A Versatile Theranostic Platform for Colorectal Cancer Peritoneal Metastases: Real‐Time Tumor‐Tracking and Photothermal‐Enhanced Chemotherapy

Abstract A versatile tumor‐targeting stimuli‐responsive theranostic platform for peritoneal metastases of colorectal cancer is proposed in this work for tumor tracking and photothermal‐enhanced chemotherapy. A quenched photosensitizer (“off” state) is developed and escorted into a tumor‐targeting oxaliplatin‐embedded micelle. Once reaching the tumor cell, the micelle is clasped to release free oxaliplatin, as well as the “off” photosensitizer, which is further activated (“turned‐on”) in the tumor reducing microenvironment to provide optical imaging and photothermal effect. The combined results from hyperthermia‐enhanced chemotherapy, deep penetration, perfused O2, and the leveraged GSH‐ROS imbalance in tumor cells are achieved for improved antitumor efficacy and reduced systematic toxicity.

To be specific, to a solution of DYE (103.8 mg, 0.2 mmol, 1 eq) in anhydrous CH 2 Cl 2 (10 mL) cooled to 0 o C, Et 3 N (24.28 mg, 0.24 mmol, 1.2 eq) was added to the mixture in triple times in 10 min, during when, the temperature of the mixture was strictly maintained at 0 o C.
Then, 2,4-dinitrobenzenesulfonyl chloride (DNS, 63.84 mg, 0.24 mmol, 1.2 eq) dissolved in anhydrous CH 2 Cl 2 (10 mL) was slowly injected into the above solution in 1 h using a microinjection pump. The obtained suspension was maintained at r.t./dark overnight under Ar. Then, CH 2 Cl 2 was removed under vacuum to obtain the crude product, which was further purified by a silica gel column chromatography (DCM:mthanol=20:1, v:v) to afford S-DYE as a purple crystal with a yield of 42.78% and a UPLC-purity as 99.2% (Fig. S1). S-DYE was stored at -20 o C at dark. Rf = 0.4 (DCM:methanol=20:1, v:v). 1   PEG-Pt-PLGA was prepared following the same procedure, except for the replacement of N 3 -PEG-NH 2 to PEG-NH 2 .              Table S1. The found and calculated wavelength of DYE and S-DYE, respectively. Different from traditional "off-to-on" probe, the absorbance of S-DYE doesn't vary much upon the modification, while the emission displays a clear red-shift to silent the probe based on the calculation results.

Theoretical calculation
Calculated absorbance spectrometer of DYE in aqueous solution: Calculated emission spectrometer of DYE in aqueous solution: Calculated absorbance spectrometer of S-DYE in aqueous solution: Calculated emission spectrometer of S-DYE in aqueous solution:             The total energy conversion during the photothermal procedure can be calculated from the below formula:

Reconversion procedures
where m represents the solvent's mass, C p is the specific heat capacity, T is the solution temperature, is the energy generated from the system, is the thermal energy generated from the vial, is the released thermal energy into the air during the heat conduction. Then, where I is the laser power, is the photothermal conversion efficiency, A 680 is the UV-absorbance value at 680 nm, is the dissipative enery from the vial absorbance during the measurement. Notbly, there was nearly no temperature change in the solution without the formulated DYE upon the same laser irradiation, and was ignored.
is was directly proportional to the temperature, H is the efficiency constant of heat transfer, S is the superficial area of the vial, T amb is the environment temperature.
When the system reaches the maximum value, the input heat energy equals to the output energy, Therefore, the photothermal conversion efficiency can be calculated from the below formula: where, was measured to be 0 mW. Based on the heating curve upon laser-irradiation from the results of Fig. S28B, (T max -T amb ) is 4.7 o C, I is 0.3 W/cm 2 , and A 680 is 0.77454. hS was calculated by introduction with θ, with a defination as: The time constant τ s of the sample can be defined as: Which as assigned into formular (1), During the photothermal conversion, and the laser was shot down to result Q CS +Q B = 0, and the formula was simplified to give: which was integrated as: Thus, during the cooling procedure of the sample, the fitting analysis was carried out to give the heat conduction constant τ s as 369.9 s, and m is 1 g, C is 4.2 J/g.
Based on the formular (7), hS is 11.4 mW/°C, which was assigned into formula (5) to give the η value as 21.5 %.