Multifunctional CT Contrast Agents For Cancer Theranostics

X-ray computed tomography(CT) is one of the most commonly used diagnostic imaging modality in clinic due to its unique advantages, such as high spatial resolution. However, CT imaging also has some intrinsic limitations, such as poor sensitivity in soft tissues, which limits its application. Thus, contrast agents are needed to further expand its application range and increase the accuracy in the diagnosis of disease.Noninvasive medical imaging is an essential tool for the diagnosis of disease. Each medical imaging modality has its own advantages and disadvantages. Thus, in recent years, the idea of acquiring and combining information from more than one imaging method has gained popularity among researchers. Due to their synergistic advantages over any modality alone, the doctor can obtain more information about the disease which is conducive to improving diagnosis accuracy. In addition, diagnosis and therapy of the disease are usually carried out separately in the tradition medical treatment. And in the conventional medical procedures, diagnostic agent and therapeutic agent are also separated, which could give more pressure on the process of metabolism and produce more side effects. Hence, in this paper CT imaging integrated with cancer therapy as a new theranostic concept was developed to overcome the inefficiency of treatment.Gold nanostructures as CT contrast agent have received much attention. Compared with iodine based CT contrast agent they have many advantages, such as high X-ray absorption coefficients and good biocompatibility. In this study, the gold nanoparticles loaded poly(lactic acid) microbubbles(Au@PLA MBs) were generated by the double emulsion method using biocompatible gold nanoparticles and biodegradable poly(lactic acid)(PLA). And the the graphene oxide were adsorbed on the surface the microbubbles through electrostatic adsorption to form the graphene modified Au@PLA MBs(Au@PLA-(PAH/GO)n MBs). The Au@PLA-(PAH/GO)n MBs were proved to have great capabilities of CT and ultrasound contrast enhancement as well as NIR photothermal therapy, which can improve the diagnostic and therapeutic accuracy and effectiveness. Most importantly, the in vitro/vivo imaging experiments and photothermal ablation experiments were successfully carried out with Au@PLA-(PAH/GO)2 MBs, indicating that when the n=2 the microbubbles have excellent imaging capability and good photothermal ablation of cancer.In order to reduce the cost and make the CT contrast with high dose effectively circulate in the body, the tantalum oxide nanoparticles(Ta Ox NPs) were generated by a microemulsion method and the Ta Ox NPs were further encapsulated into the uniform polypyrrole nanoparticles(Ta Ox@PPy NPs) were developed through a facile one-step aqueous dispersion polymerization method. Tantalum is much cheaper than gold while processing a comparable X-ray attenuation coefficient, which could greatly reduce the cost of CT contrast agent. The imaging and photothermal therapy evaluation have proved that the Ta Ox@PPy NPs can serve as dual-modal CT and PA contrast agent and photoabsorbers for imaging-guided photothermal ablation therepy, with good biocompatibility and the Ta Ox@PPy NPs could effectively accumulat at the tumor site.To further enhance the accumulation effect of the contrast agent at the tumor site, targeted Ta Ox NPs conjugated with hyaluronic acid(HA) molecules on their surface were developed for targeted imaging for cancer. Then the surfaces of Ta O x NPs were readily modified with a NIR fluorescence dye Cy7(Ta Ox@Cy7-PEG-HA NPs) using various silane derivatives through simple in situ sol-gel reaction and the combination of CT imaging and fluorescence imaging were successfully achieved. Due to the acidic microenvironments in the extracellular tissues of the tumor and the intracellular lysosomes and endosomes, multifunctional Ta Ox@Cy7-HA NPs cross-linked with DOX(Ta Ox@Cy7-DOX-PEG-HA NPs) were further prepared for selective drug release which attributed to p H degradation of chemical bond formed through glutaraldehyde cross-linking method. The obtained nanoparticles combined the CT/fluorescence imaging, p H-responsive drug delivery in one particle for targeted cancer treatment and further improved the effectiveness of the diagnosis and therapy of cancer.Due to the non-specific targeting of the HA, cetuximab a kind of monoclonal antibody was used to replace the HA, which further enhanced the accumulation effect of the contrast agent at the tumor site, the accuracy of the diagnosis and the effectiveness of therapy of the disease.In summary, in this paper a series of theranostic agents based on CT contrast agent were developed and the imaging-guided cancer therapy was achieved. In the early further, the multifunctional CT contrast agents may provide an alternative methodology for their clinical application.