Upregulation of Key Molecules for Targeted Imaging and Therapy.

Targeted diagnosis and therapy enable precise tumor detection and treatment. Successful examples for precise tumor targeting are diagnostic and therapeutic radioligands. However, patients with tumors expressing low levels of the relevant molecular targets are deemed ineligible for such targeted approaches. METHODS: We performed a screen for drugs that upregulate the somatostatin receptor subtype 2 (sstr2). Then, we characterized the effects of these drugs on transcriptional, translational, and functional levels in vitro and in vivo. RESULTS: We identified 9 drugs that act as epigenetic modifiers, including the inhibitor of DNA methyltransferase decitabine as well as the inhibitors of histone deacetylase tacedinaline and romidepsin. In vitro, these drugs upregulated sstr2 on transcriptional, translational, and functional levels in a time- and dose-dependent manner. Thereby, their combinations revealed synergistic effects. In vivo, drug-based sstr2 upregulation improved the tumor-to-background and tumor-to-kidney ratios, which are the key determinants of successful sstr2-targeted imaging and radiopeptide therapy. CONCLUSION: We present an approach that uses epigenetic modifiers to improve sstr2 targeting in vitro and in vivo. Translation of this method into the clinic may potentially convert patients ineligible for targeted imaging and therapy to eligible candidates.

Indium-111 labeled gold nanoparticles for in-vivo molecular targeting.

The present report describes the synthesis and biological evaluation of a molecular imaging platform based on gold nanoparticles directly labeled with indium-111. The direct labeling approach facilitated radiolabeling with high activities while maintaining excellent stability within the biological environment. The resulting imaging platform exhibited low interference of the radiolabel with targeting molecules, which is highly desirable for in-vivo probe tracking and molecular targeted tumor imaging. The indium-111 labeled gold nanoparticles were synthesized using a simple procedure that allowed stable labeling of the nanoparticle core with various indium-111 activities. Subsequent surface modification of the particle cores with RGD-based ligands at various densities allowed for molecular targeting of the αvß3 integrin in-vitro and for molecular targeted imaging in human melanoma and glioblastoma models in-vivo. The results demonstrate the vast potential of direct labeling with radioisotopes for tracking gold nanoparticles within biological systems.

Fe3O4-PEI-RITC magnetic nanoparticles with imaging and gene transfer capability: development of a tool for neural cell transplantation therapies.

PURPOSE: To develop Fe(3)O(4)-PEI-RITC magnetic nanoparticles with multimodal MRI-fluorescence imaging and transfection capability, for use in neural cell replacement therapies. METHODS: The Fe(3)O(4)-PEI-RITC MNPs were synthesised through a multi-step chemical grafting procedure: (i) Silanisation of MNPs with 3-iodopropyltrimethoxysilane; (ii) PEI coupling with iodopropyl groups on the MNP surface; and (iii) RITC binding onto the PEI coating. The cell labelling and transfection capabilities of these particles were evaluated in astrocytes derived from primary cultures. RESULTS: Fe(3)O(4)-PEI-RITC MNPs did not exert acute toxic effects in astrocytes (at ≤ 6 days). Cells showed rapid and extensive particle uptake with up to 100% cellular labelling observed by 24 h. MRI and microscopy studies demonstrate that the particles have potential for use in bimodal MR-fluorescence imaging. Additionally, the particles were capable of delivering plasmids encoding reporter protein (approximately 4 kb) to astrocytes, albeit with low efficiencies. CONCLUSIONS: Multifunctional Fe(3)O(4)-PEI-RITC MNPs were successfully prepared using a multi-step synthetic pathway, with the PEI and RITC chemically bound onto the MNP surface. Their combined MR-fluorescence imaging capabilities with additional potential for transfection applications can provide a powerful tool, after further development, for non-invasive cell tracking and gene transfer to neural transplant populations.

Novel magnetite-silica nanocomposite (Fe3O4-SBA-15) particles for DNA binding and gene delivery aided by a magnet array.

Novel magnetite-silica nanocomposite particles were prepared using SBA-15 nanoporous silica as template. Magnetite nanoparticles were impregnated into the nanopore array of the silica template through thermal decomposition of iron(III) acetylacetonate, Fe(AcAc)3 at 200 degrees C. These composite particles were characterized using TEM, XRD and SQUID magnetometry. The TEM images showed that the size of composite particles was around 500 nm and the particles retained the nanoporous array of SBA-15. The formation of magnetite nanoparticles was confirmed by the powder XRD study. These composite particles also exhibited ferrimagnetic properties. By coating with short chain polyethyleneimine (PEI), these particles are capable of binding DNA molecules for gene delivery and transfection. With an external magnetic field, the transfection efficiency was shown to have an increase of around 15%. The results indicated that these composite nanoparticles may be further developed as a new tool for nanomagnetic gene transfection.