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Anti-TNFR2 Antibody-Conjugated PLGA Nanoparticles for Targeted Delivery of Adriamycin in Mouse Colon Cancer
Ping Li1,2, Yang Yang1, Yifei Wang1
1Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macau, China.
Abstract:
High levels of tumor necrosis factor receptor type II (TNFR2) are preferentially expressed by immunosuppressive CD4+Foxp3+ regulatory T cells (Tregs), especially those present in the tumor microenvironment, as initially reported by us. There is compelling evidence that targeting TNFR2 markedly enhances antitumor immune responses. Furthermore, a broad spectrum of human cancers also expresses TNFR2, while its expression by normal tissue is very limited. We thus hypothesized that TNFR2 may be harnessed for tumor-targeted delivery of chemotherapeutic agents. In this study, we performed a proof-of-concept study by constructing a TNFR2-targeted PEGylated poly(dl-lactic-co-glycolic acid) (PLGA-PEG) nanodrug delivery system [designated as TNFR2-PLGA-ADR (Adriamycin)]. The results of in vitro study showed that this TNFR2-targeted delivery system had the properties in cellular binding and cytotoxicity toward mouse colon cancer cells. Further, upon intravenous injection, TNFR2-PLGA-ADR could efficiently accumulate in MC38 and CT26 mouse colon tumor tissues and preferentially bind with tumor-infiltrating Tregs. Compared with ADR and ISO-PLGA-ADR, the in vivo antitumor effect of TNFR2-PLGA-ADR was markedly enhanced, which was associated with a decrease of TNFR2+ Tregs and an increase of IFNγ+CD8+ cytotoxic T lymphocytes in the tumor tissue. Therefore, our results clearly show that targeting TNFR2 is a promising strategy for designing tumor-specific chemoimmunotherapeutic agent delivery system.
Insights
Targeting tumor necrosis factor receptor type II (TNFR2) with a novel nanodrug delivery system enhances antitumor immunity. This TNFR2-targeted approach reduces immunosuppressive cells and boosts cytotoxic T lymphocytes in tumors.
Area of Science:
- Immunology
- Nanotechnology
- Oncology
Background:
- Tumor necrosis factor receptor type II (TNFR2) is highly expressed on immunosuppressive regulatory T cells (Tregs) within the tumor microenvironment.
- Targeting TNFR2 shows potential for enhancing antitumor immune responses.
- TNFR2 is broadly expressed in human cancers with limited normal tissue expression, suggesting its utility for tumor-specific delivery.
Purpose of the Study:
- To develop and evaluate a TNFR2-targeted nanodrug delivery system for chemotherapeutic agents.
- To assess the efficacy of this system in vitro and in vivo for colon cancer treatment.
Main Methods:
- Construction of a TNFR2-targeted PEGylated poly(dl-lactic-co-glycolic acid) (PLGA-PEG) nanodrug delivery system loaded with Adriamycin (ADR), designated TNFR2-PLGA-ADR.
- In vitro evaluation of cellular binding and cytotoxicity against mouse colon cancer cells.
- In vivo assessment of tumor accumulation, Treg binding, and antitumor effects in mouse colon tumor models (MC38 and CT26).
Main Results:
- The TNFR2-PLGA-ADR system demonstrated effective cellular binding and cytotoxicity in vitro.
- In vivo studies showed efficient tumor accumulation and preferential binding to tumor-infiltrating Tregs.
- TNFR2-PLGA-ADR exhibited enhanced antitumor effects compared to untargeted ADR and ISO-PLGA-ADR, correlating with reduced TNFR2+ Tregs and increased IFNγ+CD8+ cytotoxic T lymphocytes.
Conclusions:
- Targeting TNFR2 represents a promising strategy for developing tumor-specific chemoimmunotherapeutic delivery systems.
- The developed TNFR2-targeted nanodrug system effectively delivers chemotherapeutics and modulates the tumor immune microenvironment.
- This approach holds potential for improving cancer treatment by enhancing antitumor immunity.
