Cancer photoimmunotherapy by layer-by-layer hybrid nanoparticles to combine NIR therapy and regulatory T cell modulation.

Pham Le Minh¹, Wenquan Ou¹, Srijan Maharjan¹, Kishwor Poudel¹, Chul Soon Yong¹, Jong Oh Kim¹

¹College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea

Corresponding authors: csyong@ynu.ac.kr, jongohkim@yu.ac.kr

ABSTRACT

Background: 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.

Objective: In the present study, we have designed a strategy based on photoimmunotherapy that involves a combination of photothermal and photodynamic therapies, followed by suppression of Treg cells, for eliciting an immune response with IR-780- and imatinib-loaded layer-by-layer hybrid nanoparticles.

Materials and Methods: The layer-by-layer hybrid nanoparticles were prepared through electrostatic interactions. Thermal effects, photodynamic effects as well as inhibitory effects of inhibitory function of Treg cells have been studied in vitro and in vivo. Their anti-cancer effects were assessed using mice with tumor B16 /BL6 and MC-38.

Results: The layer-by-layer and pH-sensitive hybrid nanoparticles, have allowed the release of dyes IR-780 for photodynamic and photothermal effects induced by NIR. 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 when exposed to NIR lead to apoptosis / tumor necrosis directly and the production of tumor-related antigens promoted dendritic cell maturation and enhanced the presence of tumor-related antigens 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 significant photothermal, photodynamic and immunotherapies, the system successfully eliminated tumor growth, reduced tumor recurrence and improved survival in vivo.

Keywords: imatinib, immunotherapy, IR-780, layer by layer, photodynamic therapy, photothermal therapy, Treg cell.