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Cabazitaxel-Loaded Nanoparticles Reduce the Invasiveness in Metastatic Prostate Cancer Cells: Beyond the Classical Taxane Function

Pharmaceutics 2023, 15(2), 662; https://doi.org/10.3390/pharmaceutics15020662

by Jana B. Lampe¹, Priyanka P. Desai¹, Amit K. Tripathi¹

, Nirupama A. Sabnis¹, Zhe Chen²

, Amalendu P. Ranjan¹ and Jamboor K. Vishwanatha^1,*

Reviewer 1:

Mahesh Gokara

Reviewer 2:

Zhengwei Huang

Reviewer 3: Anonymous

Reviewer 4:

Farid Menaa

Pharmaceutics 2023, 15(2), 662; https://doi.org/10.3390/pharmaceutics15020662

Submission received: 19 December 2022 / Revised: 9 February 2023 / Accepted: 9 February 2023 / Published: 16 February 2023

Round 1

Reviewer 1 Report

Thank you for submitting your manuscript titled "Beyond the Classical Taxane Function: Cabazitaxel-Loaded Nanoparticles in Prostate Cancer Cells" to our journal. We have carefully reviewed your submission and believe that it has the potential to make a significant contribution to the field.

Overall, we were impressed with the quality of the work and the thoroughness of the research. However, we did identify a few areas where the English language could be refined to enhance the overall clarity and readability of the manuscript.

Other than these minor language adjustments, we do not require any further revisions to the manuscript and believe it is ready for acceptance. Please take the time to carefully proofread and refine the English language in the manuscript and resubmit it as a revised version.

Thank you again for choosing to submit your work to our journal. We look forward to the opportunity to review the revised manuscript.

Sincerely,

Author Response

Comments and Suggestions for Authors

Thank you again for choosing to submit your work to our journal. We look forward to the opportunity to review the revised manuscript.

Sincerely,

Authors’ response: We thank the reviewer for pointing out the changes that need attention. Please find the changes to my citations below:

We have made changes in Line 20: “3” removed from the word “changes.”

We have made changes in Line 22: Comma added after 416.

We have made changes in Line 24: The phrase “expression of” was removed for clarity.

We have made changes in Line 33: Comma added after “diagnosed.”

We have made changes in Line 41/42: “bone-metastasis” changed to “bone metastasis.”

We have made changes in Line 102: “ a broad” was changed to “an overall.”

We have made changes in Line 117: Comma added after “(Monmouth Junction, NJ, US).”

We have made changes in Line 126: The phrase “left to stir” was changed to “stirred.)

We have made changes in Line 217: The hyphen was removed from “dose-curves.”

We have made changes in Line 218: The phrase “96-well-plates” was changed to “96-well plates.”

We have made changes in Lines 223-224: The position of the comma was moved “(WST-8/CCK-8), (Abcam, Waltham, MA, US)” to “(WST-8/CCK-8) (Abcam, Waltham, MA, US), which.”

We have made changes in Line 229: A hyphen was added “wound-healing assay.”

We have made changes in Line 249: “5 × 104 PC3” was changed to “5 × 10⁴PC3.”

We have made changes in Line 285: The word “Then” was changed to Subsequently.”

We have made changes in Line 293: Two sentences were combined – “times. And” was changed to times, incubated for …”

We have made changes in Line 311: the word “and” was added.

We have made changes in Line 350 – 351: An @ symbol was changed to a plus/minus symbol in four places.

We have made changes in Line 326: The words “stability of the” were omitted and the word “was,” was changed to “were.” Also, an extra space was omitted between sentences.

We have made changes in Line 362: Figure 3 readjusted.

We have made changes in Line 373: A comma was added between “T CBZ NP” and “10.52 nM.”

We have made changes in Line 399: An “s” was added to the word “figure.”

We have made changes in Line 401: A comma was added after “(UNT).”

We have made changes in Line 436: The words “found to be lower” were changed to “were considerably lower.”

We have made changes in Line 486: The phrase “in the literature about the ZP values that represent…” was changed to “ in the literature about which values represent…”

We have made changes in Line 525: A capital letter was changed to a lower-case letter for “slug, snail, and vimentin.”

Reviewer 2 Report

Jana B. Lampe et al. reported a cabazitaxel-loaded modified PLGA nanosystems for prostate cancer therapy. It was shown that invasion, migration and EMT of prostate cancer cells could be inhibited by the proposed nanosystem. The manuscript was to some degree well organized and written. The reviewer believed that it fell within the scope of Pharmaceutics. However, there were still some issues pending addressed before a second consideration of this work. A Major Revision was mandatory. Detailed comments:

Q1: There were 8 keywords. Maybe some peripheral ones could be removed, since ≤ 6 keywords were common in published works.

Q2: The reviewer appreciated the authors’ design for bone-targeting. However, as prostate region was the major lesion site of PCa, why did not the authors try a prostate-targeting? Besides, why did the authors only pick up metastasis in bone? And, the function of PLGA was not demonstrated in the Introduction Section. Please clearly state the related principles in the Introduction Section.

Q3: It was suggested to show the schematic and chemical structure of the final synthesized products.

Q4: Please double-check the parameters in the Methods Section. For example, Line 176, 1,400 ‘L’ of PBS, are you sure of the volume?

Q5: Figure 2 should be enlarged to make it clearer.

Q6: Line 326-328: Please unify the significant digits of DL and EE values.

Q7: Figure 3: Please ensure that SD bars were included in the right panel. In addition, there might be a redundant ‘330’ at the bottom.

Q8: Please make sure that the wound lines were marked correctly in Figure 4A. Seemingly, some lines were not in consistent with the wound edges.

Q9: It was to provide a quantitative result for the WB blots.

Q10: It was encouraging that CBZ-loaded nanoparticles could exert significant tumor inhibitory effects. If the authors could perform some experiments like fluorescence staining and WB to analyze the tumor-killing mechanisms of the nanosystem (apoptosis, necrosis, etc.), the logic would be perfected.

Q11: Please carefully check the data of mRNA expression in Figure 5-8. The deviation of some bars was too great, which impacted the credibility.

Q12: The significant digits of values in Supplementary Table S1 should be reconsidered. For instance, was the value of 0.0000001 nm meaningful? Also, the reviewer suggested to merge all supplementary into one single file.

Q13: A minor advice: As an Original Article, up to 90 references might be too many. If possible, some less important citations could be reduced.

Author Response

Comments and Suggestions for Authors

Authors’ response: We thank the reviewer for pointing out the changes that need attention. Please find the changes to my citations below:

Q1: There were 8 keywords. Maybe some peripheral ones could be removed, since ≤ 6 keywords were common in published works. The authors removed Invasion and Migration removed in line 28.

Q2: The reviewer appreciated the authors’ design for bone- targeting. However, as prostate region was the major lesion site of PCa, why did not the authors try a prostate-targeting? Besides, why did the authors only pick up metastasis in bone? And, the function of PLGA was not demonstrated in the Introduction Section. Please clearly state the related principles in the Introduction Section.

The authors have chosen to target bone rather than the prostate because it represents a greater medical need. Because the 5-year overall survival rate for patients whose cancer is treated in the early stages is about 100%, the prostate itself is not the ideal target. In 90% of advanced PCa, bone is the primary site of metastasis, therefore, we chose this strategy.

Our lab expertise is in bone-targeting and has been shown to effectively target bone in vivo. See the references below.

S. Gdowski, A. Ranjan, M.R. Sarker, J.K. Vishwanatha, Bone-targeted cabazitaxel nanoparticles for metastatic prostate cancer skeletal lesions and pain, Nanomedicine (London, England) 12(17) (2017) 2083-2095.
I. Thamake, S.L. Raut, Z. Gryczynski, A.P. Ranjan, J.K. Vishwanatha, Alendronate coated poly-lactic-co-glycolic acid (PLGA) nanoparticles for active targeting of metastatic breast cancer, Biomaterials 33(29) (2012) 7164-73.

The authors have inserted the following paragraph pertaining to the role of PLGA at line 85-89:

The function of PLGA is to act as a drug delivery vehicle for the CBZ. PLGA is a hydrolyzable, biodegradable polymer that provides slow release of the drug over time. These characteristics enable improved pharmacokinetics because the drugs are prevented from interacting with the biological fluids in the body, and in turn prolong the half-life of their cargo.

Also, chemotherapeutic drugs, such as cabazitaxel, have low solubility rates due to their hydrophobic nature. Nanoparticles provide a more effective means of transport for these drugs.

Kucuksayan, F. Bozkurt, M.T. Yilmaz, A. Sircan-Kucuksayan, A. Hanikoglu, T. Ozben, A new combination strategy to enhance apoptosis in cancer cells by using nanoparticles as biocompatible drug delivery carriers, Scientific Reports 11(1) (2021) 13027, DOI: 10.1038/s41598-021-92447-x.

Q3: It was suggested to show the schematic and chemical
structure of the final synthesized products.

The authors have moved Fig. S1. To Main Fig. 1: Schematic of Nanoparticles. Nanoparticles were prepared using an Emulsion-Diffusion-Evaporation Technique. Images created using BioRender.com and ChemDraw.

The authors have also added a caption to Lines 159-167:

Figure 1. (A) Schematic representing the Emulsion-Diffusion-Evaporation Technique for preparing drug-loaded NPs. Schematic created using Biorender.com and ChemDraw. (B) Conjugation of Alendronate to the BS3 Crosslinker confers bone-targeting to the drug-loaded nanoparticle. (1) The nitrogen of the 1° amine on the alendronate performs a nucleophilic attack on the carbonyl of the sulfo-NHS ester on the BS3 linker. A proton is taken by a basic species in solution to leave the intermediate alkoxide. Which in (2), reforms the carbonyl, displacing the hydroxysulfo-NHS leaving group to complete the amide formation. Image created with ChemDraw.

Q4: Please double-check the parameters in the Methods Section. For example, Line 176, 1,400 ‘L’ of PBS, are you sure of the volume? The authors have corrected line 176: “1,400 L” was changed to 14 L.”

Q6: Line 326-328: Please unify the significant digits of DL and EE values.

The abbreviation “(EE)” was added and the drug loading of “12.195%” was changed to “12.2%.”

Q7: Figure 3: Please ensure that SD bars were included in the right panel. In addition, there might be a redundant ‘330’ at the bottom.

The authors have found that the error bars on the 72-h graph are so small they are not visible, but they are there. The 330 was the line number.

Q8: Please make sure that the wound lines were marked correctly in Figure 4A. Seemingly, some lines were not in consistent with the wound edges.

The authors have corrected the wound lines.

Q9: It was to provide a quantitative result for the WB blots.

The authors have added quantification graphs to figure 7.

We appreciate the reviewer’s suggestions. We performed the Western Blot experiment with different apoptosis markers such as BID, BCl-2, Cytochrome-c, PUMA, cleaved and total Caspase-3, cleaved and total PARP. We found increases in cleaved caspase-3 and PUMA. At the 2.5 nM concentration, we did not see any significant apoptotic mechanism for the other apoptotic proteins in the cells treated with NT and T CBZ NPs. This suggests that CBZ-loaded NPs inhibit EMT markers, migration, and invasion predominantly. (See Supplementary figure 3.) However, it is possible that these markers would be more intensified after drug-loaded NPs at a higher concentration. (Figure S4)

The authors referred to this in Lines 609-611:

Additionally, our CBZ-loaded NT and T NPs have shown effective apoptosis in PCe prostate cancer cells via increased expression of PUMA and by activating and cleaving Caspase-3 (Supplementary Figure 4).

Natsagdorj, A, Izumi, K, Hiratsuka, K, et al. CCL2 induces resistance to the antiproliferative effect of cabazitaxel in prostate cancer cells. Cancer Sci. 2019; 110: 279– 288. https://doi.org/10.1111/cas.13876

Q11: Please carefully check the data of mRNA expression in Figure 5-8. The deviation of some bars was too great, which impacted the credibility.

The authors have checked the coefficient of variance (CV%) for each separate “n” and have found that they fall within the accepted parameters found in the literature. The higher standard deviations can be attributed to the variation resulting from various passage numbers of the samples. We have included references concerning the acceptable CV% ranges.

https://blog.qbaseplus.com/four-tips-for-rt-qpcr-data-normalization-using-reference-genes
Chia CY, Lim CW, Leong WT, Ling MH. High expression stability of microtubule affinity regulating kinase 3 (MARK3) makes it a reliable reference gene. IUBMB Life. 2010 Mar;62(3):200-3. doi: 10.1002/iub.295. PMID: 20087965.
Kim HJ, Na JI, Min BW, Na JY, Lee KH, Lee JH, Lee YJ, Kim HS, Park JT. Evaluation of Protein Expression in Housekeeping Genes across Multiple Tissues in Rats. Korean J Pathol. 2014 Jun;48(3):193-200. doi: 10.4132/KoreanJPathol.2014.48.3.193. Epub 2014 Jun 26. PMID: 25013417; PMCID: PMC4087132.
Pfaffl MW, Tichopad A, Prgomet C, Neuvians TP. Determination of stable housekeeping genes, differentially regulated target genes and sample integrity: BestKeeper--Excel-based tool using pair-wise correlations. Biotechnol Lett. 2004 Mar;26(6):509-15. doi: 10.1023/b:bile.0000019559.84305.47. PMID: 15127793.

The authors have corrected these numbers.

Q13: A minor advice: As an Original Article, up to 90 references might be too many. If possible, some less important citations could be reduced.

We have thoroughly revised the references section and referred to the literature that was most relevant to our research.

The authors have added some new references and removed the following references:

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Reviewer 3 Report

The manuscript presents preparation and characterization of the nanoparticles for cabazitaxel delivery. The solid preliminary study conducted under in vitro conditions show very interesting results, so I would recommend the manuscript for publishing. However, the quality of Fig. 1, 2 and 4 should be improved.

Author Response

Comments and Suggestions for Authors

Authors’ response: We thank the reviewer for pointing out the changes that need attention. Please find the changes to my citations below:

We have improved the quality of figures 1, 2, and 4.

Reviewer 4 Report

Dear authors,

your manuscript is interesting and fits the scope of the journal. Additional Physical Characterizations of the loaded NPs are needed. Also, the title is more a title of a review article than an original article: please change it to make it informative of your findings; some typos and grammatical mistakes were encountered, please go through the entire manuscript to correct it; also, please add a model of molecular mechanism based on your findings. Introduction and discussion parts can be improved comparing with literature data and other Taxan derivatives encapsulated or not. In other words, the novelty and pertinence must be better highlighted. Also, please provide the structure of Cabazitaxel. Please provide the chemical structure of this compound and present its advantages and drawbacks compared to that of other compounds of the same (taxane) class; in particular physicochemical and pharmacokinetics properties of Cabazitazel must be better highlighted.

I also strongly suggest to review and cite these following articles:

1- Kommineni N, Mahira S, Domb AJ, Khan W. Cabazitaxel-Loaded Nanocarriers for Cancer Therapy with Reduced Side Effects. Pharmaceutics. 2019 Mar 25;11(3):141. doi: 10.3390/pharmaceutics11030141. PMID: 30934535; PMCID: PMC6470818.

2- Shah KA, et al. Rizatriptan-Loaded Oral Fast Dissolving Films: Design and Characterizations. Pharmaceutics. 2022 Dec 1;14(12):2687. doi: 10.3390/pharmaceutics14122687. PMID: 36559181; PMCID: PMC9780891.

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best,

the reviewer

Author Response

Comments and Suggestions for Authors

Authors’ response: We thank the reviewer for pointing out the changes that need attention. Please find the changes to my citations below:

Dear authors,

Authors’ response: We thank the reviewer for pointing out the changes that need attention. Please find the changes to my citations below:

your manuscript is interesting and fits the scope of the journal. Additional Physical Characterizations of the loaded NPs are needed.

Due to the limitations at our university, we are unable to do x-ray Diffraction analysis at this time. Also, due to funding limitations we were unable to carry out further characterization of the NPs. We can assure you that this will not impact the results of our study.

Also, the title is more a title of a review article than an original article: please change it to make it informative of your findings.

The authors have changed the title to “Cabazitaxel-Loaded nanoparticles Reduce the Invasiveness in Metastatic Prostate Cancer Cells: Beyond the Classical Taxane Function.”

some typos and grammatical mistakes were encountered, please go through the entire manuscript to correct it;