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Drug Design, Development and Therapy Volume 10, 2016 - Issue
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Original Research

Loading cisplatin onto 6-mercaptopurine covalently modified MSNS: a nanomedicine strategy to improve the outcome of cisplatin therapy

Xiaojie Lv1 Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Beijing Laboratory of Biomedical Materials, College of Pharmaceutical Sciences, Capital Medical University, Beijing, People’s Republic of China
,
Ming Zhao1 Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Beijing Laboratory of Biomedical Materials, College of Pharmaceutical Sciences, Capital Medical University, Beijing, People’s Republic of China;2 Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, TaiwanCorrespondence[email protected] [email protected]
,
Yuiji Wang1 Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Beijing Laboratory of Biomedical Materials, College of Pharmaceutical Sciences, Capital Medical University, Beijing, People’s Republic of China
,
Xi Hu1 Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Beijing Laboratory of Biomedical Materials, College of Pharmaceutical Sciences, Capital Medical University, Beijing, People’s Republic of China
,
Jianhui Wu1 Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Beijing Laboratory of Biomedical Materials, College of Pharmaceutical Sciences, Capital Medical University, Beijing, People’s Republic of China
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Xueyun Jiang1 Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Beijing Laboratory of Biomedical Materials, College of Pharmaceutical Sciences, Capital Medical University, Beijing, People’s Republic of China
,
Shan Li1 Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Beijing Laboratory of Biomedical Materials, College of Pharmaceutical Sciences, Capital Medical University, Beijing, People’s Republic of China
,
Chunying Cui1 Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Beijing Laboratory of Biomedical Materials, College of Pharmaceutical Sciences, Capital Medical University, Beijing, People’s Republic of China
&
Shiqi Peng1 Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Beijing Laboratory of Biomedical Materials, College of Pharmaceutical Sciences, Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence[email protected] [email protected]
 show all
Pages 3933-3946 | Published online: 01 Dec 2016

Figures & data

Table 1 Some interesting clinical combinations and the outcomes of CDDP-based therapy

Figure 1 Preparation of MSNS-6MP/CDDP.

Abbreviations: MSNS, SH surfaced mesoporous silica nanoparticles; MSNS-6MP, 6MP covalently modified MSNS; MSNS-6MP/CDDP, CDDP-loaded MSNS-6MP; 6MP, 6-mercaptopurine; CDDP, cisplatin; TEOS, tetraethylorthosilicate; MPTMS, tetraethoxy-silane-3-(trimethoxysilypropane)-1-thiol.
Figure 1 Preparation of MSNS-6MP/CDDP.

Figure 2 DSC spectra of MSNS, CDDP, 6MP, MSNS + CDDP, MSNS + 6MP, MSNS + CDDP + 6MP and MSNS-6MP/CDDP.

Abbreviations: DSC, differential scanning calorimeter; MSNS, SH surfaced mesoporous silica nanoparticles; CDDP, cisplatin; 6MP, 6-mercaptopurine; MSNS-6MP, 6MP covalently modified MSNS; MSNS-6MP/CDDP, CDDP-loaded MSNS-6MP.
Figure 2 DSC spectra of MSNS, CDDP, 6MP, MSNS + CDDP, MSNS + 6MP, MSNS + CDDP + 6MP and MSNS-6MP/CDDP.

Figure 3 TEM images of (A) MSNS, (B) MSNS-6MP and (C) MSNS-6MP/CDDP.

Note: Concentration of MSNS, MSNS-6MP and MSNS-6MP/CDDP is 0.5 mg/mL.
Abbreviations: TEM, transmission electron microscope; MSNS, SH surfaced mesoporous silica nanoparticles; 6MP, 6-mercaptopurine; CDDP, cisplatin; MSNS-6MP, 6MP covalently modified MSNS; MSNS-6MP/CDDP, CDDP-loaded MSNS-6MP.
Figure 3 TEM images of (A) MSNS, (B) MSNS-6MP and (C) MSNS-6MP/CDDP.

Figure 4 Accumulative release of 6MP from MSNS-6MP.

Notes: (A) GSH promoted accumulative release profiles of 6MP from MSNS-6MP in pH 7.4 PBS; (B) DTT promoted accumulative release profiles of 6MP from MSNS-6MP in pH 7.4 PBS; (C) the accumulative release profiles of 6MP from MSNS-6MP in rat serum.
Abbreviations: 6MP, 6-mercaptopurine; MSNS, SH surfaced mesoporous silica nanoparticles; GSH, glutathione; PBS, phosphate buffered saline; DTT, dithiolthreitol; MSNS-6MP, 6MP surfaced MSNS.
Figure 4 Accumulative release of 6MP from MSNS-6MP.

Figure 5 The release profile of CDDP from MSNS-6MP/CDDP.

Notes: (A) Release profile of CDDP from MSNS-6MP/CDDP at pH 5.5, 6.5 and 7.4; (B) release profile of CDDP from MSNS-6MP/CDDP in rat serum.
Abbreviations: CDDP, cisplatin; MSNS, SH surfaced mesoporous silica nanoparticles; 6MP, 6-mercaptopurine; MSNS-6MP, 6MP covalently modified MSNS; MSNS-6MP/CDDP, CDDP-loaded MSNS-6MP; PBS, phosphate buffered saline.
Figure 5 The release profile of CDDP from MSNS-6MP/CDDP.

Figure 6 Survival numbers of S180 mice and healthy ICR mice.

Notes: (A) Overall survival rates of S180 mice during 8-day and 13-day therapies of CMCNa, CDDP alone, CDDP plus 6MP, MSNS-6MP and MSNS-6MP/CDDP; (B) overall survival rates of healthy ICR mice during 13-day therapies of CDDP alone and MSNS-6MP/CDDP.
Abbreviations: CMCNa, sodium carboxyl methyl cellulose; CDDP, cisplatin; 6MP, 6-mercaptopurine; MSNS, SH surfaced mesoporous silica nanoparticles; MSNS-6MP, 6MP covalently modified MSNS; MSNS-6MP/CDDP, CDDP-loaded MSNS-6MP.
Figure 6 Survival numbers of S180 mice and healthy ICR mice.

Figure 7 Tumor volumes of the treated mice.

Notes: CMCNa, CDDP plus 6MP, MSNS-6MP and MSNS-6MP/CDDP; because the overall survival rates of 8-day therapies of CDDP alone and CDDP plus 6MP were only 50% and 42%, respectively, the tumor sizes of 13-day treatments of them were unavailable; n=12.
Abbreviations: CMCNa, sodium carboxyl methyl cellulose; CDDP, cisplatin; 6MP, 6-mercaptopurine; MSNS, SH surfaced mesoporous silica nanoparticles; MSNS-6MP, 6MP covalently modified MSNS; MSNS-6MP/CDDP, CDDP-loaded MSNS-6MP.
Figure 7 Tumor volumes of the treated mice.

Figure 8 Tumor weights of S180 mice treated with CMCNa, MSNS-6MP and MSNS-6MP/CDDP, n=12.

Abbreviations: CMCNa, sodium carboxyl methyl cellulose; MSNS, SH surfaced mesoporous silica nanoparticles; 6MP, 6-mercaptopurine; CDDP, cisplatin; MSNS-6MP, 6MP covalently modified MSNS; MSNS-6MP/CDDP, CDDP-loaded MSNS-6MP.
Figure 8 Tumor weights of S180 mice treated with CMCNa, MSNS-6MP and MSNS-6MP/CDDP, n=12.

Table 2 Body weight (mean ± SD, g) and ratio of organ weight/body weight (mean ± SD, %) of S180 mice treated by 6MP plus CDDP and MSNS-6MP/CDDP

Figure 9 Serum ALT, AST and Cr levels of the mice treated with CMCNa, CDDP, CDDP plus 6MP and MSNS-6MP/CDDP.

Note: (A) serum ALT and AST of the S180 mice treated by CMCNa, CDDP plus 6MP, CDDP and MSNS-6MP/CDDP; (B) serum Cr of the S180 mice treated by CMCNa, CDDP plus 6MP, CDDP and MSNS-6MP/CDDP.
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; Cr, creatinine; CMCNa, sodium carboxyl methyl cellulose; CDDP, cisplatin; 6MP, 6-mercaptopurine; MSNS, SH surfaced mesoporous silica nanoparticles; MSNS-6MP, 6MP covalently modified MSNS; MSNS-6MP/CDDP, CDDP-loaded MSNS-6MP.
Figure 9 Serum ALT, AST and Cr levels of the mice treated with CMCNa, CDDP, CDDP plus 6MP and MSNS-6MP/CDDP.

Figure 10 Effect of CMCNa, MSNS, 6MP plus CDDP and MSNS-6MP/CDDP on the left kidney histology.

Notes: (A) Left kidney histology of S180 mice treated by CMCNa; (B) left kidney histology of S180 mice treated by MSNS (50 mg·kg−1·day−1); (C) left kidney histology of S180 mice treated by 6MP (1 mg·kg−1·day−1) plus CDDP (5 mg·kg−1·day−1), and the area labelled by yellow circles show damage to the tubular epithelium, the formation of intratubular cast and tubular dilatation; (D) left kidney histology of S180 mice treated by MSNS-6MP/CDDP (50 mg·kg−1·day−1, corresponding to 1 mg·kg−1·day−1 of 6MP and 5 mg·kg−1·day−1 of CDDP); H&E stain, original magnification 40×, n=5.
Abbreviations: CMCNa, sodium carboxyl methyl cellulose; MSNS, SH surfaced mesoporous silica nanoparticles; 6MP, 6-mercaptopurine; CDDP, cisplatin; MSNS-6MP, 6MP covalently modified MSNS; MSNS-6MP/CDDP, CDDP-loaded MSNS-6MP; H&E, hematoxylin and eosin.
Figure 10 Effect of CMCNa, MSNS, 6MP plus CDDP and MSNS-6MP/CDDP on the left kidney histology.

Figure 11 Effect of CMCNa, MSNS, 6MP plus CDDP and MSNS-6MP/CDDP on mouse myocardium histology.

Notes: (A) Effect of CMCNa on mouse myocardium histology; (B) effect of MSNS on mouse myocardium histology; (C) effect of 6MP plus CDDP on mouse myocardium histology, and the area labelled by yellow circles show damage to the tubular epithelium, the (D) effect of MSNS-6MP/CDDP on mouse myocardium histology, and the edematous and hemorrhagic myocardium with expanded interstitium, visualizes hyperchromatic, polymorphic and irregularly localized nuclei and discloses eosinophilia in the cytoplasm of necrosis area were labelled by yellow circles; H&E stain, original magnification 40×, n=5.
Abbreviations: CMCNa, sodium carboxyl methyl cellulose; MSNS, SH surfaced mesoporous silica nanoparticles; 6MP, 6-mercaptopurine; CDDP, cisplatin; MSNS-6MP, 6MP covalently modified MSNS; MSNS-6MP/CDDP, CDDP-loaded MSNS-6MP; H&E, hematoxylin and eosin.
Figure 11 Effect of CMCNa, MSNS, 6MP plus CDDP and MSNS-6MP/CDDP on mouse myocardium histology.

Figure 12 Distribution of Pt in S180 mice treated by MSNS-6MP/CDDP and CDDP (μg/g).

Notes: For CDDP group, n=2, the survival mice; for MSNS-6MP/CDDP group, n=7.
Abbreviations: MSNS, SH surfaced mesoporous silica nanoparticles; 6MP, 6-mercaptopurine; CDDP, cisplatin.
Figure 12 Distribution of Pt in S180 mice treated by MSNS-6MP/CDDP and CDDP (μg/g).

Figure S1 Standard curve of 6MP (4–20 mg/mL).

Abbreviation: 6MP, 6-mercaptopurine.
Figure S1 Standard curve of 6MP (4–20 mg/mL).

Figure S2 Standard curve of platinum (0–50 mg/mL).

Figure S2 Standard curve of platinum (0–50 mg/mL).

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