Easy but Efficient: Facile Approach to Molecule with Theoretically Justified Donor–Acceptor Structure for Effective Photothermal Conversion and Intravenous Photothermal Therapy

Abstract To accelerate the pace in the field of photothermal therapy (PTT), it is urged to develop easily accessible photothermal agents (PTAs) showing high photothermal conversion efficiency (PCE). As a proof‐of‐concept, hereby a conventional strategy is presented to prepare donor–acceptor (D–A) structured PTAs through cycloaddition‐retroelectrocyclization (CA–RE) reaction, and the resultant PTAs give high PCE upon near‐infrared (NIR) irradiation. By joint experimental‐theoretical study, these PTAs exhibit prominent D–A structure with strong intramolecular charge transfer (ICT) characteristics and significantly twisting between D and A units which account for the high PCEs. Among them, the DMA‐TCNQ exhibits the strongest absorption in NIR range as well as the highest PCE of 91.3% upon irradiation by 760‐nm LED lamp (1.2 W cm−2). In vitro and in vivo experimental results revealed that DMA‐TCNQ exhibits low dark toxicity and high phototoxicity after IR irradiation along with nude mice tumor inhibition up to 81.0% through intravenous therapy. The findings demonstrate CA–RE reaction as a convenient approach to obtain twisted D–A structured PTAs for effective PTT and probably promote the progress of cancer therapies.


Table of contents
General procedure

Materials and characterization
The starting materials, reagents, and solvents were procured from commercial sources (J&K, Zhengzhou Alfa, and Acros) and were used as received without any further purification.Solution 1 H NMR spectra were acquired using a 400 MHz Bruker Quadrupole Mass Spectrometer (Thermo Fisher).The transmission electron microscope (TEM) images were collected by Hitachi HT7700.

Computational details
S1] The PBE0-D3 functional coupled with a 6-311g(d) basis set was utilized for optimizing the geometric structures.S2-S4] Vibrational frequencies at the optimized structures were also calculated using the same DFT method to verify that the optimized structure represented the local minimal on the S0 energy surface.The excited state electronic properties of D-A structured molecules were performed using TD-DFT with PBE0-D3 functional coupled with a 6-311g(d) basis set was utilized.S5] The radiative decay rate (kp = E 2 f/1.499 s -1 ) was evaluated employing the Einstein spontaneous emission relationship, where  represents the vertical excitation energy, f denotes the oscillator strength.S6] Experimental procedures Scheme S1.Synthetic scheme for D-A structured molecules.
superconducting magnet high-field Nuclear Magnetic Resonance (NMR) spectrometer at 298.15 K, with tetramethylsilane (TMS) serving as the internal standard.UV-Vis-NIR spectra were recorded using a UV-Visible Near Infra-Red Spectrophotometer with Integrating Sphere (Shimazu 3600 plus).The temperature change was monitored in real-time using an IR thermal camera (Thermo X, Shanghai Magnity Technologies Electronics Co. Ltd.).Dynamic light scattering (DLS) particle size analysis were performed using a Nanosight NS300HSBF instrument.The small animal phototherapy irradiator used was PR-LED5-760nm (Shenzhen Puri Materials Technologies, Co., Ltd.).For experimental animal studies, individually ventilated cages were utilized (Techniplast/IVC SealsafeTM, Italy).The vernier caliper employed was DigitalCalipers 111-101-40 (Guilin Guanglu Measuring Instrument Co., Ltd.).The fluorescence spectra were measured using HORIBA Scientific Fluorolog-3 at room temperature.The mass spectra (ESI-MS) were collected by TSQ Endura Triple

Figure S1 .
Figure S1.The 1 H NMR spectrum of compound 1-Me in CDCl3

Figure S3 .
Figure S3.The 1 H NMR spectrum of compound 2-Me in CDCl3

Figure S4 .
Figure S4.The 1 H NMR spectrum of compound 2-Ph in CDCl3

Figure S21 .Figure S22 .
Figure S21.Hemolysis assays of DMA-TCNQ.(a) OD value of different groups (Inset: A photograph was taken after 24-hour incubation with DMA-TCNQ) (b) Hemolysis rate of various concentrations was calculated.

Figure S23 .Figure S24 .
Figure S23.Infrared photographs of mice in the light group before and after individual treatments at day 8.

Table S7 .
The calculation table of PCE with detailed parameters.

Table S1 .
The optimized atomic coordinates and HOMO-LUMO orbital composition of DMA-TCNE in ground state.a a The composition analysis based on Hirshfeld method.

Table S2 .
The optimized atomic coordinates and HOMO-LUMO orbital composition of DPA-TCNE in ground state.a a The composition analysis based on Hirshfeld method.

Table S3 .
The optimized atomic coordinates and HOMO-LUMO orbital composition of DMA-TCNQ in ground state.a The composition analysis based on Hirshfeld method. a

Table S4 .
The optimized atomic coordinates and HOMO-LUMO orbital composition of DPA-TCNQ in ground state.a a The composition analysis based on Hirshfeld method.

Table S5 .
The fraction of electron, hole, overlap, and difference of D-A structured molecules in excited state.

Table S6 .
The hole-electron index of D-A structured molecules in excited state.

Table S7 .
The calculation table of PCE with detailed parameters.

Table S8 .
The photothermal conversion efficiency (PCE) of small-molecular organic PTAs in the reported literatures.