Advanced search
Publication Cover
International Journal of Nanomedicine Volume 10, 2015 - Issue
Submit an article Journal homepage
59
Views
9
CrossRef citations to date
0
Altmetric
Original Research

Glutathione-degradable drug-loaded nanogel effectively and securely suppresses hepatoma in mouse model

Xingang Liu1 Department of Critical Care Medicine, The First Hospital of Jilin University, Changchun, People’s Republic of China
,
Jianmeng Wang2 Department of Geriatrics, The First Hospital of Jilin University, Changchun, People’s Republic of ChinaCorrespondence[email protected]
,
Weiguo Xu3 Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Jilin University, Changchun, People’s Republic of China
,
Jianxun Ding3 Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Jilin University, Changchun, People’s Republic of ChinaCorrespondence[email protected]
,
Bo Shi4 Center for Biological Experiment, College of Basic Medicine, Jilin University, Changchun, People’s Republic of China
,
Kexin Huang4 Center for Biological Experiment, College of Basic Medicine, Jilin University, Changchun, People’s Republic of China
,
Xiuli Zhuang3 Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Jilin University, Changchun, People’s Republic of China
&
Xuesi Chen3 Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Jilin University, Changchun, People’s Republic of China
 show all
Pages 6587-6602 | Published online: 22 Oct 2015

Figures & data

Figure 1 Synthetic pathway for mPEG–P(LP-co-LC) nanogel and schematic illustrations about circulation, intratumoral accumulation, endocytosis, and targeting intracellular DOX release of DOX-loaded nanogel after intravenous injection.

Notes: mPEG–P(LP-co-LC) nanogel synthesis (A), DOX encapsulation and intravenous injection (B), in vivo circulation and intratumoral accumulation (C), and endocytosis and GSH-triggered intracellular DOX release (D). All the arrows indicate the preparation and in vivo metabolic process of DOX-loaded nanogel.

Abbreviations: DOX, doxorubicin; GSH, glutathione; mPEG–P(LP-co-LC), methoxy poly(ethylene glycol)–poly(L-phenylalanine-co-L-cystine).

Figure 1 Synthetic pathway for mPEG–P(LP-co-LC) nanogel and schematic illustrations about circulation, intratumoral accumulation, endocytosis, and targeting intracellular DOX release of DOX-loaded nanogel after intravenous injection.Notes: mPEG–P(LP-co-LC) nanogel synthesis (A), DOX encapsulation and intravenous injection (B), in vivo circulation and intratumoral accumulation (C), and endocytosis and GSH-triggered intracellular DOX release (D). All the arrows indicate the preparation and in vivo metabolic process of DOX-loaded nanogel.Abbreviations: DOX, doxorubicin; GSH, glutathione; mPEG–P(LP-co-LC), methoxy poly(ethylene glycol)–poly(L-phenylalanine-co-L-cystine).

Figure 2 Typical TEM microimage and Rh of mPEG–P(LP-co-LC) nanogel.

Abbreviations: TEM, transmission electron microscopy; Rh, hydrodynamic radius; mPEG–P(LP-co-LC), methoxy poly(ethylene glycol)–poly(L-phenylalanine-co-L-cystine).

Figure 2 Typical TEM microimage and Rh of mPEG–P(LP-co-LC) nanogel.Abbreviations: TEM, transmission electron microscopy; Rh, hydrodynamic radius; mPEG–P(LP-co-LC), methoxy poly(ethylene glycol)–poly(L-phenylalanine-co-L-cystine).

Figure 3 Percent body weights, survival rates, and organ indices in MTD detections.

Notes: Percent body weights, survival rates, and organ indices of Kunming mice after disposable intravenous injection of NG at doses of 100.0 mg (kg BW)−1, 300.0 mg (kg BW)−1, and 500.0 mg (kg BW)−1, and DOX·HCl and NG/DOX at equivalent DOX·HCl doses of 5.0 mg (kg BW)−1, 10.0 mg (kg BW)−1, and 15.0 mg (kg BW)−1. The statistical data are presented as a mean ± SD.

Abbreviations: BW, body weight; DOX, doxorubicin; DOX·HCl, doxorubicin hydrochloride; MTD, maximum tolerated dose; NG, nanogel; NG/DOX, DOX-loaded nanogel; SD, standard deviation.

Figure 3 Percent body weights, survival rates, and organ indices in MTD detections.Notes: Percent body weights, survival rates, and organ indices of Kunming mice after disposable intravenous injection of NG at doses of 100.0 mg (kg BW)−1, 300.0 mg (kg BW)−1, and 500.0 mg (kg BW)−1, and DOX·HCl and NG/DOX at equivalent DOX·HCl doses of 5.0 mg (kg BW)−1, 10.0 mg (kg BW)−1, and 15.0 mg (kg BW)−1. The statistical data are presented as a mean ± SD.Abbreviations: BW, body weight; DOX, doxorubicin; DOX·HCl, doxorubicin hydrochloride; MTD, maximum tolerated dose; NG, nanogel; NG/DOX, DOX-loaded nanogel; SD, standard deviation.

Figure 4 Tissue distribution.

Notes: Ex vivo DOX fluorescence images (A) and semi-quantitatively analyzed average fluorescence intensities (B) of tumors and major visceral organs (ie, kidney, heart, spleen, lung, and liver) isolated at 12 hours postinjection of free DOX·HCl or NG/DOX at a dose of 3.0 mg or 6.0 mg DOX·HCl equivalent per kilogram body weight toward BALB/c nude mice bearing HepG2 tumors. The statistical data are represented as mean ± SD (n=3; #P<0.001).

Abbreviations: DOX, doxorubicin; DOX·HCl, doxorubicin hydrochloride; NG/DOX, DOX-loaded nanogel; SD, standard deviation.

Figure 4 Tissue distribution.Notes: Ex vivo DOX fluorescence images (A) and semi-quantitatively analyzed average fluorescence intensities (B) of tumors and major visceral organs (ie, kidney, heart, spleen, lung, and liver) isolated at 12 hours postinjection of free DOX·HCl or NG/DOX at a dose of 3.0 mg or 6.0 mg DOX·HCl equivalent per kilogram body weight toward BALB/c nude mice bearing HepG2 tumors. The statistical data are represented as mean ± SD (n=3; #P<0.001).Abbreviations: DOX, doxorubicin; DOX·HCl, doxorubicin hydrochloride; NG/DOX, DOX-loaded nanogel; SD, standard deviation.

Figure 5 In vivo antitumor efficacies.

Notes: In vivo antitumor efficacies of NS as control, and free DOX·HCl and NG/DOX at a dosage of 3.0 and 6.0 mg DOX·HCl equivalent per kg body weight toward H22 hepatoma-xenografted BALB/c mouse models. Each set of data is represented as mean ± SD (n=10; *P<0.001).

Abbreviations: DOX, doxorubicin; DOX·HCI, doxorubicin hydrochloride; NG/DOX, DOX-loaded nanogel; NS, normal saline; SD, standard deviation.

Figure 5 In vivo antitumor efficacies.Notes: In vivo antitumor efficacies of NS as control, and free DOX·HCl and NG/DOX at a dosage of 3.0 and 6.0 mg DOX·HCl equivalent per kg body weight toward H22 hepatoma-xenografted BALB/c mouse models. Each set of data is represented as mean ± SD (n=10; *P<0.001).Abbreviations: DOX, doxorubicin; DOX·HCI, doxorubicin hydrochloride; NG/DOX, DOX-loaded nanogel; NS, normal saline; SD, standard deviation.

Figure 6 Histopathological and immunohistochemical analyses.

Notes: Histopathological (ie, H&E) and immunohistochemical (ie, caspase-3, survivin, Bax, and Bcl-2) analyses of tumor tissues sections after treatment of NS as control, or free DOX·HCl or NG/DOX at a dosage of 3.0 mg or 6.0 mg DOX·HCl equivalent per kilogram body weight. The arrows indicate the typical necrotic area. Magnification: 200×.

Abbreviations: DOX, doxorubicin; DOX·HCl, doxorubicin hydrochloride; H&E, hematoxylin and eosin; NG/DOX, DOX-loaded nanogel; NS, normal saline.

Figure 6 Histopathological and immunohistochemical analyses.Notes: Histopathological (ie, H&E) and immunohistochemical (ie, caspase-3, survivin, Bax, and Bcl-2) analyses of tumor tissues sections after treatment of NS as control, or free DOX·HCl or NG/DOX at a dosage of 3.0 mg or 6.0 mg DOX·HCl equivalent per kilogram body weight. The arrows indicate the typical necrotic area. Magnification: 200×.Abbreviations: DOX, doxorubicin; DOX·HCl, doxorubicin hydrochloride; H&E, hematoxylin and eosin; NG/DOX, DOX-loaded nanogel; NS, normal saline.

Figure 7 Semi-quantitative analyses of histopathological and immunohistochemical results.

Notes: Tumor necrotic area from H&E (A), and relative optical densities of tumor sections from caspase-3 (B), survivin (C), Bax (D), and Bcl-2 (E) after treatment with NS as control, or free DOX·HCl or NG/DOX at a dosage of 3.0 mg or 6.0 mg DOX·HCl equivalent per kg body weight. Each set of data is represented as mean ± SD (n=10; #P<0.05, &P<0.01, *P<0.001).

Abbreviations: DOX, doxorubicin; DOX·HCl, doxorubicin hydrochloride; H&E, hematoxylin and eosin; NG/DOX, DOX-loaded nanogel; NS, normal saline; SD, standard deviation.

Figure 7 Semi-quantitative analyses of histopathological and immunohistochemical results.Notes: Tumor necrotic area from H&E (A), and relative optical densities of tumor sections from caspase-3 (B), survivin (C), Bax (D), and Bcl-2 (E) after treatment with NS as control, or free DOX·HCl or NG/DOX at a dosage of 3.0 mg or 6.0 mg DOX·HCl equivalent per kg body weight. Each set of data is represented as mean ± SD (n=10; #P<0.05, &P<0.01, *P<0.001).Abbreviations: DOX, doxorubicin; DOX·HCl, doxorubicin hydrochloride; H&E, hematoxylin and eosin; NG/DOX, DOX-loaded nanogel; NS, normal saline; SD, standard deviation.

Figure 8 Body weight changes.

Notes: Body weight changes of H22 hepatoma-bearing BALB/c mice in the course of treatment with NS as control, or free DOX·HCl or NG/DOX at a dosage of 3.0 mg or 6.0 mg DOX·HCl equivalent per kg body weight. Each set of data is represented as mean ± SD (n=10; *P<0.001).

Abbreviations: DOX, doxorubicin; DOX·HCl, doxorubicin hydrochloride; NG/DOX, DOX-loaded nanogel; NS, normal saline; SD, standard deviation.

Figure 8 Body weight changes.Notes: Body weight changes of H22 hepatoma-bearing BALB/c mice in the course of treatment with NS as control, or free DOX·HCl or NG/DOX at a dosage of 3.0 mg or 6.0 mg DOX·HCl equivalent per kg body weight. Each set of data is represented as mean ± SD (n=10; *P<0.001).Abbreviations: DOX, doxorubicin; DOX·HCl, doxorubicin hydrochloride; NG/DOX, DOX-loaded nanogel; NS, normal saline; SD, standard deviation.

Figure 9 Histopathology analyses of visceral organ sections.

Notes: Histopathology analyses of visceral organ sections, that is, heart, liver, spleen, lung, kidney, thymus, and marrow, from normal mice, or H22 hepatoma-xenografted BALB/c mice after treatment with NS as control, or free DOX·HCl or NG/DOX at a dosage of 3.0 mg or 6.0 mg DOX·HCl equivalent per kg body weight. The arrows in the heart, liver, and kidney sections indicate a certain myocardial damage and fracture, the blood oozing and nucleus shrinking of liver tissue, and nephrotoxicity judged from the glomerular mesangial cell proliferation, respectively. The virtual coil indicates the tumor metastasis in thymus. Magnification: 200×.

Abbreviations: DOX, doxorubicin; DOX·HCl, doxorubicin hydrochloride; NG/DOX, DOX-loaded nanogel; NS, normal saline.

Figure 9 Histopathology analyses of visceral organ sections.Notes: Histopathology analyses of visceral organ sections, that is, heart, liver, spleen, lung, kidney, thymus, and marrow, from normal mice, or H22 hepatoma-xenografted BALB/c mice after treatment with NS as control, or free DOX·HCl or NG/DOX at a dosage of 3.0 mg or 6.0 mg DOX·HCl equivalent per kg body weight. The arrows in the heart, liver, and kidney sections indicate a certain myocardial damage and fracture, the blood oozing and nucleus shrinking of liver tissue, and nephrotoxicity judged from the glomerular mesangial cell proliferation, respectively. The virtual coil indicates the tumor metastasis in thymus. Magnification: 200×.Abbreviations: DOX, doxorubicin; DOX·HCl, doxorubicin hydrochloride; NG/DOX, DOX-loaded nanogel; NS, normal saline.

Figure 10 MMCR and WBC count.

Notes: MMCR (A) and WBC count (B) of normal mice, or H22 hepatoma-xenografted BALB/c mice after treatment with NS as control, or free DOX·HCl or NG/DOX at a dosage of 3.0 mg or 6.0 mg DOX·HCl equivalent per kg body weight. Each set of data is represented as mean ± SD (n=10, *P<0.001).

Abbreviations: DOX, doxorubicin; DOX·HCl, doxorubicin hydrochloride; NG/DOX, DOX-loaded nanogel; MMCR, marrow micronucleus cell rate; NS, normal saline; WBC, white blood cell; SD, standard deviation.

Figure 10 MMCR and WBC count.Notes: MMCR (A) and WBC count (B) of normal mice, or H22 hepatoma-xenografted BALB/c mice after treatment with NS as control, or free DOX·HCl or NG/DOX at a dosage of 3.0 mg or 6.0 mg DOX·HCl equivalent per kg body weight. Each set of data is represented as mean ± SD (n=10, *P<0.001).Abbreviations: DOX, doxorubicin; DOX·HCl, doxorubicin hydrochloride; NG/DOX, DOX-loaded nanogel; MMCR, marrow micronucleus cell rate; NS, normal saline; WBC, white blood cell; SD, standard deviation.

Figure 11 Biochemical analyses of corresponding organs.

Notes: Evaluations of CK-MB (A, heart), LDH (B, heart), ALT (C, liver), AST (D, liver), BUN (E, kidney), and Cr (F, kidney) in corresponding internal organs of normal mice or H22 hepatoma-xenografted BALB/c mice after treatment with NS as control, or free DOX·HCl or NG/DOX at a dosage of 3.0 mg or 6.0 mg DOX·HCl equivalent per kg body weight. Each set of data is represented as mean ± SD (n=10, *P<0.001).

Abbreviations: DOX, doxorubicin; DOX·HCl, doxorubicin hydrochloride; NG/DOX, DOX-loaded nanogel; NS, normal saline; CK-MB, creatine kinase isoenzyme; LDH, lactate dehydrogenase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; Cr, creatinine; SD, standard deviation.

Figure 11 Biochemical analyses of corresponding organs.Notes: Evaluations of CK-MB (A, heart), LDH (B, heart), ALT (C, liver), AST (D, liver), BUN (E, kidney), and Cr (F, kidney) in corresponding internal organs of normal mice or H22 hepatoma-xenografted BALB/c mice after treatment with NS as control, or free DOX·HCl or NG/DOX at a dosage of 3.0 mg or 6.0 mg DOX·HCl equivalent per kg body weight. Each set of data is represented as mean ± SD (n=10, *P<0.001).Abbreviations: DOX, doxorubicin; DOX·HCl, doxorubicin hydrochloride; NG/DOX, DOX-loaded nanogel; NS, normal saline; CK-MB, creatine kinase isoenzyme; LDH, lactate dehydrogenase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; Cr, creatinine; SD, standard deviation.

Figure 12 Blood biochemical analyses.

Notes: Evaluations of CK-MB (A), LDH (B), ALT (C), AST (D), BUN (E), and Cr (F) in serum of normal mice or H22 hepatoma-xenografted BALB/c mice after treatment with NS as control, or free DOX·HCl or NG/DOX at a dosage of 3.0 mg or 6.0 mg DOX·HCl equivalent per kg body weight. Each set of data is represented as mean ± SD (n=10, *P<0.001).

Abbreviations: DOX, doxorubicin; DOX·HCl, doxorubicin hydrochloride; NG/DOX, DOX-loaded nanogel; NS, normal saline; CK-MB, creatine kinase isoenzyme; LDH, lactate dehydrogenase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; Cr, creatinine; SD, standard deviation.

Figure 12 Blood biochemical analyses.Notes: Evaluations of CK-MB (A), LDH (B), ALT (C), AST (D), BUN (E), and Cr (F) in serum of normal mice or H22 hepatoma-xenografted BALB/c mice after treatment with NS as control, or free DOX·HCl or NG/DOX at a dosage of 3.0 mg or 6.0 mg DOX·HCl equivalent per kg body weight. Each set of data is represented as mean ± SD (n=10, *P<0.001).Abbreviations: DOX, doxorubicin; DOX·HCl, doxorubicin hydrochloride; NG/DOX, DOX-loaded nanogel; NS, normal saline; CK-MB, creatine kinase isoenzyme; LDH, lactate dehydrogenase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; Cr, creatinine; SD, standard deviation.

Related research

People also read lists articles that other readers of this article have read.

Recommended articles lists articles that we recommend and is powered by our AI driven recommendation engine.

Cited by lists all citing articles based on Crossref citations.
Articles with the Crossref icon will open in a new tab.