Nanoengineering a metal–organic framework for osteosarcoma chemo-immunotherapy by modulating indoleamine-2,3-dioxygenase and myeloid-derived suppressor cells

Abstract

Background The high postoperative recurrence rate and refractoriness of relapsed tumors are still a conundrum for the clinical management of osteosarcoma (OS). New therapeutic options are urgently needed. Depriving the nourishment of myeloid-derived suppressor cells is a novel strategy to improve the immunosuppressive tumor microenvironment for enhanced OS therapy. Methods We synthesized a hyaluronic acid (HA)-modified metal–organic framework for combinational chemotherapy and immunotherapy of OS. Zeolitic Imidazolate Framework-8 (ZIF-8) was prepared by a one-pot synthetic method, Gemcitabine (Gem) and D-1-Methyltryptophan (D-1-MT) were loaded into the ZIF-8 during the synthesis process to make ZIF-8@Gem/D-1-MT nanoparticles (NPs). The end product (HA/ZIF-8@Gem/D-1-MT NPs) was obtained by HA modification on the surface of ZIF-8@Gem/D-1-MT NPs. The obtained HA/ZIF-8@Gem/D-1-MT NPs have excellent potential as a drug delivery vector for chemotherapy and immunotherapy in vitro and vivo. Results The results indicate that HA/ZIF-8@Gem/D-1-MT NPs were readily taken up by OS cells, and that the Gem and D-1-MT were effectively released into the acidic environment. The HA/ZIF-8@Gem/D-1-MT NPs could efficiently decrease OS cell viability (proliferation, apoptosis, cell cycle, migration and invasion). And HA/ZIF-8@Gem/D-1-MT NPs could reactivate antitumor immunity by inhibiting indoleamine 2,3 dioxygenase and myeloid-derived suppressor cells. Furthermore, animal experiments confirmed that HA/ZIF-8@Gem/D-1-MT NPs could induce intratumoral immune responses and inhibit tumor growth. Additionally, HA/ZIF-8@Gem/D-1-MT NPs have a good safety profile. Conclusions Our findings demonstrate that the combination of Gem with D-1-MT brings new hope for the improved treatment of OS, while the generation of the nanosystem has increased the application potential and flexibility of this strategy.

Nanoengineering a Zeolitic Imidazolate Framework‐8 Capable of Manipulating Energy Metabolism against Cancer Chemo‐Phototherapy Resistance

“…CS‐functionalized ZIF‐8@A780/DOX NPs were fabricated using Zn(NO 3 ) 2 ·6H 2 O, 2,4‐methylimidazole, hydrophobic A780, and CS in a one‐pot synthetic method similar to that described previously. [ 20 ] The synthesis of IR780‐COOH and A780 is shown in Figure S1A, Supporting Information. The 1 H NMR analysis of IR780, IR780‐COOH, A780, and mass spectroscopy analysis of IR780‐COOH and A780 indicated the successful synthesis of A780 (Figure S1B–G, Supporting Information).…”

“…Synthesis of ZIF-8: ZIF-8 nanoparticles were synthesized following a reported method. [20] 1 mL of 160 mm 2-methylimidazole (dissolved in deionized water) was agitated magnetically (300 rpm) for 5 min at room temperature. Then, 1 mL of 10 mm zinc nitrate hexahydrate (dissolved in deionized water) was added dropwise.…”

“…Synthesis of ZIF-8@DOX/A780: ZIF-8@DOX/A780 NPs were synthesized using the "one pot" method described previously. [20] Briefly, 40 mg of A780 and 20 mg of DOX were dissolved in 4 mL of double-distilled water (ddH 2 O) as solution A, 100 mg of zinc nitrate hexahydrate was dissolved in 0.4 mL of ddH 2 O as solution B, and 1.0 g of 2-methylimidazole was dissolved in 4 mL of ddH 2 O as solution C. Solution B was stirred (600 rpm, 5 min), and solution A was added dropwise with stirring for 10 min. Then, the mixture was added dropwise with stirring (800 rpm) to solution C and stirred for an additional 15 min.…”

Modulation of immunosuppressive cells and noncoding RNAs as immunotherapy in osteosarcoma

“…OS immunotherapy primarily targets immunosuppressive cells in the TME, which are regulated by cytokines, chemokines, and an anaerobic environment ( 171 ). Gemcitabine effectively inhibited the progression of osteosarcoma by inducing cell apoptosis and inhibiting the accumulation of MDSCs ( 172 ). Additionally, when it binds to specific inhibitors of indoleamine 2, 3-dioxygenase, it can more effectively prevent the recruitment of MDSCs and the differentiation of Treg cells ( 172 ).…”

Nanoscale Zeolitic Imidazolate Framework (ZIF)–8 in Cancer Theranostics: Current Challenges and Prospects

“…Compared with conventional treatments such as radiotherapy and chemotherapy, the frequency and severity of side effects are significantly reduced. With the in–depth studies of ZIF–8, it has been more and more widely used in immunotherapy [ 13 , 34 , 35 , 36 , 37 , 38 ], as the carrier of immune checkpoint inhibitors, immune adjuvants, or cancer vaccines ( Table 2 ).…”