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Dual actions of albumin packaging and tumor targeting enhance the antitumor efficacy and reduce the cardiotoxicity of doxorubicin in vivo.

Zheng K, Li R, Zhou X, Hu P, Zhang Y, Huang Y, Chen Z, Huang M - Int J Nanomedicine (2015)

Bottom Line: However, in tumor-bearing mice, ATF-HSA:DOX was demonstrated to have an enhanced tumor-targeting and antitumor efficacy compared with free DOX.More importantly, histopathological examinations of the hearts from the mice treated with ATF-HSA:DOX showed a significantly reduced cardiotoxicity compared with hearts from mice treated with free DOX.These results demonstrate the feasibility of this approach in reducing the cardiotoxicity of DOX while strengthening its antitumor efficacy.

View Article: PubMed Central - PubMed

Affiliation: College of Chemistry, Fuzhou University, Fuzhou, People's Republic of China.

ABSTRACT
Doxorubicin (DOX) is an effective chemotherapy drug used to treat different types of cancers. However, DOX has severe side effects, especially life-threatening cardiotoxicity. We herein report a new approach to reduce the toxicity of DOX by embedding DOX inside human serum albumin (HSA). HSA is further fused by a molecular biology technique with a tumor-targeting agent, amino-terminal fragment of urokinase (ATF). ATF binds with a high affinity to urokinase receptor, which is a cell-surface receptor overexpressed in many types of tumors. The as-prepared macromolecule complex (ATF-HSA:DOX) was not as cytotoxic as free DOX to cells in vitro, and was mainly localized in cell cytosol in contrast to DOX that was localized in cell nuclei. However, in tumor-bearing mice, ATF-HSA:DOX was demonstrated to have an enhanced tumor-targeting and antitumor efficacy compared with free DOX. More importantly, histopathological examinations of the hearts from the mice treated with ATF-HSA:DOX showed a significantly reduced cardiotoxicity compared with hearts from mice treated with free DOX. These results demonstrate the feasibility of this approach in reducing the cardiotoxicity of DOX while strengthening its antitumor efficacy. Such a tumor-targeted albumin packaging strategy can also be applied to other antitumor drugs.

No MeSH data available.


Related in: MedlinePlus

Flow cytometric distribution of H1299 cells after treatment with and without DOX (10 μM) or ATF–HSA:DOX (10 μM) for 12 hours.Notes: (A) The cells were stained by FITC-labeled Annexin V and PI. (B) Quantifications of the cell population show that ATF–HSA:DOX is less toxic than DOX. ATF–HSA:DOX given for 12 hours produced significantly fewer early apoptotic cells than did DOX and ~three times fewer early apoptotic cells than late apoptotic cells, suggesting that ATF–HSA:DOX-induced cell death is likely due to a different mechanism from DOX. **P<0.01. ***P<0.001.Abbreviations: ATF, amino-terminal fragment of urokinase; DOX, doxorubicin; FITC, fluorescein isothiocyanate; HSA, human serum albumin; PI, propidium iodide.
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f5-ijn-10-5327: Flow cytometric distribution of H1299 cells after treatment with and without DOX (10 μM) or ATF–HSA:DOX (10 μM) for 12 hours.Notes: (A) The cells were stained by FITC-labeled Annexin V and PI. (B) Quantifications of the cell population show that ATF–HSA:DOX is less toxic than DOX. ATF–HSA:DOX given for 12 hours produced significantly fewer early apoptotic cells than did DOX and ~three times fewer early apoptotic cells than late apoptotic cells, suggesting that ATF–HSA:DOX-induced cell death is likely due to a different mechanism from DOX. **P<0.01. ***P<0.001.Abbreviations: ATF, amino-terminal fragment of urokinase; DOX, doxorubicin; FITC, fluorescein isothiocyanate; HSA, human serum albumin; PI, propidium iodide.

Mentions: Apoptosis and necrosis are two major types of cell death. Does the different subcellular localization of ATF–HSA:DOX affect the mechanism of cell death? We incubated H1299 with ATF–HSA:DOX (10 μM) or DOX (10 μM) for 12 hours and stained the cells with FITC-label Annexin V and PI for a flow cytometry analysis. The Annexin V is commonly used to measure the extracellular exposure of phosphotidylserine, a sign of apoptosis. PI is a probe for nucleic acid and measures the number of necrotic cells. High Annexin V but low PI staining is an indication of early apoptosis of cells, whereas strong staining of both Annexin V and PI indicates the cells are in the stage of late apoptosis or necrosis. Figure 5 shows that the number of cells treated with DOX in both early apoptosis and necrosis quarters was higher than that treated with ATF–HSA:DOX, demonstrating that DOX was more toxic than ATF–HSA:DOX. The early apoptotic cells after the treatment with DOX were four-fold more than those treated with ATF–HSA:DOX (Figure 5B). Interestingly, the number of early apoptotic cells after the treatment with ATF–HSA:DOX (10 μM) was ~three-fold less than cells of the late apoptotic or necrosis (Figure 5A and B) after a 12-hour incubation, which was different from the case of DOX (10 μM). This difference suggests that ATF–HSA:DOX may induce cell death by a mechanism different from that of DOX.


Dual actions of albumin packaging and tumor targeting enhance the antitumor efficacy and reduce the cardiotoxicity of doxorubicin in vivo.

Zheng K, Li R, Zhou X, Hu P, Zhang Y, Huang Y, Chen Z, Huang M - Int J Nanomedicine (2015)

Flow cytometric distribution of H1299 cells after treatment with and without DOX (10 μM) or ATF–HSA:DOX (10 μM) for 12 hours.Notes: (A) The cells were stained by FITC-labeled Annexin V and PI. (B) Quantifications of the cell population show that ATF–HSA:DOX is less toxic than DOX. ATF–HSA:DOX given for 12 hours produced significantly fewer early apoptotic cells than did DOX and ~three times fewer early apoptotic cells than late apoptotic cells, suggesting that ATF–HSA:DOX-induced cell death is likely due to a different mechanism from DOX. **P<0.01. ***P<0.001.Abbreviations: ATF, amino-terminal fragment of urokinase; DOX, doxorubicin; FITC, fluorescein isothiocyanate; HSA, human serum albumin; PI, propidium iodide.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4554405&req=5

f5-ijn-10-5327: Flow cytometric distribution of H1299 cells after treatment with and without DOX (10 μM) or ATF–HSA:DOX (10 μM) for 12 hours.Notes: (A) The cells were stained by FITC-labeled Annexin V and PI. (B) Quantifications of the cell population show that ATF–HSA:DOX is less toxic than DOX. ATF–HSA:DOX given for 12 hours produced significantly fewer early apoptotic cells than did DOX and ~three times fewer early apoptotic cells than late apoptotic cells, suggesting that ATF–HSA:DOX-induced cell death is likely due to a different mechanism from DOX. **P<0.01. ***P<0.001.Abbreviations: ATF, amino-terminal fragment of urokinase; DOX, doxorubicin; FITC, fluorescein isothiocyanate; HSA, human serum albumin; PI, propidium iodide.
Mentions: Apoptosis and necrosis are two major types of cell death. Does the different subcellular localization of ATF–HSA:DOX affect the mechanism of cell death? We incubated H1299 with ATF–HSA:DOX (10 μM) or DOX (10 μM) for 12 hours and stained the cells with FITC-label Annexin V and PI for a flow cytometry analysis. The Annexin V is commonly used to measure the extracellular exposure of phosphotidylserine, a sign of apoptosis. PI is a probe for nucleic acid and measures the number of necrotic cells. High Annexin V but low PI staining is an indication of early apoptosis of cells, whereas strong staining of both Annexin V and PI indicates the cells are in the stage of late apoptosis or necrosis. Figure 5 shows that the number of cells treated with DOX in both early apoptosis and necrosis quarters was higher than that treated with ATF–HSA:DOX, demonstrating that DOX was more toxic than ATF–HSA:DOX. The early apoptotic cells after the treatment with DOX were four-fold more than those treated with ATF–HSA:DOX (Figure 5B). Interestingly, the number of early apoptotic cells after the treatment with ATF–HSA:DOX (10 μM) was ~three-fold less than cells of the late apoptotic or necrosis (Figure 5A and B) after a 12-hour incubation, which was different from the case of DOX (10 μM). This difference suggests that ATF–HSA:DOX may induce cell death by a mechanism different from that of DOX.

Bottom Line: However, in tumor-bearing mice, ATF-HSA:DOX was demonstrated to have an enhanced tumor-targeting and antitumor efficacy compared with free DOX.More importantly, histopathological examinations of the hearts from the mice treated with ATF-HSA:DOX showed a significantly reduced cardiotoxicity compared with hearts from mice treated with free DOX.These results demonstrate the feasibility of this approach in reducing the cardiotoxicity of DOX while strengthening its antitumor efficacy.

View Article: PubMed Central - PubMed

Affiliation: College of Chemistry, Fuzhou University, Fuzhou, People's Republic of China.

ABSTRACT
Doxorubicin (DOX) is an effective chemotherapy drug used to treat different types of cancers. However, DOX has severe side effects, especially life-threatening cardiotoxicity. We herein report a new approach to reduce the toxicity of DOX by embedding DOX inside human serum albumin (HSA). HSA is further fused by a molecular biology technique with a tumor-targeting agent, amino-terminal fragment of urokinase (ATF). ATF binds with a high affinity to urokinase receptor, which is a cell-surface receptor overexpressed in many types of tumors. The as-prepared macromolecule complex (ATF-HSA:DOX) was not as cytotoxic as free DOX to cells in vitro, and was mainly localized in cell cytosol in contrast to DOX that was localized in cell nuclei. However, in tumor-bearing mice, ATF-HSA:DOX was demonstrated to have an enhanced tumor-targeting and antitumor efficacy compared with free DOX. More importantly, histopathological examinations of the hearts from the mice treated with ATF-HSA:DOX showed a significantly reduced cardiotoxicity compared with hearts from mice treated with free DOX. These results demonstrate the feasibility of this approach in reducing the cardiotoxicity of DOX while strengthening its antitumor efficacy. Such a tumor-targeted albumin packaging strategy can also be applied to other antitumor drugs.

No MeSH data available.


Related in: MedlinePlus