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Page 8 of 17 Sun et al. Chem Synth 2023;3:16 https://dx.doi.org/10.20517/cs.2022.45

PHOTOTHERMAL AGENTS
The efficient distribution of photothermal agents to tumor issues is important for photothermal therapy. In
many reported cases, the photothermal agents accumulated at tumor sites via the enhanced permeability
and retention effect [55,56] . It has been demonstrated that nanomaterials with relatively large sizes, 200 nm,
have higher efficiency of accumulation at tumor sites [57,58] . However, due to the high interstitial fluid
pressure and dense extracellular matrix, it is difficult for large nanospecies to penetrate deeply into tumor
[59]
tissues . Given the contradictory size requirements between tumor accumulation and penetration, tumor
environment stimulated size switch of photothermal agents, undoubtedly, will be a reasonable solution to
facilitate both cases and, further, the performance of photothermal therapy.

Our group reported host-guest assemblies with polyethylene glycol-modified aniline tetramer (TAPEG) and
[60]
WP5 [Figure 4A] . At pH 7.4, it was demonstrated that the WP5⊃TAPEG formed core-shell architecture
with an average size of 200 nm through multi-micelle aggregation mechanism. However, at pH 4.5, due to
the proton doping of TAPEG, the hydrophobicity of the WP5⊃TAPEG was decreased and the intermicelle
aggregation was interrupted. As a result of the acidic condition, micelles with an average diameter of 20 nm
were observed. The tumor pH-induced size switch behavior of WP5⊃TAPEG-based host-guest assemblies
perfectly promoted the high accumulation and deep penetration at tumor sites, which further resulted in
improved photothermal tumor therapy.

Wang et al. reported another size switch related photothermal therapy utilizing host-guest interaction
[Figure 4B] . They elaborately prepared -cyclodextrin-capped CuS NPs (CD-CuS) and ferrocene-capped
[61]
CuS NPs (Fc-CuS). When phagocytosed by macrophages, the CD-CuS and Fc-CuS formed large
supramolecular assemblies through the host-guest interaction between CD and Fc. Upon entry into the
tumor environment, the higher amount of hydrogen peroxide led to the oxidation of Fc. As a result of the
Fc oxidation-induced disassociation of the host-guest interaction between CD and Fc, the large
supramolecular aggregates were switched to individual small nanoparticles. The size switch system, on the
one hand, efficiently hindered their efflux from the macrophages, thereby leading to the desired
accumulation at tumor sites. On the other hand, it promoted the deep penetration of the CuS-based
photothermal agents through tumor sites. Both in vitro and in vivo experiments verified the improved
photothermal therapy of the host-guest interaction-manipulated size switch system.

From the abovementioned examples, it is obvious that a tumor microenvironment-triggered size switch
system is advantageous for photothermal cancer therapy. To design photothermal agents with size
switchable features, the on/off interaction, i.e., stimuli-responsive interaction, among small-sized
photothermal species is an important factor that needs to be considered. Given that host-guest assemblies
are featured with stimuli-responsive performance, they are regarded as excellent candidates for the
construction of size switch photothermal systems under tumor microenvironment (e.g., low pH,
concentrated GSH, high amount of H O ).
2
2
HOST-GUEST INTERACTION-ACTUATED PHOTOTHERMAL THERAPY-DERIVED
SYNERGISTIC THERAPY
Synergistic therapy is emerging as a popular direction for the improvement of cancer therapy [62,63] . To
further optimize the photothermal curative efficacy, the construction of photothermal-based synergistic
therapy (i.e., chemo-photothermal therapy, photodynamic-photothermal therapy, immunotherapy-
photothermal therapy) is considered as an alternative strategy. This section discusses the superiority of host-
guest assemblies from the perspective of synergistic therapy.