1776P - Targeting B7H3 biomimetic nanoparticles for strengthening osteosarcoma photodynamic therapy through aggravating DNA damage

Background

Osteosarcoma is the most common bone tumor, characterized by its extreme heterogeneity. Currently, there is no standard therapy for osteosarcoma, and patients often face a therapeutic deadlock upon developing chemotherapy resistance. Therefore, there is an urgent need to explore effective treatment strategies for osteosarcoma.

Methods

We developed a dual-drug codelivery system based on Metal organic Framework(MOF), scarrying a specific ratio of CDK4/6 inhibitors and PARP inhibitors, and combined it with photodynamic therapy to achieve the maximum synergistic effect. To improve biocompatibility and tumor-specific targeting of MOFs, we coated a layer of macrophage membrane on it. Since osteosarcoma tissue expresses high level of B7H3, a member of the B7 family, we expressed B7H3 antibody on the macrophage membrane using genetic engineering to endow the nanocarrier with tumor-targeting ability.

Results

As expected, we found that the nanoparticles coated B7H3-targeting biological membrane could better accumulate in tumors in vitro and vivo. After co-incubation with glutathione, the nanoparticles were able to degrade and release Meso-tetra (4-carboxyphenyl) porphine (TCPP), followed by the generation of reactive oxygen species upon laser irradiation at a wavelength of 660 nm. By evaluating cell proliferation, DNA damage levels, and apoptosis levels, we observed that the combination of CDK4/6 inhibitors with PARP inhibitors significantly reduces the DNA repair capacity of tumor cells. Additionally, in the presence of ROS, the DNA damage in tumor cells is further magnified, leading to a substantial increase in tumor cell death. The same results were also confirmed in animal experiments. Further findings demonstrated that this treatment regimen led to an elevation in infiltrating immune cell levels within tumors and induced activation of the immune microenvironment, as evidenced by histological sections and multi-color flow cytometry analysis in murine models.

Conclusions

Overall, we developed a targeted co-delivery nanocarrier with excellent anti-tumor efficacy and safety in preclinical models of osteosarcoma.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The author.

Funding

National Natural Science Foundation of China.

Disclosure

The author has declared no conflicts of interest.