Application Of Degradable Photosensitive Nanoparticles In Image Tracing And Cancer Theranostics

Cancer seriously threats people’s health and life. In recent years, morbidity and mortality of cancer is increasing, and accurate diagnosis and effective treatment of cancer is a hot spot in current research. Nanotechnology fusing multi-disciplinary, such as medicine, biology, pharmacology, pharmacy, chemistry, material science, and engineering, brings new ideas and conceptual change for tumor treatment. Nano-scale drug-delivery systems combining the advantages of long circulation time, targeting, controlled release and penetrating mucous membrane/skin can overcome the defects, including low bioavailability, poor stability, short time of drug action, serious adverse reaction and unsynchronized theranostics. We developed two kinds of new type of biodegradable nanoparticles, including lipid-polymer nanoparticles and lipid nanoparticles, and these nanoparticles were applied to imaging, targeting therapy and theranostics of tumor. The therapeutic strategy that packages imaging，targeting，theranostics simultaneous in one of nanoscaled carrier system may provide a novel thoughtway to resolve the unsynchronized diagnosis and therapy, high side effects, poor effects and relapse.1. Novel biodegradable lipid-polymer nanoparticles were Developed and applied as tumor targeting nanoprobes for in vitro and in vivo imaging. In this paper, folate receptor-targeted, indocyanine green (ICG) dye-doped poly(d,l-lactide-co-glycolide)(PLGA) lipid nanoparticles (FA-INPs) were constructed by a single-step self-assemble and nanoprecipitation method. The prepared FA-INPs exhibited good biocompatibility, monodispersity, excellent NIR penetration ability, significant stability against photobleaching and long circulation time. The intracellular uptake experiment proved the targeting efficacy of the FA-INPs was more effective in folate receptor over-expressing MCF-7cells than folate receptor negative A549cells. Furthermore, the in vivo experiments showed the FA-INPs were specifically targeted to the tumor, and its circulation time was much longer than free ICG. These biocompatible and biodegradable NIR-NPs prove a potential application in tumor diagnosis and targeted imaging due to its high aqueous stability, excellent NIR optical properties and significantly targeting property in vivo. Related results were published in Biomaterials(2012,33(22),5603-5609)、Nano Life (2012,2(1),1250002), and applyed for6national patents (201310740415.8、201310516245.5、201210424026.X、201410092529.0、ZL201010608538.2-Licensed patent、ZL201010196264.0-Licensed patent)。2. In combination therapy aspect, doxorubicin (DOX)/ICG loaded lipid–polymer nanoparticles (DINPs) were used for cancer imaging and chemo-photothermal therapy. We fabricated DOX and ICG loaded PLGA–lecithin–polyethylene glycol (PEG) nanoparticles (DINPs) using a single-step sonication method. The DINPs exhibited good monodispersity, excellent fluorescence/size stability, and consistent spectra characteristics compared with free ICG or DOX. Moreover, the DINPs showed higher temperature response, faster DOX release under laser irradiation, and longer retention time in tumor. In the meantime, the fluorescence of DOX and ICG in DINPs was also visualized for the process of subcellular location in vitro and metabolic distribution in vivo. In comparison with chemo or photothermal treatment alone, the combined treatment of DINPs with laser irradiation synergistically induced the apoptosis and death of DOX-sensitive MCF-7and DOX-resistant MCF-7/ADR cells, and suppressed MCF-7and MCF-7/ADR tumor growth in vivo. Notably, no tumor recurrence was observed after only a single dose of DINPs with laser irradiation. Hence, the well-defined DINPs exhibited great potential in targeting cancer imaging and chemo-photothermal therapy. Related results were published in ACS nano (2013,7(3),2056-2067)、Journal of Nanoscience and Nanotechnology (2014, in press, DOI:10.1166/jnn.2014.9604)、Biomaterials (2014，Accepted), and applyed for4national patents (201310740459.0、201320877099.4、201210563118.6、2012105482618.0).3. Novel biodegradable FA-targeted lipid nanoparticles were developed and applied as tumor theranostics.We directly self-assembled a biodegradable FA-targeted ultra-small NPs encapsulated ICG (FA-LNP) with intrinsic FA targeted ligands, using the film hydration via strong sonication followed by extrusion technique. The FA-LNP with good monodispersity exhibited excellent size and fluorescence stability, preferable temperature response under laser irradiation, and specific molecular targeting to MCF-7cells with FA receptor overexpression, compared to free ICG. The FA-LNP enabled NIR fluorescence imaging to in situ monitor the tumor accumulation of the ICG. The cell survival rate assays in vitro and photothermal therapy treatments in vivo indicated that FA-LNP could efficiently targeted and suppressed MCF-7cells and xenograft tumors. Hence, the FA-LNP are notable theranostic NPs for imaging-guided cancer therapy in clinical application. Related results were published in ACS Applied Materials&Interfaces (DOI:10.1021/am5004393), and applyed for1national patent (201310740459.0).