Hepatocellular carcinoma (HCC) is frequently metastatic once diagnosed and less likely to respond to curative surgery, emphasizing the need for the development of more sensitive and effective diagnostic and therapeutic strategies. Epithelial cell adhesion molecule (EpCAM) is deemed as the biomarker of cancer stem cells (CSCs), which are mainly responsible for the recurrence, metastasis and prognosis of HCC. In this study, we discuss the use of mitoxantrone (MX), an antitumor drug and a photosensitizer, for designing upconversion nanoparticle-based micelles grafted with the anti-EpCAM antibody, for dual-modality magnetic resonance/upconversion luminescence (MR/UCL)-guided synergetic chemotherapy and photodynamic therapy (PDT). The obtained micelles exhibit good biocompatibility, high specificity to HCC cells and superior fluorescent/magnetic properties in vitro. In vivo results demonstrate that the targeted micelles exhibited much better MR/UCL imaging qualities compared to the nontargeted micelles after the intravenous injection. More importantly, PEGylated UCNP micelles loaded with MX and grafted with anti-EpCAM antibody, denoted as anti-EpCAM-UPGs-MX, showcased the most effective synergetic antitumor efficacy compared with other treatment groups both in vitro and vivo. The remarkable antitumor effect, coupled with superior simultaneous dual-modality MR/UCL imaging as well as good biocompatibility and negligible toxicity, makes the UPG micelles promising for future translational research in HCC diagnosis and therapy.
BackgroundPancreatic cancer remains the leading cause of cancer-related deaths, the existence of cancer stem cells and lack of highly efficient early detection may account for the poor survival rate. Gadolinium ion-doped upconversion nanoparticles (UCNPs) provide opportunities for combining fluorescent with magnetic resonance imaging, and they can improve the diagnostic efficacy of early pancreatic cancer. In addition, as one transmembrane glycoprotein overexpressed on the pancreatic cancer stem cells, CD326 may act as a promising target. In this study, we developed a facile strategy for developing anti-human CD326-grafted UCNPs-based micelles and performed the corresponding characterizations. After conducting in vitro and vivo toxicology experiments, we also examined the active targeting capability of the micelles upon dual-mode imaging in vivo.ResultsWe found that the micelles owned superior imaging properties and long-time stability based on multiple characterizations. By performing in vitro and vivo toxicology assay, the micelles had good biocompatibility. We observed more cellular uptake of the micelles with the help of anti-human CD326 grafted onto the micelles. Furthermore, we successfully concluded that CD326-conjugated micelles endowed promising active targeting ability by conducting dual-mode imaging in human pancreatic cancer xenograft mouse model.ConclusionsWith good biocompatibility and excellent imaging properties of the micelles, our results uncover efficient active homing of those micelles after intravenous injection, and undoubtedly demonstrate the as-obtained micelles holds great potential for early pancreatic cancer diagnosis in the future and would pave the way for the following biomedical applications.
Cancer stem cells (CSCs) are thought to be responsible for the recurrence of liver cancer, highlighting the urgent need for the development of effective treatment regimens. In this study, 17-allylamino-17-demethoxygeldanamycin (17-AAG) and thermosensitive magnetoliposomes (TMs) conjugated to anti-CD90 (CD90@17-AAG/TMs) were developed for temperature-responsive CD90-targeted synergetic chemo-/magnetic hyperthermia therapy and simultaneous imaging in vivo. The targeting ability of CD90@DiR/TMs was studied with near-infrared (NIR) resonance imaging and magnetic resonance imaging (MRI), and the antitumor effect of CD90@17-AAG/TM-mediated magnetic thermotherapy was evaluated in vivo. After treatment, the tumors were analyzed with Western blotting, hematoxylin and eosin staining, and immunohistochemical (IHC) staining. The relative intensity of fluorescence was approximately twofold higher in the targeted group than in the non-targeted group, while the T2 relaxation time was significantly lower in the targeted group than in the non-targeted group. The combined treatment of chemotherapy, thermotherapy, and targeting therapy exhibited the most significant antitumor effect as compared to any of the treatments alone. The anti-CD90 monoclonal antibody (mAb)-targeted delivery system, CD90@17-AAG/TMs, exhibited powerful targeting and antitumor efficacies against CD90+ liver cancer stem cells in vivo.
Background: Pancreatic cancer (PC) is one of the most devastating types of cancers worldwide and has a remarkably poor survival rate, emphasizing the need for more effective strategies for the diagnosis and therapy of PC. Upconversion nanoparticles (UCNPs) have gained a privileged place in the biomedical field due to their outstanding properties. Besides, epithelial cell adhesion molecule (EpCAM) as one of the key biomarkers of pancreatic cancer stem cells, is a vital target for theranostic, diagnostic, and/or therapeutic intervention in nanomedicine. In this study, the theranostic nanosystem (EpCAM-UCMSNs-MX) was formed from the mesoporous silica-coated UCNPs functionalized with anti-EpCAM monoclonal antibody, and then one anticancer drug and photosensitizer, mitoxantrone (MX), was loaded into the mesoporous silica. The nanotheranostic system was used to target caner stem cells for realizing simultaneous dual-modality MR/UCL imaging and synergetic chemotherapy and NIR-triggered PDT. Results: After conducting series of characterizations, the nanotheranostic systems own superior uniform sphericity and long-time stability. In vitro and vivo experiments show the nanocomposites have good biocompatibility and can target caner stem cells to realize simultaneous dual-modality MR/UCL imaging. Furthermore, in comparison with UCMSNs-MX and free MX, MX-loaded UCMSNs conjugated with anti-EpCAM monoclonal antibody (EpCAM-UCMSNs-MX) are efficiently endocytosed by cancerous cells and show synergetic effect with PDT in vitro. In vivo experiments reconfirm the synergistic effects observed with the combination of EpCAM-UCMSNs-MX and PDT, which results in better treatment outcomes as compared to chemotherapy or NIR irradiation alone that fail to show any noticeable systemic toxicity.Conclusions: The resulting nanotheranostics were shown to target caner stem cells to confer simultaneous dual-modality MR/UCL imaging and induced intracellular reactive oxygen species exposed to 980 nm excitation, leading to synergetic chemotherapy and NIR-triggered PDT. These results offer a promising strategy for designing a multifunctional nanotheranostic system for dual-modality imaging-guided synergistic oncotherapy.
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