Targeted Single-Walled Carbon Nanotubes for Photothermal Therapy Combined with Immune Checkpoint Inhibition for the Treatment of Metastatic Breast Cancer

Abstract

The greatest contributors to cancer mortality are metastasis and the consequences of its treatment. Here, we present a novel treatment of metastatic breast cancer that combines photothermal therapy with targeted single-walled carbon nanotubes (SWCNTs) and immunostimulation with a checkpoint inhibitor. We find that the selective near-infrared photothermal ablation of primary orthotopic EMT6 breast tumors in syngeneic BALB/cJ mice using an annexin A5 (ANXA5) functionalized SWCNT bioconjugate synergistically enhances an anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4)-dependent abscopal response, resulting in an increased survival (55%) at 100 days after tumor inoculation. In comparison, there was no survival at 100 days for either photothermal therapy by itself or immunostimulation by itself. Prior to photothermal therapy, the SWCNT-ANXA5 bioconjugate was administered systemically at a relatively low dose of 1.2 mg/kg, where it then accumulated in tumor vasculature via ANXA5-dependent binding. During photothermal therapy, the average maximum temperature in the tumor reached 54 °C (duration 175 s). The mechanism of prolonged survival resulting from combinatorial photothermal ablation and immune stimulation was evaluated by flow cytometric quantification of splenic antitumoral immune effector cells and serum cytokine quantification.

Harvesting Light To Produce Heat: Photothermal Nanoparticles for Technological Applications and Biomedical Devices

“… [99] Individual, separated SWCNT fluoresce intensely, but when associated in bundles vibrational relaxation is preferred, [99] with strong enhancement of the photothermal yield. [ 49 , 50 , 51 , 100 ] Prussian blue (PB) is a coordination polymer alternating [Fe(CN) 6 ] 4− centers (Fe in oxidation state II) with Fe 3+ ions octahedrally coordinated by the N atoms of the cyanide ligands. [40] PB NP absorb at ∼700 nm thanks to a charge transfer electronic transition from Fe II to Fe III centers, [101] followed by non‐emissive relaxation.…”

“…Moreover, this review takes into account the wide arsenal of photothermal NP that has recently joined AuNP. As absorption in the NIR remains in most cases a sought after feature, this has lead to the use of NIR‐absorbing and photothermally relaxing NP of materials such as Prussian blue,[ 39 , 40 ] polypyrrole,[ 41 , 42 ] porous silicon,[ 43 , 44 ] carbon (graphene,[ 45 , 46 ] fullerene,[ 47 , 48 ] nanotubes,[ 49 , 50 , 51 ] nanohorns[ 52 , 53 ]), copper sulfide,[ 54 , 55 , 56 ] silver,[ 2 , 7 , 57 , 58 ] iron oxides,[ 59 , 60 ] tungsten oxides,[ 61 , 62 ] molybdenum chalcogenides,[ 59 , 63 , 64 ] titanium oxide,[ 65 , 66 ] p‐block metals chalcogenides[ 67 , 68 ] black phosphorus[ 69 , 70 , 71 ] and NIR‐absorbing molecular dyes. [72] In the last case, a supramolecular approach is often designed, in which indocyanine green (IDG),[ 73 , 74 , 75 ] zinc phthalocyanine[ 76 , 77 ] or multiple dyes[ 78 , 79 , ...…”

“…As absorption in the NIR remains in most cases a sought after feature, this has lead to the use of NIR-absorbing and photothermally relaxing NP of materials such as Prussian blue, [39,40] polypyrrole, [41,42] porous silicon, [43,44] carbon (graphene, [45,46] fullerene, [47,48] nanotubes, [49][50][51] nanohorns [52,53] ), copper sulfide, [54][55][56] silver, [2,7,57,58] iron oxides, [59,60] tungsten oxides, [61,62] molybdenum chalcogenides, [59,63,64] titanium oxide, [65,66] p-block metals chalcogenides [67,68] black phosphorus [69][70][71] and NIRabsorbing molecular dyes. [72] In the last case, a supramolecular approach is often designed, in which indocyanine green (IDG), [73][74][75] zinc phthalocyanine [76,77] or multiple dyes [78][79][80] are included in NP of non absorbing materials (e. g., silica, organic polymers), this preserving their photostabi...…”

Cancer Targeting and Diagnosis: Recent Trends with Carbon Nanotubes

“…Also, even at a lower concentration of 0.32 nm, the developed nano-hybrid showed enhanced photothermal efficiency in killing cancer cells. In another study, McKernan et al developed a SWCNT-based new strategy for the treatment of metastatic breast cancer cells by combining the effects of PTT and immunostimulation using annexin A5 (ANXA5)-conjugated SWCNTs and an anti-CTLA-4 check point inhibitor [86]. ANXA5 acts as a tumor-targeting protein and reduces the amount of SWCNTs required to eradicate the primary tumor.…”

“…SWNTs produced by the CoMoCAT ® method are known to be highly enriched with nanotube chirality and exhibit an absorption band at 980 nm. Its photothermal activity has also been widely used for selective phototissue interaction [86,88]. Zhou et al conjugated the CoMoCAT ® -SWCNTs with folate, which can effectively bind to the folate receptor present on the tumor's surface [89].…”