Indocyanine green and poly I:C containing\xa0thermo-responsive liposomes used in immune-photothermal therapy prevent cancer growth and metastasis

Li Xu,Hae-Bin Park,Peter C W Lee,Wei Zhang,Junghwan Oh,Jun-O Jin,Minseok Kwak

doi:10.1186/s40425-019-0702-1

Abstract

BackgroundEfficient cancer therapy is sought not only for primary tumor treatment but also for the prevention of metastatic cancer growth. Immunotherapy has been shown to prevent cancer metastasis by inducing antigen-specific immune responses. Indocyanine green (ICG) has a peak spectral absorption at about 800 nm, which makes it a photothermal reagent for direct treatment of solid tumors by photothermal therapy (PTT). Since PTT alone cannot fully induce antigen-specific immune response for prevention of cancer metastasis, the combination of PTT and immunotherapy has been developed as a new strategy of cancer treatment.MethodsThermal responsive liposomes (TRL) were synthesized by incorporating ICG into the lipid bilayer and encapsulating the water-soluble immune stimulatory molecule polyinosinic:polycytidylic acid (poly I:C) in the hydrophilic core. The poly I:C- and ICG-containing TRLs (piTRLs) were analyzed according to size, and their photothermal effect was evaluated following laser irradiation at 808 nm. Moreover, the temperature-dependent release of poly I:C was also measured. For cancer therapy, CT-26 (carcinoma) and B16 (melanoma) cells were subcutaneously inoculated to build the 1st transplanted tumor in BALB/c and C57BL/6 mice, respectively. These mice received a 2nd transplantation with the same cancer cells by intravenous inoculation, for evaluation of the anti-metastatic effects of the liposomes after PTT.ResultsNear-infrared (NIR) laser irradiation increased the temperature of piTRLs and effectively released poly I:C from the liposomes. The increased temperature induced a photothermal effect, which promoted cancer cell apoptosis and dissolution of the 1st transplanted tumor. Moreover, the released poly I:C from the piTRL induced activation of dendritic cells (DCs) in tumor draining lymph node (tdLN). Cancer cell apoptosis and DC-activation-mediated cancer antigen-specific immune responses further prevented growth of lung metastatic cancer developed following intravenous transplantation of cancer cells.ConclusionThese results demonstrated the potential usage of a piTRL with laser irradiation for immuno-photothermal therapy against various types of cancer and their metastases.

Highlights

Efficient cancer therapy is sought for primary tumor treatment and for the prevention of metastatic cancer growth
For evaluation of the photothermal efficiency of poly I:C- and ICG-containing TRLs (piTRLs), we measured the changes in temperature under laser irradiation (1 W/cm2) at 808 nm for 5 min and found that the piTRLs showed greater temperature increases in a dose-dependent manner when compared to phosphate-buffered saline (PBS)
While the iTRL treatment with laser irradiation successfully cured the1st transplanted tumors in our study, it could not inhibit growth of the 2nd transplanted cancer growth in BALB/c and C57BL/6 mice. This failure of iTRL to provide protection against the2nd transplanted cancer may be due to less immune activation by apoptosis-generated molecules [36,37,38,39], as we have shown that iTRL treatment with laser irradiation did not promote dendritic cell (DC) activation in tumor draining lymph node (tdLN) and specific killing of cancer Ag-coated splenocytes

Summary

Introduction

Efficient cancer therapy is sought for primary tumor treatment and for the prevention of metastatic cancer growth. Immunotherapy has been shown to prevent cancer metastasis by inducing antigenspecific immune responses. Indocyanine green (ICG) has a peak spectral absorption at about 800 nm, which makes it a photothermal reagent for direct treatment of solid tumors by photothermal therapy (PTT). Since PTT alone cannot fully induce antigen-specific immune response for prevention of cancer metastasis, the combination of PTT and immunotherapy has been developed as a new strategy of cancer treatment. Photothermal therapy (PTT) has been developed as an alternative treatment strategy for tumors. This technique that uses heat-generated thermal energy to kill tumor cells by nanoparticles absorbing near-infrared (NIR) light [1,2,3,4]. ICG has been approved as a NIR clinical imaging agent by the Food and Drug Administration (FDA) in the USA due to low incidence rates of adverse reactions [12, 13]

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Conclusion