Background Hepatocellular carcinoma (HCC), arising from hepatocytes, is the most common primary liver cancer. It is urgent to develop novel therapeutic approaches to improve the grim prognosis of advanced HCC. 10-hydroxycamptothecin (HCPT) has good antitumor activity in cells; however, its hydrophobicity limits its application in the chemotherapy of HCC. Recently, nanoscale porphyrin metal-organic frameworks have been used as drug carriers due to their low biotoxicity and photodynamic properties. Methods Nanoscale zirconium porphyrin metal-organic frameworks (NMOFs) were coated with arginine-glycine-aspartic acid (RGD) peptide to prepare NMOFs-RGD first. The HepG2 cell line, zebrafish embryos and larvae were used to test the biotoxicity and fluorescence imaging capability of NMOFs-RGD both in vitro and in vivo. Then, NMOFs were used as the skeleton, HCPT was assembled into the pores of NMOFs, while RGD peptide was wrapped around to synthesize a novel kind of nanocomposites, HCPT@NMOFs-RGD. The tissue distribution and chemo- and photodynamic therapeutic effects of HCPT@NMOFs-RGD were evaluated in a doxycycline-induced zebrafish HCC model and xenograft mouse model. Results NMOFs-RGD had low biotoxicity, good biocompatibility and excellent imaging capability. In HCC-bearing zebrafish, HCPT@NMOFs-RGD were specifically enriched in the tumor by binding specifically to integrin α v β 3 and led to a reduction in tumor volume. Moreover, the xenografts in mice were eliminated remarkably following HCPT@NMOFs-RGD treatment with laser irradiation, while little morphological change was found in other main organs. Conclusion The nanocomposites HCPT@NMOFs-RGD accomplish tumor targeting and play synergistic chemo- and photodynamic therapeutic effects on HCC, offering a novel imaging-guided drug delivery and theranostic platform.

Background: The myelin sheath can be damaged by genetic and/or environmental factors, leading to demyelinating diseases, for which effective treatments are lacking. Recently, cyclooxygenase-2 (COX-2) overexpression was detected in demyelinating lesions both in patients and animal models, opening an avenue for promoting endogenous remyelination. The aim of this study was to investigate the therapeutic effect of celecoxib, a selective COX-2 inhibitor, against demyelination in a zebrafish model. Methods: The biotoxicity of celecoxib was evaluated on zebrafish embryos. Metronidazole was used to deplete the oligodendrocytes in Tg (mbp:nfsB-egfp) transgenic fish. Celecoxib was then administered both in larvae and adults. The regeneration of the myelin sheath and the underlying mechanisms were explored by immunohistochemistry, flow cytometry, Western blot analysis, quantitative real-time polymerase chain reaction, and behavioral test. Results: Celecoxib had low in vivo toxicity. A stable and practical demyelination model was established by metronidazole induction. Following celecoxib treatment, the number of oligodendrocytes was increased significantly and the concentric structure of the myelin sheath reappeared. The locomotor ability was notably improved and was close to its physiological levels. The expression of arg1, mrc1, il-10, and il-4 was upregulated, while that of il-1β, il-12, tnf-α, il-6, caspase-3 and caspase-7 was downregulated. Conclusion: Inhibition of COX-2 contributed to the transformation of microglia/macrophages from the M1 to the M2 phenotype, improved the inflammatory microenvironment, and suppressed caspase-dependent apoptosis, thus exerting a therapeutic effect against demyelination.

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Photoreceptor degeneration is one of the major causes of progressive blindness which lacks of curative treatment. GW2580, a highly selective inhibitor of colony-stimulating factor 1 receptor, has the protective potential on neurons; however, little was known about the application of GW2580 on photoreceptor degeneration. In this study, BV-2 and 661W cells coculture system was constructed to investigate the interaction between microglia and photoreceptors. GW2580 was loaded into zeolitic imidazolate framework-90-rhodamine B (ZIF-90-RhB) to synthesize a novel kind of nanoparticles, namely, ZIF-90-RhB-GW2580, through a one-step self-assembly approach. A photoreceptor degeneration model was generated by intense light exposure in zebrafish and ZIF-90-RhB-GW2580 nanoparticles were delivered by the intraocular injection. The results showed that in vitro GW2580 treatment promoted phenotypic transformation in microglia and led to the blockade of photoreceptor apoptosis. Following the intraocular delivery of ZIF-90-RhB-GW2580 nanoparticles, the microglial proliferation and inflammatory response were significantly inhibited; moreover, the photoreceptors underwent alleviated injury with a recovery of retinal structure and visual function. In conclusion, the intraocular injection of ZIF-90-RhB-GW2580 at the early stage enables the precise delivery and sustained release of the GW2580, thus preventing the progression of photoreceptor degeneration. Graphical Abstract

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