Hyaluronate-Based Self-Stabilized Nanoparticles for Immunosuppression Reversion and Immunochemotherapy in Osteosarcoma Treatment

Abstract

Immunotherapy is regarded as a potential strategy to combat cancer, especially when immunotherapy is combined with appropriate chemotherapy. However, the immunosuppressive tumor microenvironment (TME) and serious side effects extremely limit the application of immunotherapy. Herein, a self-stabilized hyaluronic acid nanoparticle is synthesized for tumor-targeted delivery of doxorubicin (DOX), cisplatin (CDDP), and resiquimod (R848) in osteosarcoma immunochemotherapy, which is referred to as CDDPNPDOX&R848. CDDPNPDOX&R848 exhibits sufficient stability, great pH responsibility, and brilliant tumor-targeting accumulation in vivo, which make it suitable for further in vivo applications. After intravenous injection, CDDPNPDOX&R848 can release the loaded cargoes under the acidic TME continuously. DOX can induce tumor cell apoptosis in combination with CDDP and trigger immunogenic cell death. More importantly, the immune-activated TME created by R848 can facilitate tumor-associated antigen presentation and antitumor immunity elicitation. Benefiting from the synergistic effect of chemotherapy and immunotherapy, the growth of tumors and lung metastasis was greatly inhibited by CDDPNPDOX&R848 in the K7M2 orthotopic osteosarcoma mouse model. Thus, this intelligent codelivery platform might be a competitive candidate for osteosarcoma immunochemotherapy.

Macrophage polarization synergizes with oxaliplatin in lung cancer immunotherapy via enhanced tumor cell phagocytosis

“…Reagents inducing M2 macrophage polarization lead to the reduction of immunosuppressive cells in TME, and their incorporation in chemotherapy exerts enhanced local and/or systemic anti-tumor immune responses in many cancers, including glial brain tumors, colorectal cancer and osteosarcoma [32] , [33] , [34] . Recently Bahmani B et al.…”

Managing the immune microenvironment of osteosarcoma: the outlook for osteosarcoma treatment

“… 391 Some immune cells, such as DCs, have been shown to be efficacious in osteosarcoma therapy in combination with low-concentration chemotherapeutic agents, such as doxorubicin (DOX), which can effectively induce ICD to further activate immunity against osteosarcoma. 392 , 393 CAR-T lymphocytes combined with antibodies and other T lymphocyte-based treatments, such as adoptive T-lymphocyte transfer, are also becoming increasingly common. 394 Overall, combination immunotherapy can boost the duration of the immune response because the double-agent treatment activates antitumor immune memory effects in osteosarcoma patients who do not respond to monotherapy.…”

“…A number of reports have shown that dying osteosarcoma cells are immunogenic and can enhance immunity against osteosarcoma after treatment with certain chemotherapies or radiotherapy. 393 , 403 Anthracyclines, including doxorubicin (DOX), mitoxantrone (MTO), oxaliplatin, bortezomib, and cyclophosphamide, are the most classic ICD inducers. 404 For instance, a mitochondria-targeted nanomicelle (named OPDEA-PDCA) capable of initiating mitochondrial oxidative stress was designed to induce pyroptosis of osteosarcoma cells.…”

Immunotherapy in soft tissue and bone sarcoma: unraveling the barriers to effectiveness

“…However, anti-PD-1 and AMD3100 co-administration synergistically expands infiltrating CTLs, enhances tumor growth control and prolongs survival 80 . Similarly to CXCR4 antagonist, a variety of iSV agents have reported synergistic effects in the context of NK and T cell based ACT 81 - 85 , DC vaccination 86 , 87 and chemotherapy 88 or radiotherapy 89 . Regarding cancer vaccines, CTLA-4 blockade was found to cooperate with cryotreated tumor lysate-pulsed DC vaccine in a primary tumor control to prevent the outgrowth of lung metastasis by reducing levels of Tregs and increasing infiltration of cytotoxic CD8 + lymphocytes inside the metastatic tumor 90 .…”