Three in One: In Vitro and In Vivo Evaluation of Anticancer Activity of a Theranostic Agent that Combines Magnetic Resonance Imaging, Optical Bioimaging, and Photodynamic Therapy Capabilities.

Cancer treatment is a crucial area of research and development, as current chemotherapeutic treatments can have severe side effects or poor outcomes. In the constant search for new strategies that are localized and minimally invasive and produce minimal side effects, photodynamic therapy (PDT) is an exciting therapeutic modality that has been gaining attention. The use of theranostics, which combine diagnostic and therapeutic capabilities, can further improve treatment monitoring through image guidance. This study explores the potential of a theranostic agent consisting of four Gd(III) DTTA complexes (DTTA: diethylenetriamine-N,N,N″,N″-tetraacetate) grafted to a meso-tetraphenylporphyrin core for PDT, fluorescence, and magnetic resonance imaging (MRI). The agent was first tested in vitro on both nonmalignant TIB-75 and MRC-5 and tumoral CT26 and HT-29 cell lines and subsequently evaluated in vivo in a preclinical colorectal tumor model. Advanced MRI and optical imaging techniques were employed with engineered quantitative in vivo molecular imaging based on dynamic acquisition sequences to track the biodistribution of agents in the body. With 3D quantitative volume computed by MRI and tumoral cell function assessed by bioluminescence imaging, we could demonstrate a significant impact of the molecular agent on tumor growth following light application. Further exhaustive histological analysis confirmed these promising results, making this theranostic agent a potential drug candidate for cancer.

Doxorubicin (DOX) Gadolinium-Gold-Complex: A New Way to Tune Hybrid Nanorods as Theranostic Agent.

INTRODUCTION: In this paper, we have designed and formulated, a novel synthesis of doxorubicin (DOX) loaded bimetallic gold nanorods in which gold salt (HAuCl4) is chelated with anthracycline (DOX), diacid polyethylene-glycol (PEG-COOH) and gadolinium salt (GdCl3 * 6 H2O) to form DOX IN-Gd-AuNRs compared with DOX ON-Gd-AuNRs in which the drug was grafted onto the bimetallic pegylated nanoparticle surface by electrostatic adsorption. MATERIAL AND METHOD: The physical and chemical evaluation was performed by spectroscopic analytical techniques (Raman spectroscopy, UV-Visible and transmission electron microscopy (TEM)). Magnetic features at 7T were also measured. Photothermal abilities were assessed. Cytotoxicity studies on MIA PaCa-2, human pancreatic carcinoma and TIB-75 hepatocytes cell lines were carried out to evaluate their biocompatibility and showed a 320 fold higher efficiency for DOX after encapsulation. RESULTS: Exhaustive physicochemical characterization studies were conducted showing a mid size of 20 to 40 nm diameters obtained with low polydispersity, efficient synthesis using seed mediated synthesis with chelation reaction with high scale-up, long duration stability, specific doxorubicin release with acidic pH, strong photothermal abilities at 808 nm in the NIR transparency window, strong magnetic r1 relaxivities for positive MRI, well adapted for image guided therapy and therapeutical purpose in biological tissues. CONCLUSION: In this paper, we have developed a novel theranostic nanoparticle composed of gadolinium complexes to gold ions, with a PEG biopolymer matrix conjugated with antitumoral doxorubicin, providing multifunctional therapeutic features. Particularly, these nano conjugates enhanced the cytotoxicity toward tumoral MIAPaCa-2 cells by a factor of 320 compared to doxorubicin alone. Moreover, MRI T1 features at 7T enables interesting positive contrast for bioimaging and their adapted size for potential passive targeting to tumors by Enhanced Permeability Retention. Given these encouraging antitumoral and imaging properties, this bimetallic theranostic nanomaterial system represents a veritable promise as a therapeutic entity in the field of medicinal applications.

Theranostic MRI liposomes for magnetic targeting and ultrasound triggered release of the antivascular CA4P.

Theranostic nanocarriers of antivascular drug encapsulated in thermosensitive ultramagnetic liposomes can be advantageously designed to provide a locally high concentration and an active delivery, with image-guided Magnetic Resonance Imaging (MRI) so as to reliably cure tumor. We propose a novel therapeutic strategy consisting of the magnetic accumulation of Ultra Magnetic Liposomes (UML) followed by High-Intensity Focused Ultrasound (HIFU) to trigger the release of an antivascular agent monitored by MRI. For this purpose, we co-encapsulated Combretastatin A4 phosphate (CA4P), a vascular disrupting agent, in the core of UML to obtain CA4P-loaded thermosensitive Ultra Magnetic Liposomes (CA4P-UML). To assess the HIFU parameters, the CA4P release has been triggered in vitro by local heating HIFU at the lipids transition temperature. Morphology of endothelial cells was assessed to evaluate the effect of encapsulated versus non-encapsulated CA4P. The efficiency of a treatment combining the magnetic targeting of CA4P-UML with the CA4P release triggered by HIFU was studied in CT26 murine tumors. Tumor perfusion and volume regression parameters were monitored by multiparametric quantitative anatomical and dynamic in vivo MRI at 7 T. Additionally, vascularization and cellularity were evaluated ex-vivo by histology. This thorough investigation showed that the combined treatment exhibited a full benefit. A 150-fold improvement compared with the chemotherapy alone was obtained using a magnetic targeting of CA4P-UML triggered by HIFU, and was consistent with an expected effect on vascularization 24 h after treatment.

Design and Synthesis of Gold-Gadolinium-Core-Shell Nanoparticles as Contrast Agent: a Smart Way to Future Nanomaterials for Nanomedicine Applications.

INTRODUCTION: The development of biopolymers for the synthesis of Gd(III) nanoparticles, as therapeutics, could play a key role in nanomedicine. Biocompatible polymers are not only used for complex monovalent biomolecules, but also for the realization of multivalent active targeting materials as diagnostic and/or therapeutic hybrid nanoparticles. In this article, it was reported for the first time, a novel synthesis of Gd(III)-biopolymer-Au(III) complex, acting as a key ingredient of core-shell gold nanoparticles (Gd(@AuNPs). MATERIAL AND METHODS: The physical and chemical evaluation was carried out by spectroscopic analytical techniques (Raman spectroscopy, UV-visible and TEM). The theoretical characterization by DFT (density functional theory) analysis was carried out under specific conditions to investigate the interaction between the Au and the Gd precursors, during the first nucleation step. Magnetic features with relaxivity measurements at 7T were also performed as well as cytotoxicity studies on hepatocyte cell lines for biocompatibility studies. The in vivo detailed dynamic biodistribution studies in mice to characterize the potential applications for biology as MRI contrast agents were then achieved. RESULTS: Physical-chemical evaluation confirms the successful design and reaction supposed. Viabilities of TIB-75 (hepatocytes) cells were evaluated using Alamar blue cytotoxic tests with increasing concentrations of nanoparticles. In vivo biodistribution studies were then accomplished to assess the kinetic behavior of the nanoparticles in mice and characterize their stealthiness property after intravenous injection. CONCLUSION: We demonstrated that Gd@AuNPs have some advantages to display hepatocytes in the liver. Particularly, these nanoconjugates give a good cellular uptake of several quantities of Gd@NPs into cells, while preserving a T1 contrast inside cells that provide a robust in vivo detection using T1-weighted MR images. These results will strengthen the role of gadolinium as complex to gold in order to tune Gd(@AuNPs) as an innovative diagnostic agent in the field of nanomedicine.