Moderating hypoxia and promoting immunogenic photodynamic therapy by HER-2 nanobody conjugate nanoparticles for ovarian cancer treatment

Abstract

Photodynamic therapy (PDT) and immunotherapy have been often adopted for ovarian cancer therapy, yet their application is limited by the high recurrence rate and toxic side effects. Intriguingly, nanoparticles contribute to enhancing the performance of PDT. Here, we investigated the synthesis of HER-2-Nanobody (Nb)-conjugated human serum albumin (HSA) incorporated with chlorin (Ce6) and catalase (CAT) (Nb@HCC), and analyzed the synergic effect of Nb@HCC-mediated PDT and immunotherapy for SK-OV-3 tumors. The Ce6 and CAT were incorporated into HSA to construct the HCC nanoparticles. HER-2-Nanobody was the purified bacterial crude extract, and conjugated with HCC to prepare Nb@HCC via heterodisulfide. The effects of Nb@HCC with near infrared ray (NIR) irradiation on moderating hypoxia and hypoxia inducible factor-1α (HIF-1α) expression were evaluated in the SK-OV-3 cells and tumor tissues. A SK-OV-3 tumor-bearing model was developed, where the synergistic effect of Nb@HCC-mediated PDT and anti-CTLA-4 therapy was investigated. Nb@HCC with a 660 nm laser irradiation could induce massive reactive oxygen species and trigger apoptosis in SK-OV-3 cells. Nb@HCC and PDT promoted danger-associated molecular patterns (DAMPs), which indicated immunogenic cell death and maturation of dendritic cells in the SK-OV-3 cells. Irradiated by NIR, Nb@HCC alleviated the hypoxia and decreased the expression of HIF-1α. The Nb@HCC-mediated PDT and anti-CTLA-4 therapy synergically inhibited the progression of distant tumor, and induced T cell infiltration. Biosafety tests suggested that Nb@HCC would not cause damage to the major organs with less toxicity and side effects. To conclude, a combination of Nb@HCC-mediated PDT and anti-CTLA-4 therapy could inhibit the progression of distant tumor to attain remarkable therapeutic outcomes.

Preparation of a Nanobody Specific to Dectin 1 and Its Anti-inflammatory Effects on Fungal Keratitis

“…35 Because they possess many desirable attributes, such as small molecules, low immunogenicity, strong penetration, and high binding affinity, different types nanobodies have become novel diagnosis and treatment methods for tumors and infectious diseases. [36][37][38] We constructed a nanobody specific to dectin 1, which is an important PRR in fungal infection. We also verified that this nanobody can bind to the dectin 1 antigen and relieve the inflammatory response in fungal keratitis.…”

Roles of reactive oxygen species in inflammation and cancer

“…Studies have proved that ROS plays essential role in the response of ICB. In ovarian cancer, a novel synthesis stimulating ROS production has exhibited synergistic effects with anti‐CTLA‐4 therapy, effectively impeding tumor metastasis progression and promoting the infiltration of T cells 257 . Furthermore, heightened levels of ROS and oxidative stress within the TME have been associated with intensified immunosuppression mediated by Tregs.…”

“…In ovarian cancer, a novel synthesis stimulating ROS production has exhibited synergistic effects with anti‐CTLA‐4 therapy, effectively impeding tumor metastasis progression and promoting the infiltration of T cells. 257 Furthermore, heightened levels of ROS and oxidative stress within the TME have been associated with intensified immunosuppression mediated by Tregs. Apoptotic Tregs have demonstrated greater efficacy in suppressing T cell activation and have been implicated in undermining the therapeutic efficacy of PD‐L1 blockade in mouse models bearing tumors.…”

Single-domain antibodies as therapeutics for solid tumor treatment

“…developed an albumin-based NP by decorating the HSA with an anti-HER2 sdAb. Besides, Chlorin (Ce6) and catalase (CAT) were encapsulated to the HSA for PDT of ovarian cancer 132 . The generated complex has demonstrated synergistic effect with anti-CTLA-4 therapy to inhibit the progression of distant tumors and induce T cell infiltration in SK-OV-3 cells and SK-OV-3 tumor-bearing mouse model 132 .…”