Periodic Reporting for period 1 - MCNANO (“Multi-component nanoparticles as bimodal contrast agents for MRI and optical detection of tumors and for targeted photodynamic therapy”)
Berichtszeitraum: 2016-04-01 bis 2018-03-31
Magnetic resonance imaging (MRI) is a powerful technique for obtaining tomographic images of biological targets in a noninvasive manner, with high spatial/temporal resolution, which makes it a vital component for diagnosing diseases such as cancer. Numerous studies have shown that the diagnostic value of MRI can be further improved by applying vectorized contrast agents, capable of delivering a high payload of para magnetic/superparamagnetic substances at the site of interest. However, because of the low intrinsic sensitivity of MRI compared to optical imaging, a relatively large local concentration of contrast agent is required to achieve the desired contrast enhancement. Looking exclusively at the sensitivity, optical imaging (OI) is more adequate for imaging as the local concentrations of contrast agents required are significantly lower. This issue of higher injection dose can be circumvented by adopting the technique of multimodal imaging, where different imaging modalities are combined within the frame of a single examination to obtain complementary information. Thus in the present study, a novel type of multimodal, magnetic resonance imaging/optical imaging (MRI/OI) contrast agent was developed, based on core–shell lanthanide fluoride nanoparticles composed of a b-NaHoF4 core plus a b-NaGdF4:Yb3+, Tm 3+ shell with an average size of ~24 nm. The biocompatibility of the particles was ensured by a surface modification with poly acrylic acid (PAA) and further functionalization with an affinity ligand, folic acid (FA). When excited using 980 nm near infrared (NIR) radiation, the contrast agent (CA) shows intense emission at 802 nm with lifetime of 791+/_3 ms, due to the transition 3H4!3H6 of Tm3+. Proton nuclear magnetic relaxation dispersion (1H-NMRD) studies and magnetic resonance (MR) phantom imaging showed that the newly synthesized nanoparticles, decorated with poly(acrylic acid) and folic acid on the surface (NP-PAA-FA), can act mainly as a T1weighted contrast agent below 1.5 T, a T1/T2 dual-weighted contrast agent at 3 T, and as highly efficient T2-weighted contrast agent at ultrahigh fields. In addition, NP-PAA-FA showed very low cytotoxicity and no detectable cellular damage up to a dose of 500 mgmL-1.
"The main aim of this project was to develop nano-architectures based on Lanthanide fluorides with the aim of using them as multimodal contrast agents for bioimaging and further to use them as photo theranostic agents. During the project, we have developed core-shell nanoparticles containing Yb/Er or Yb/Tm as upconversion luminescent centers and Gd, Dy, Ho as magnetic centers for increasing the contrast of both magnetic resonance imaging (MRI) and optical imaging (OI). The most exciting result is that nanoparticles with the structure NaHoF4#NaGdF4:Yb/Tm display magnetic field dependent contrasting properties apart from intense upconverted NIR emission at 802nm. They act predominantly as T1-weighted MRI contrast agent below 1.5 Tesla, and as a T1-T2 dual weighted contrast agent at 3 Tesla. At high magnetic fields, they serve as efficient T2-weighted contrast agents. Such magnetic field dependent changes are also reflected in their contrast behavior, which switches from positive to negative, making the here-developed material unique. Further, synthesized nanoparticles can be readily transferred to aqueous solutions with high colloidal stability and biocompatibility by ligand exchange with poly(acrylic acid) and folic acid. The efficiency of surface modification was evidenced from its very high degree of cell viability, exhibited by the nanoparticles in all four cell lines studied (up to 500 mgmL-1), and long lived luminescence emission signal in the NIR region in water. The uptake of NP-PAA-FA to SKOV3 cells could be inhibited by free folic acid, indicating that the internalization could be mediated by the folate receptor."
A current trend in magnetic resonance biomedical imaging technology involves the application of higher magnetic fields to improve sensitivity and spatial resolution. Instruments operating at 7.0 Tesla have been validated for clinical applications both in Europe and the USA, and fields as high as 21 Tesla are already used in preclinical research, which require the highest possible resolution. However, the use of the current family of Gd(III) based contrast agents in these ultra-high field MRI instruments is hampered by the fact that their optimum performance occurs below 1.5 Tesla. Another recent challenge is to develop ’’dual-weighted“ contrast agents, wherein two different contrast mechanisms (T1 and T2 relaxation) are utilized. Integrating two mechanisms can provide more comprehensive and synergistic diagnostic information than that obtained in a single modality. Designing such contrast agents requires conceptually new approaches and ”out of the box thinking