The article "Pharmacokinetic Evaluation of Paclitaxel, Albumin-Binding Paclitaxel, and Liposomal-Encapsulated Albumin-Binding Paclitaxel upon Gastric Subserosal Administration" by Dr. Lee et al. uses radiotracer methods to compare the pharmacokinetics of paclitaxel, albumin-paclitaxel (APN), and liposomal-encapsulated APN (L-APN) in rats. The radiolabelled drugs were injected in the subserosa of the stomach of rats (n = 3 for each drug) and imaged by SPECT scanning. Based on the time-activity curves, the authors find that L-APN has the largest area under curve (AUC) in the stomach, and reaches its maximal value latest in the intestine. The authors conclude that this suggests that L-APN is promising for treatment of gastric cancer. The article gives a good report of the preparation of the 123I-labelled variants of the drug and demonstrates successful preparation. However, a bit more caution should be included in the interpretation of the pharmacokinetic results. The results are interesting, but their weight is difficult to assess in the present version.

MAJOR 1. In lines 112-114, the AUC of the three drug variants are compared. Rounding the (unimportant) decimals, the AUCs are 983 +/- 167 for L-APN, 892 +/- 160 for APN, and 838 +/- 44 for paclitaxel, respectively. It is correct that AUC is largest for L-APN, but the difference does not appear to be statistically significant (and the text does not comment on the statistics here). Looking at Fig. 5, it is not visually clear that the AUCs differ much. Please either strengthen this comparison or avoid basing the conclusion upon it. (Is it instead of importance that the L-APN curve appears more flat originally, indicating that it takes a longer time before L-APN leaves the injection site, compared to the other drug variants? This might be tied to the finding that the intestine curve peaks latest for L-APN, and is slower to rise also in the other organ curves.) 2. Throughout the paper, the word "significant" is used in ways where it is unclear whether the meaning is "notably" or "statistically significant". For instance in line 151: "The significant area under the curve (AUC) ...". In way is this AUC "significant"? To avoid confusion, please use the wording "statistically significant" whenever this is the meaning, and avoid the word "significant" when the meaning is not statistical. 3. It is suggested to enhance the description of drug stability. Radioimaging methods like SPECT will show where the radionuclide (I-123) goes, but this is only fully representative of the drug if the labelling is stable. The authors already comments on this in the results line 123-124 (and by reference in line 57), but the information can easily be overlooked. It is suggested to stress this result more by starting a new paragraph by line 123 ("The uptake of free I-123 ... was not observed ...") and also augment this new paragraph (at least one more sentence). With such a paragraph, the reader will be better prepared for the Discussion, which does stress that the material had high stability (lines 132-133).

MINOR 4. To help the reader interpret the curves in Fig. 5, it is suggested to standardize the scales. For instance, the scaling could be the same for stomach and intestine (e.g. 0-120 %ID/g for both curve sets) to make these directly comparable, and then use a common scaling for the remaining curves (e.g. 0-0.6 %ID/g). In any case, it is suggested to add a note to the figure legend on the differences in scaling, for instance like this: "Please note the differences in scaling, with liver, hearth, kidney, and urinary bladder having uptake <1 %ID/g." 5. The notation [123I]paclitaxel is imprecise, as iodine is not part of paclitaxel. As noted by the authors in line 174, the 123I-labelled paclitaxel is in fact iodo-paclitaxel, which is chemically (slightly) different from paclitaxel. A more correct and precise notation would be [123I]I-paclitaxel. This notation is in line with a widely accepted consensus paper with guidelines for radiochemistry nomenclature, published in 2017 and summarized in a widely published open letter that can be found for instance here: https://doi.org/10.1186/s41181-018-0047-y . The European Association of Nuclear Medicine (EANM) has abbreviated it to a short guideline on their web page: eanm.org/publications/guidelines/nomenclature/ According to these guidelines, radiopharmaceuticals should be written with the full molecule (including the atom used for labelling), with the specific isotope in square parentheses right to the left of this. Thus: Please use [123I]I-paclitaxel for the iodine-labelled paclitaxel. (If APN is defined as an abbreviation of "albumin-iodo-paclitaxel nanoparticle", [123I]APN and L-[123I]APN will still be correct.) 6. In Table 2, and in the main text, please avoid using more than at most 3 significant figures. E.g., please round AUC for the stomach from "837.93 (43.99)" [five significant figures] to "838 (44)", while it does make sense to report AUC for the liver as "0.93 (0.54)". As a rule of thumb, a result should be rounded to a level where the standard deviation is reported with at most two significant figures - more decimals will not give the reader more USEFUL information. 7. The first sentence of the introduction is not quite clear to this reviewer. Is the meaning to say that the incidence rate of gastric cancer is increasing and now at the highest level to date? Should the second half of the sentence be read as re-assuring (the cancer is found early) - if yes, perhaps ", but" will be better than "and": "Gastric cancer has the highest incidence rate ..., but is often diagnosed early owing to the national screening program." 8. The abbreviation "DLS" is used first time in line 85, but not defined until line 243. Please define at first use. 9. The abbreviation "UHP" (ultra-high purity?) is used in lines 209 and 225, but is not defined. 10. The abbreviation "PBS" is used in line 85, but is not defined.

The revised version of the paper is a considerable improvement, both the augmented Introduction and in relation to the issues raised. Some minor issues can be further improved.

MINOR

1. The more precise notation for the radiolabelled tracers is acknowledged. However, the text in Fig. 1 should be changed accordingly. As an open question (I am not a chemist): Is there systematics in when the iodination of paclitaxel is referred to as "I-paclitaxel" and when as "iodo-paclitaxel"?

2. Lines 146-152: It is suggested to rephrase to keep to comparison of paclitaxel, APN, and L-APN in the same sentence. Suggestion: "... in the stomach. In decreasing order, the AUCs were 893 +/- 160 for L-APN, 893 +/- 160 for APN, and 838 +/- 44 for paclitaxel. Although the differences were not statistically significant, likely due to the limited number of animals in each study group ( ... ), the combination for L-APC of highest AUC and initially flat curves in all organs, seems to indicate a prolonged and sustained presence of L-APC in the stomach."

3. Lines 159-161: It is not quite clear what the reported numbers in parentheses are representing - AUCs or max values? Please be specific about this, and add units in the parentheses.

4. Line 163: Should "stability" in this place be "instability" (thyroid uptake indicates free I-123, which again is a sign of instability of the labeling)? Thus, "in vivo instability, was not observed" (change in line 163) leading to "The in vivo stability seemed to be very high" (no change in line 164)?

5. Table 1: Acknowledged, several not-very-informative decimals have been rounded. But the standard error should not have more decimals than the number. As a comparison from everyday life, consider the sentence: "The lanes were measured and found to have a length of 487 +/- 44.2 meters." This does not really contain more information than rounding standard deviation to as few decimals as the length: "The lanes were measured and found to have a length of 487 +/- 44 meters." (Compare with AUC for intestine in Table 1.)

6. Lines 195-196: It is suggested to write just "noteworthy" rather than "particularly noteworthy", given that the result was not statistically significant (but still noteworthy because it was in line with the other findings described).

7. Line 231: "demonstrated" may be a bit to strong, "indicated" is suggested instead.