Combination of NIR therapy and regulatory T cell modulation using layer-by-layer hybrid nanoparticles for effective cancer photoimmunotherapy

Abstract

The efficacy of combined near-infrared (NIR) and immune therapies for inhibiting tumor growth and recurrence has gained increasing research attention. Regulatory T cells in the tumor microenvironment constitute a major obstacle in achieving robust CD8+ T cell antitumor immunotherapy. In the present study, we designed a photoimmunotherapy-based strategy involving a combination of photothermal and photodynamic therapies, followed by Treg cell suppression, for eliciting an immune response with IR-780- and imatinib-loaded layer-by-layer hybrid nanoparticles.Methods: The layer-by-layer hybrid nanoparticles were prepared through electrostatic interactions. Their photothermal effect, photodynamic effect as well as their effect on inhibiting Treg cells' suppressive function were investigated in vitro and in vivo. Their antitumor effect was evaluated using B16/BL6 and MC-38 tumor-bearing mice.Results: The layer-by-layer hybrid nanoparticles, which were pH-sensitive, enabled the release of IR-780 dye for NIR-induced photothermal and photodynamic effects, and the release of imatinib-loaded glucocorticoid-induced TNF receptor family-related protein/poly(lactic-co-glycolic acid) (GITR-PLGA) nanoparticles to initiate antitumor immunotherapy. The photothermal and photodynamic effects caused by IR-780 under NIR exposure resulted in direct tumor apoptosis/necrosis and the production of tumor-associated antigen, promoted dendritic cell maturation, and enhanced the presentation of tumor-associated antigen to T cells, while the imatinib-loaded GITR-PLGA cores reduced the suppressive function of Treg cells, and consequently activated effective CD8+ T cells towards tumors.Conclusion: With the significant photothermal, photodynamic and immunotherapies, the system successfully eradicated tumor growth, diminished tumor recurrence, and improved survival in vivo. The proposed nanoparticles provide a novel and versatile approach to boost antitumor photoimmunotherapy.

Thirty Years of Cancer Nanomedicine: Success, Frustration, and Hope

“…Similarly, Tregs mediate the immunosuppression by inhibiting the activation and expansion of effector T cells, and their downregulation could be ameliorated by the use of NCs. In particular, Tregs can be actively targeted by using their specific markers, such as glucocorticoid-induced Tumor Necrosis Factor Receptor-related protein (GITR), or neuropilin-1 receptor by binding of tLyp1 peptide [145,146]. However, this therapeutic strategy needs to be further validated because Tregs instability could be associated with the onset of autoimmune disorders [147].…”

Materials for Immunotherapy

“…Liu and co‐workers showed that PLGA nanoparticles encapsulating indocyanine green (ICG, a PTT agent) and imiquimod (an adjuvant) in combination with free anti‐cytotoxic T lymphocyte antigen (CTLA)‐4 (a checkpoint inhibitor) led to potent antitumor responses in mice with 4T1 triple negative breast cancer . In the same year, Kim and co‐workers developed a PLGA nanoparticle encapsulating IR‐780 iodide (an infrared dye) to enable photodynamic therapy (PDT) and antigen formation after tumor localization as well as imatinib (a chemotherapeutic drug for leukemia) to reduce the suppressive function of regulatory T cells . Overall, PLGA nanoparticles engender a range of therapeutic strategies by virtue of their facile incorporation and decoration of drugs, cytokines, antibodies, and other immunomodulatory agents.…”

Advanced biomaterials for cancer immunotherapy

“…In addition, the coadministration of anti-PD-1 peptide (AUNP12) and hollow gold nanoshell coencapsulated PLGA NPs with CpG has been proven to mediate the maturation of DCs in vitro and enable direct tumor necrosis in bilateral and lung metastatic 4T1 tumor-bearing mice [169]. The antibody-modified PLGA core was used to load the hydrophobic drug imatinib (IMT), which was developed as an inhibitor of tyrosine kinase and then manufactured as IR-780 and IMT codelivery PH-sensitive NPs, which showed a great capacity to stimulate an effective CD8 + T-cell antitumor immune response [170].…”