24 h administering to MCF-10A human normal breast cell lines.

Han et al. developed a hypoxia-targeting dendritic MRI contrast agent based on internally hydroxy dendrimer (IHD) with β-CD core [77]. The disturbance of the zwitterionic surface reduces unspecific cellular uptake by normal cells. In vivo imaging of an orthotopic breast tumor in mice injected with the developed contrast agent showed the maximization of CNR in 1 h post-injection. Han et al. observed CNR reaching the level of 10, remaining constant during the second hour, and slightly decaying 3 h post-injection.
