A Near-Infrared BODIPY-Based Rhomboidal Metallacycle for Imaging-Guided Photothermal Therapy

Round 1

Reviewer 1 Report

 

The manuscript titled ‘A Near-infrared BODIPY-based Rhomboidal Metallacycle for Imaging-guided Photothermal Therapy’ describes BODIPY-based metallacycle/Pluronic F127 nanoparticles, their characterization and biological evaluations for treatment cancer. Photothermal therapy is modern approach utilized electromagnetic radiation for treatment of various medicinal conditions. For this application light wavelength should fall in so-called 'therapeutic window'. Authors synthesized metallacycle with styryl-substituted BODIPY fragment, which could work as antenna in NIR region. Due to hydrophobic character of metallacycle authors encapsulated it in Pluronic F127 nanoparticles (NPs). This NPs were characterized with various methods and were shown to accumulate in cancer cells. Laser irradiation causes death of cells incubated with NPs. Anticancer effect was also demonstrated in in vivo experiments. Overall, this work describes a strategy for the construction of phototherapeutic agents by encapsulation of BODIPY-conjugated metallacycle into nanoparticles. In my opinion, this manuscript is of high novelty and originality, and it could be accepted for publication after some minor revisions.

- Authors should comment the role of metal fragment in metallacycle. Because styryl-substituted BODIPY is responsible for the NIR light absorption, it is interesting to provide control experiments with encapsulated BODIPY dyes 1 or 3 (see SI), if such encapsulation is possible.

- Authors recorded ¹⁹F spectra for intermediate BODIPYs, but not for product M. Why?

- Various BODIPYs are known as singlet oxygen generators. Are the metallacycle M or the prepared NPs capable to generate singlet oxygen or other reactive oxygen species? I thing such measurements should be provided to exclude the role of singlet oxygen in anti-cancer activity.

- Photos on Fig 4d are too small. It is hard to see anything on these pictures.

Author Response

1. Authors should comment the role of metal fragment in metallacycle.Because styryl-substituted BODIPY is responsible for the NIR light absorption, it is interesting to provide control experiments with encapsulated BODIPY dyes 1 or 3 (see SI), if such encapsulation is possible.

Reply: In our work, the metal fragments as building blocks combined with ligands through metal-ligand coordination to generate the metallacycles, which served as the agents for PTT and fluorescent imaging.

We have tried to encapsulate BODIPY 1 with F127, however, it doesn’t work because of the poor solubility of BODIPY 1, which prevents us from obtaining satisfactory nanoparticles.

 

2. Authors recorded¹⁹F spectra for intermediate BODIPYs, but not for product M. Why?

Reply: We have added the ¹⁹F NMR spectra of product M (Figure S16) in the revised supporting information.

 

3. Various BODIPYs are known as singlet oxygen generators. Are the metallacycleM or the prepared NPs capable to generate singlet oxygen or other reactive oxygen species? I think such measurements should be provided to exclude the role of singlet oxygen in anti-cancer activity.

Reply: According to the ESR spectra, metallacycle M is capable to generate singlet oxygen. However, the values of the singlet oxygen yield of metallacycle M (Φ = 0.05) and NPs (Φ = 0.03) were very low when zinc phthalocyanine (Φ = 0.60) is used as a reference. Thus, in our case, PTT played a major role in the tumor treatment process.

 

Figure R1 (a) 2,2,6,6-Tetramethylpiperidine spin-trapping electron spin resonance spectra of 1 and M with and without irradiation. (b) Plot of the normalized absorption intensity of 1,3-diphenylisobenzofuran as a function of irradiation time.

4. Photos on Fig 4d are too small. It is hard to see anything on these pictures.

Reply: We have adjusted the size of Figure 4d.

Author Response File: Author Response.doc

Reviewer 2 Report

Dear Editor

In this paper, authors describe an NIR-based metallacycle constructed by coordination-driven self-assembly using dipyridyl BODIPY land  threne-based diplatinum(II) 2 as the building blocks. Based on a Knoevenagel condensation, a N, N-diethyl-4-aminophenyl group is introduced into the 3,5-positions of the BODIPY cores to obtain BODIPY ligands with strong NIR absorption properties. Due to its NIR emission, the visualization and localization of metallacycle are also investigated. Furthermore, metallacycle is encapsulated in micelles of Pluronic F127 to produce F127/M nanoparticles (NPs), whose photothermal conversion behaviors and fluorescent imaging properties are evaluated both in vitro and in vivo. This paper can be accepted with some addition and corrections. 

1-Quantum yield of compounds should be given in main text. they are not available although it writing "quantum yields were determined on this equipment using an integral sphere at a concentration of 5 µM" in Suppl. info. 

2- The FT-IR of spectra of compounds should be given.

3- The fluorescence spectra of compounds 1,3,4, M should be given in only one graph in Suppl. for comparision. 

4- Some references should be added on Bodipy and applications.

Best Regards

Author Response

1. Quantum yield of compoundsshould be given in main text. they are not available although it writing "quantum yields were determined on this equipment using an integral sphere at a concentration of 5 µM" in Suppl. info.

Reply: We have added fluorescence quantum yield of M in the revised manuscript.

 

2. The FT-IR spectra of compounds should be given.

Reply: As shown in Figure S6, S11 and S18, FT-IR spectra of compounds have been added in the revised manuscript.

 

3. The fluorescence spectra of compounds 1,3, 4, M should be given in only one graph in Suppl. for comparision.

Reply: Fluorescence spectra of compounds 1, 3, 4, M have been given in one graph. As shown in Figure S19, compounds 1, 3, 4, M exhibit emission maxima at 521, 805, 791, and 798 nm, respectively.

 

4. Some references should be added on Bodipy and applications.

Reply: We have added related references (28, 29, 30, 31, 34, 35, 38, 39, 50) about BODIPY and applications in the revised manuscript.

Author Response File: Author Response.doc