Dear. Leming Sun, Ph.D.
Academic Editor
PLOS ONE
The authors thank you very much for giving us a chance to revise our manuscript. The
reviewers’ comments are valuable and very helpful for improving our research paper.
We have carefully read all comments and have tried our best to revise the manuscript
as per reviewers’ suggestions, which we hope to meet with acceptance requirements.
We also thank the reviewers for the comments and suggestions.
Responses to Reviewer´s #1 Comments
1. Some language errors should be carefully revised throughout the manuscript.
The manuscript was revised. If the language is still not clear enough, as well as
in the case of any specific typographical or grammatical error, we would be grateful
if in the next round of revision the reviewer could indicate the sentences we should
improve.
2. In the introduction part, it is better to list one or two examples to clarify the
meaning and application of CaP delivery systems.
According to the reviewer´s suggestion, we added some examples in the manuscript to
clarify the meaning and application of CaP delivery systems in Introduction (Manuscript,
p. 3, lines 60, 62-67). It was pointed out that CaPs could be used as nanopowders
or composites to produce delivery systems to be systemically administrated as alternatives
to traditional drugs. However, granulated CaP, as well as cements and blocks, have
been used as bone fillers. The addition of drugs in these materials is a way to deliver
the drugs locally, avoiding the side effects of systemic administration. References
were added/used in the manuscript to exemplify this question (BARADARI et al., 2012;
BENEDETTI et al., 2015, 2016; CHINDAMO et al., 2020; DHATCHAYANI et al., 2020; KHALIFEHZADEH;
ARAMI, 2020; LUCAS-APARICIO et al., 2020; MURATA et al., 2018; SWET et al., 2014).
3. The authors use the vacuum pressures to improve the penetration of an anticancer
drug in calcium phosphate blocks, however the further prospect is not clear, the authors
should further clarify it.
The reviewer has correctly pointed out that the further prospect of the vacuum method
can be clarified in the paper. According to the reviewer´s suggestion, we added some
explanation in Introduction (p. 4, lines 92-95) to clarify that the impregnation method
using high-vacuum pressure followed by solvent volatilization was applied in this
research on purpose to improve the carboplatin loaded within the porous structure
of granulated CaPs. It was further demonstrated in the results that the carboplatin-loaded
in microporous structure affected the drug release due to the initial burst release
of the drug precipitated on the surface followed by a sustained release from the dissolution
of the drug from microporous (SHAO et al., 2012).
References were added/used in the manuscript to exemplify this question (CHEVALIER
et al., 2009; GBURECK et al., 2007).
4. In the material part, if the preparation of granular biomaterials adopts the previous
preparation method, please provide the related literature.
It was mentioned the related previous work in Materials and Methods – Synthesis and
preparation of granular biomaterials (p. 5, lines 121-122), but we have added other
literature (p. 6, line 133). We would like to point out that the Biomaterials Research
Group at Santa Catarina State University used the method described in this paper to
obtain granular biomaterials in different researches, with some modification. Hydroxyapatite
and β-tricalcium phosphate powders were obtained by wet chemical methods using a calcium
source and phosphoric acid (DALMÔNICO, 2015; DOROZHKIN, 2007; MUNARIN et al., 2015;
RAYNAUD et al., 2002). The Biomaterials Group obtained CaP powders from calcium carbonate
from calcareous marine sediment and H3PO4 raw materials by Silva et al. (2016). In
the present paper, the research group described the modified method using the sonicated
slurry of synthetic CaCO3 for the first time. Dalmonico et al. (2017) and Camargo
et al. (2014) described the production of granular CaPs biomaterials.
References were added/used in the manuscript to exemplify this question (CAMARGO et
al., 2014; DALMÔNICO et al., 2017; SILVA et al., 2016).
5. As for the result part, the pH and solvent stability of calcium phosphate (CaP)-carboplatin
should be determined.
As a part of the project, the in vitro solubility of CaP biomaterials was performed
by soaking the materials in the phosphate buffer pH 7.4 at 37 ºC for four weeks and
the materials presented stable weight stable (data not published). However, this study
was carried out in Ф 10 mm pressed discs sintered at 1,100 ºC/2h but not in the granulated
sintered CaPs. We have not included the data considering that the difference in surface
area and microstructure of the materials not allowed the comparative analysis.
The pH of CaP-carboplatin was measured in the released medium (phosphate buffer at
37 ºC) before and after the release test. The measured pH of 7.4 ± 0.1 results showed
no significant deviation from the expected value. This information was added in Materials
and Methods - Carboplatin release from the granular biomaterials (p. 7, lines 158-159)
and Results - Carboplatin release section (p 16, line 377). Carboplatin is described
as stable in aqueous solutions for 24 hours (https://pubchem.ncbi.nlm.nih.gov/compound/426756).
We would like to point out that the CaP-carboplatin stability was evaluated after
the loading process by the X-ray diffraction and infrared spectroscopy analysis, as
well as microscopy. In the release study, the UV-Vis spectroscopy was carried out
and the same behavior was verified for CaP-carboplatin and carboplatin drug solution.
The solubility and stability of calcium phosphate biomaterials were determined by
some authors and crystalline CaPs are considered stable in pH and temperature conditions
applied in this study (BERTAZZO et al., 2010; DOROZHKIN, 2007; WANG; NANCOLLAS, 2008).
In vivo implants of sintered granular calcium phosphate biomaterials could present
dissolution along the time. However, this process depends not only on the phase composition
and surface characteristics but also on the biological environment and cell activity
(DALMÔNICO et al., 2017; DOROZHKIN, 2007; DRAENERT; DRAENERT; DRAENERT, 2013).
6. The Biocompatibility of calcium phosphate (CaP)-carboplatin should be considered
and discussed in detail.
We agree that although the biocompatibility of granulated CaP-carboplatin was not
the focus in this paper, this question should be considered due to the importance
of this parameter to the applicability of the CaPs. Hence, the topic was discussed
in Discussion (p. 17-18, lines 398-418). We also would like to point out that HA,
β-TCP, and BCP granulated biomaterials, produced by the same method, have been tested
in vivo (DALMÔNICO et al., 2017). The chemical composition, crystallinity, and microstructure
of these biomaterials are quite similar to the CaPs used in this paper and they were
compared with the previous study. The present study was designed to focus specifically
on the synthesis and characterization of CaP-carboplatin biomaterials, but we have
included your point as a consideration for future studies in Conclusions (page 23,
line 540-541). References were added/used in the manuscript to exemplify this question
(AGARWAL; GARCÍA, 2015; BERTAZZO et al., 2010; DALMÔNICO et al., 2017; DRAENERT; DRAENERT;
DRAENERT, 2013; JIANG et al., 2017; SAMAVEDI; WHITTINGTON; GOLDSTEIN, 2013).
7. As for Microstructure of the biomaterials, some literatures should be cited, such
as J. Mater. Chem. A 2018 21216-21224; ACS Appl. Mat. Interfaces (2017) 32308-32315;
J. Mater. Sci. (2019) 6719-6727; Mater. Lett. (2017) 82-84
The suggested literature was carefully considered. We compared the polymer materials
in the suggested literature and cited ACS Appl. Mat. Interfaces (2017) 32308-32315
(p. 17, line 406) due to the high porosity and theoretical applicability as materials
for tissue engineering. In other literature, however, the polymer materials are described
to be suitable for another application but not as biomaterials.
8. The comparison between the current work and previous examples should be considered
in detail. The current work prospect is still not clear, which may be further explored
through the comparison.
According to the reviewer´s suggestion, porous CaPs biomaterials for local delivery
were compared to the biomaterials of the present study. A comparative analysis between
characterization and the release profile described in the literature was added in
Discussion (page 20, lines 469-473 and 478-484; page 21, lines 406-412; page 21, lines
505-505 and pages 21-22, lines 511-520). The results of the release study of the anti-inflammatory
ibuprofen from porous crystalline granular β-TCP performed by Baradari et al. (2012)
showed similar burst release of up to 70% of the drug in the first 15 minutes with
a plateau of the release of about 70 min with almost 100% of the drug released in
the first hour. The authors used the impregnation method, which depends on the drug/carrier
interaction. Another study (CHEVALIER et al., 2009) loaded ibuprofen onto granulated
β-TCP with similar composition, surface area, and porosity, using evaporation under
vacuum. The comparative analyses showed that the vacuum method improves the contact
between drug and microporosity and enhance the amount of the drug-loaded. The methodology
applied also did not modify the fast initial release pattern but changed the percentage
of the drug released at the same time. In our study, carboplatin presented similar
reversible physisorption on CaPs matrices. Similarly, the release profile of CaP-carboplatin
in this work also presented an initial fast release but showed a sustained release
of the remaining carboplatin, suggesting a combination of the release of the drug
from the surface followed by the drug in the microporosity as described by Shao et
al (2012). References were added/used in the manuscript to exemplify this question
(BARADARI et al., 2012; BARROUG et al., 2004; CHEVALIER et al., 2009; ITOKAZU et al.,
1999; UCHIDA et al., 1992).
Responses to Reviewer´s #2 Comments
Reviewer #2: I only have few comments:
1. Why did the authors use the five different compositions? Are they tipical, or simply
you wanted to test them? Please specify.
Hydroxyapatite, β-TCP, and BCP are the common composition of calcium phosphate bioceramics.
Hydroxyapatite presents well-known biocompatibility due to its chemical and crystallographic
similarity with biological apatite. Hydroxyapatite is considered the less soluble
non-substituted calcium phosphate. Therefore, the synthetic tricalcium phosphates
have been used to increase de biological dissolution of bioceramics. HA presents fine
microstructure and higher porosity, suitable to cell adhesion, than β-TCP. Biphasic
HA/β-TCP ceramics have been studied on purpose to achieve better control over both
solubility and microstructural characteristics (DALMÔNICO, 2015; DOROZHKIN, 2016;
WANG; NANCOLLAS, 2008; ZHANG et al., 2013).
The CaPs nanocomposites have been studied to modify chemical composition as well as
the microstructure of the bioceramics. Silica and magnesium have been associated with
increased biological response in bone regeneration processes (BOSE et al., 2011; PIETAK
et al., 2007; PORTER et al., 2003; SILVA et al., 2016). In the present work, β-TCP/MgO
and β-TCP /SiO2 nanocomposites were developed on purpose to achieve a higher porosity
of the β-TCP phase. Carboplatin loading was tested in nanocomposites on purpose to
verify the influence of the chemical composition in drug loading and release, due
to the lack of information on the interaction between these specific compositions
and carboplatin. The question was considered in the Introduction, and some words were
added to the manuscript (page 5, lines 103-107) as well in the Discussion (Manuscript,
pages 17-18, lines 412-418).
References were added/used in the manuscript to exemplify this question (BOSE et
al., 2011; SILVA et al., 2016; WANG et al., 2017; ZHU et al., 2011).
2. For Equation 1, Line 138, it should be "100" not "1", because the data were expressed
as 100% not 1. Please check about that.
Equation 1 was originally based on weight loss equations described in the literature
(TAN et al., 2009; TIAN; JIANG, 2018), where “1” was included to give results in terms
of remaining weight instead of weight loss:
Equation 1:
Drug loading (%)=1- (W1-W2)/W1 x 100 (1)
In which:
W1 = theoretical weight calculated by the actual weight of the biomaterials and the
drug content added, considering carboplatin and mannitol in its formulation;
W2 = weight of the CaP-carboplatin samples after the drug loading.
For the sake of clarity, we modify Equation 1 as described as follow (GUAN et al.,
2005):
Equation 1:
Remaining weight (%)=100 x W2/W1 (1)
In which:
W1 = theoretical weight calculated by the actual weight of the biomaterials and the
drug content added, considering carboplatin and mannitol in its formulation;
W2 = weight of the CaP-carboplatin samples after the drug loading.
We also modified some words in the original manuscript in the Materials and Methods
(page 6, line 149) and the Results – Carboplatin loading on granular biomaterials
(page 15, page 357).
The title of Table 3 was modified as follows (page 15, lines 361-362). Table 3 data
were not modified.
Table 3. Remaining weight of the CaP-carboplatin biomaterials after the load process
by the high-vacuum method.
3 Although UV-Vis spectra method is simple but not accurate. It could be easily influenced
by many factors. Hence, it is recommended to use other methods to verify.
We agree with the reviewer that there are more accurate methods used in carboplatin
detection, such as high-performance liquid chromatography (HPLC) (QU et al., 2017)
or platinum detection using inductively coupled plasma techniques, such as ICP-AES,
ICP-OES, and ICP-MS, (BAITUKHA et al., 2019; DOMÍNGUEZ-RÍOS et al., 2019; LELLI et
al., 2016). However, UV-Vis techniques have been widely used to determine carboplatin
in release studies from calcium phosphate biomaterials and other drug carriers (AKYUZ,
2020; BRAGTA et al., 2018; SHARMA; NASKAR; KUOTSU, 2020; SOUZA; ARDISSON; SOUSA, 2009;
THAKUR et al., 2020). UV-Vis method has been also used as a technique in release studies
of other drugs in porous drug carriers (BARADARI et al., 2012; BENEDINI et al., 2019;
CHEVALIER et al., 2009; TSENG et al., 2015; ZHU et al., 2011).
In our view, the UV-Vis method presents some advantages such as reduced sample manipulation
and easy operation method. Some standard procedures such as baseline correction, linear
calibration curve, as well as measurements of homogeneous samples in the calibration
curve range, can minimize data errors. Our study attempted to address these issues
by using a calibration curve with R = 0.99985 (S1_Sup. Information) and properly filtering
the collected samples before measuring. We would like to point out that the UV-Vis
method was used in this paper considering the influence of the CaPs biomaterials absorbance,
which was measured and corrected before calculation, as described in Materials and
Methods (page 7, lines 166-167) and Results – Ultraviolet-visible spectroscopy (page
14, lines 343-346) and showed in Figure 7 (page 15, line 350). It was also verified
the influence of mannitol of the drug, that it was considered not relevant, as described
in Results (page 15, lines 357-358).
4. Figure 8, drug release was done only in PBS but not physiological media. It is
recommended to at least add proteins into the media to make the media more representative.
Meanwhile, the authors only measured drug release once? There is no variation for
all the data?
In the consulted literature, some release studies were carried out in simulated body
fluid or Dulbecco´s Modified Eagle Medium. Sodium chloride 0,9% solution or distilled
water were also used (BAITUKHA et al., 2019; PARENT et al., 2017; PROKOPOWICZ, 2018;
SOUZA; ARDISSON; SOUSA, 2009). However, phosphate buffers pH 7.4 at 37 ºC with no
other addition has been used by most authors as a release medium for carboplatin,
as well as other drugs (BARADARI et al., 2012; BENEDINI et al., 2019; BRAGTA et al.,
2018; DALEY et al., 2018; DOMÍNGUEZ-RÍOS et al., 2019; QU et al., 2017; SHARMA; NASKAR;
KUOTSU, 2020; THAKUR et al., 2020; TSENG et al., 2015). Parent et al. (2017) pointed
out that the release experiments described in the literature present many differences
in the release medium composition, pH, agitation, and volume, as well as the apparatus
used in the experiments. In the present study, the release experiments were carried
out in the same conditions of pH, medium composition, and temperature, as described
for other authors.
As mentioned in Methods – Carboplatin release from the granular biomaterials (page
7, line 156-161), the release tests were performed in sink conditions, avoiding supersaturation,
and concentration gradient in the system. The parameters of the weight of CaP-carboplatin
in the release test, agitation, release medium volume, and withdrawn volume samples
were calculated considering the usual guidelines for sink conditions and the solubility
of carboplatin under buffers solutions as well as other unpredictable factors such
as system composition influence (SIEPMANN; SIEPMANN, 2020).
In our view, the release studies provide information about the release mechanism and
drug/carrier interaction but cannot be extrapolated to an in vivo approach, especially
in the case of local delivery matrices. For this reason, the focus of this work was
on the mechanism verified and the interaction between carboplatin and CaPs matrices.
Thus, each CaP-carboplatin juncture was measured in one experiment. Each withdrawn
sample was measured in triplicate to obtain the correct absorbance, which explains
the small variation in the data. For the reasons previously mentioned, the in vitro
release tests in this work were reported in terms of percentage, and the concentration
achieved in the initial release was mentioned just to give a parameter, but the focus
was on the release profile. A similar approach has been used in release tests described
in the literature, due to the several points measured in experiments, especially in
the case of long-term release profiles as well as researches that tested several conditions
of materials composition, drugs, or environmental release medium. In the literature,
the following research papers could be cited: (ALINAVAZ et al., 2021; BAITUKHA et
al., 2019; DADASHI; BODDOHI; SOLEIMANI, 2019; DOADRIO et al., 2015; IONITA et al.,
2017; LEGNOVERDE; BASALDELLA, 2016; LIU et al., 2005; MEDERLE et al., 2016; ZHAI;
LI, 2019).
Some explanations about the meaning and limitations of the in vitro release tests
as well as challenge of data extrapolation to in vivo behavior were added to the original
manuscript in the Discussion (pages 20-21, lines 484-491).
References were added/used in the manuscript to exemplify this question (BARADARI
et al., 2012; MARQUES et al., 2016; PARENT et al., 2017).
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