ABSTRACT
Light-mediated therapy has many unique merits but monotherapy strategies rarely completely inhibit tumor growth because resistance often develops. Combination therapy is a promising strategy in oncology and has demonstrated superior safety and efficacy over monotherapy. Here, we conjugated a scintillator complex and gold nanorod nanosensitizer for dual-modal image-guided photothermal and X-ray-induced photodynamic therapy (PDT). Lanthanide complexes were successfully conjugated and offer excellent X-ray-excited optical luminescence for PDT effects. The strong near-infrared (NIR) light and X-ray absorption abilities of gold nanorods make the nanosensitizer function as both a photothermal agent for photothermal therapy and a radiosensitizer for enhanced radiotherapy. The studies in vitro and in vivo demonstrated that the nanosensitizer offers good dual-modal imaging capability and significantly suppresses tumor progression under NIR light and X-ray irradiation. This work shows the great potential of conjugating scintillator lanthanide complexes and gold nanosensitizers for multimodal image-guided therapy of deep-seated tumors.
Subject(s)
Gold/chemistry , Nanotubes/chemistry , Optical Imaging/methods , Photochemotherapy/methods , Radiation-Sensitizing Agents/chemistry , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Cell Survival/radiation effects , Fluorescent Dyes/chemistry , Lanthanoid Series Elements/chemistry , Mice , Mice, Inbred BALB C , Radiation-Sensitizing Agents/pharmacology , Theranostic Nanomedicine , X-RaysABSTRACT
An important objective of cancer nanomedicine is to improve the delivery efficacy of functional agents to solid tumors for effective cancer imaging and therapy. Stimulus-responsive nanoplatforms can target and regulate the tumor microenvironment (TME) for the optimization of cancer theranostics. Here, we developed magnetic manganese oxide sweetgum-ball nanospheres (MMOSs) with large mesopores as tools for improved cancer theranostics. MMOSs contain magnetic iron oxide nanoparticles and mesoporous manganese oxide (MnO2) nanosheets, which are assembled into gumball-like structures on magnetic iron oxides. The large mesopores of MMOSs are suited for cargo loading with chlorin e6 (Ce6) and doxorubicin (DOX), thus producing so-called CD@MMOSs. The core of magnetic iron oxides could achieve magnetic targeting of tumors under a magnetic field (0.25 mT), and the targeted CD@MMOSs may decompose under TME conditions, thereby releasing loaded cargo molecules and reacting with endogenous hydrogen peroxide (H2O2) to generate oxygen (O2) and manganese (II) ions (Mn2+). Investigation in vivo in tumor-bearing mice models showed that the CD@MMOS nanoplatforms achieved TME-responsive cargo release, which might be applied in chemotherapy and photodynamic therapy. A remarkable in vivo synergy of diagnostic and therapeutic functionalities was achieved by the decomposition of CD@MMOSs and coadministration with chemo-photodynamic therapy of tumors using the magnetic targeting mechanism. Thus, the result of this study demonstrates the feasibility of smart nanotheranostics to achieve tumor-specific enhanced combination therapy.
Subject(s)
Doxorubicin , Magnetite Nanoparticles , Manganese Compounds , Nanospheres , Neoplasms, Experimental/drug therapy , Oxides , Porphyrins , Tumor Microenvironment/drug effects , Animals , Cell Line, Tumor , Chlorophyllides , Doxorubicin/chemistry , Doxorubicin/pharmacology , Female , Humans , Magnetite Nanoparticles/chemistry , Magnetite Nanoparticles/therapeutic use , Manganese Compounds/chemistry , Manganese Compounds/pharmacology , Mice , Mice, Inbred BALB C , Nanomedicine , Nanospheres/chemistry , Nanospheres/therapeutic use , Neoplasms, Experimental/metabolism , Neoplasms, Experimental/pathology , Oxides/chemistry , Oxides/pharmacology , Porosity , Porphyrins/chemistry , Porphyrins/pharmacologyABSTRACT
X-ray-induced photodynamic therapy (X-PDT) combines both the advantages of radiotherapy (RT) and PDT, and has considerable potential applications in clinical deep-penetrating cancer therapy. However, it is still a major challenge to prepare monodisperse nanoscintillators with uniform size and high light yield. In this study, a general and rapid synthesis method is presented that can achieve large-scale preparation of monodisperse and uniform silicate nanoscintillators. By simply adjusting the metal dopants, silicate nanoscintillators with controllable size and X-ray-excited optical luminescence (450-900 nm) are synthesized by employing a general ion-incorporated silica-templating method. To make full use of external radiation, the silicate nanoscintillators are conjugated with photosensitizer rose bengal and arginylglycylaspartic acid (RGD) peptide, making them intrinsically dual-modal targeted imaging probes. Both in vitro and in vivo experiments demonstrate that the silicate nanosensitizers can accumulate effectively in tumors and achieve significant inhibitory effect on tumor progression under low-dose X-ray irradiation, while minimally affecting normal tissues. The insights gained in this study may provide an attractive route to synthesize nanosensitizers to overcome some of the limitations of RT and PDT in cancer treatment.
