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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

In vivo antitumor efficacies of ATF–HSA:DOX and DOX on H22 tumor-bearing mice (n=8 per group) and representative histopathologic images of hearts resected from mice after treatment with 0.9% saline, ATF-HSA:DOX or free DOX for 6 days.Notes: (A) In vivo antitumor efficacies of ATF–HSA:DOX injected at 5 μmol/kg, iv and DOX injected at 5 μmol/kg, iv. Error bars represent standard error of the mean. The tumor volume of mice treated with ATF–HSA:DOX was significantly different from that of mice treated by saline; *P<0.05; **P<0.01. Representative histopathological images (H&E, 400×) of hearts resected from mice after 6 days of treatment with (B) 0.9% saline, (C) 5 μmol/kg ATF–HSA:DOX, or (D) 5 μmol/kg free DOX. Myocardial lesions were not seen in the heart tissue of mice receiving ATF–HSA:DOX, whereas heart tissue from mice treated with free DOX clearly showed swelling of myocardial cells, the loss of myofibril, and reduced interconnection between myocardial cells.Abbreviations: ATF, amino-terminal fragment of urokinase; DOX, doxorubicin; H&E, hematoxylin and eosin; HSA, human serum albumin; iv, intravenous.
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f7-ijn-10-5327: In vivo antitumor efficacies of ATF–HSA:DOX and DOX on H22 tumor-bearing mice (n=8 per group) and representative histopathologic images of hearts resected from mice after treatment with 0.9% saline, ATF-HSA:DOX or free DOX for 6 days.Notes: (A) In vivo antitumor efficacies of ATF–HSA:DOX injected at 5 μmol/kg, iv and DOX injected at 5 μmol/kg, iv. Error bars represent standard error of the mean. The tumor volume of mice treated with ATF–HSA:DOX was significantly different from that of mice treated by saline; *P<0.05; **P<0.01. Representative histopathological images (H&E, 400×) of hearts resected from mice after 6 days of treatment with (B) 0.9% saline, (C) 5 μmol/kg ATF–HSA:DOX, or (D) 5 μmol/kg free DOX. Myocardial lesions were not seen in the heart tissue of mice receiving ATF–HSA:DOX, whereas heart tissue from mice treated with free DOX clearly showed swelling of myocardial cells, the loss of myofibril, and reduced interconnection between myocardial cells.Abbreviations: ATF, amino-terminal fragment of urokinase; DOX, doxorubicin; H&E, hematoxylin and eosin; HSA, human serum albumin; iv, intravenous.

Mentions: To investigate the antitumor efficacy of ATF–HSA:DOX in H22 tumor-bearing mice, we measured the tumor volumes of mice (eight per group) for 6 continuous days after one bolus injection of ATF–HSA:DOX (5 μmol/kg), DOX (5 μmol/kg or 2.9 mg/kg), or saline (as a control) through the caudal vein. The DOX treatment inhibited the tumor growth rate (Figure 7A) compared with the untreated group. In contrast, ATF–HSA:DOX treatment further reduced the tumor growth rate compared to the group treated with DOX (~60% of the tumor size from the DOX-treated group at day 6). These data showed that ATF–HSA:DOX had an enhanced antitumor efficacy compared with 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)

In vivo antitumor efficacies of ATF–HSA:DOX and DOX on H22 tumor-bearing mice (n=8 per group) and representative histopathologic images of hearts resected from mice after treatment with 0.9% saline, ATF-HSA:DOX or free DOX for 6 days.Notes: (A) In vivo antitumor efficacies of ATF–HSA:DOX injected at 5 μmol/kg, iv and DOX injected at 5 μmol/kg, iv. Error bars represent standard error of the mean. The tumor volume of mice treated with ATF–HSA:DOX was significantly different from that of mice treated by saline; *P<0.05; **P<0.01. Representative histopathological images (H&E, 400×) of hearts resected from mice after 6 days of treatment with (B) 0.9% saline, (C) 5 μmol/kg ATF–HSA:DOX, or (D) 5 μmol/kg free DOX. Myocardial lesions were not seen in the heart tissue of mice receiving ATF–HSA:DOX, whereas heart tissue from mice treated with free DOX clearly showed swelling of myocardial cells, the loss of myofibril, and reduced interconnection between myocardial cells.Abbreviations: ATF, amino-terminal fragment of urokinase; DOX, doxorubicin; H&E, hematoxylin and eosin; HSA, human serum albumin; iv, intravenous.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4554405&req=5

f7-ijn-10-5327: In vivo antitumor efficacies of ATF–HSA:DOX and DOX on H22 tumor-bearing mice (n=8 per group) and representative histopathologic images of hearts resected from mice after treatment with 0.9% saline, ATF-HSA:DOX or free DOX for 6 days.Notes: (A) In vivo antitumor efficacies of ATF–HSA:DOX injected at 5 μmol/kg, iv and DOX injected at 5 μmol/kg, iv. Error bars represent standard error of the mean. The tumor volume of mice treated with ATF–HSA:DOX was significantly different from that of mice treated by saline; *P<0.05; **P<0.01. Representative histopathological images (H&E, 400×) of hearts resected from mice after 6 days of treatment with (B) 0.9% saline, (C) 5 μmol/kg ATF–HSA:DOX, or (D) 5 μmol/kg free DOX. Myocardial lesions were not seen in the heart tissue of mice receiving ATF–HSA:DOX, whereas heart tissue from mice treated with free DOX clearly showed swelling of myocardial cells, the loss of myofibril, and reduced interconnection between myocardial cells.Abbreviations: ATF, amino-terminal fragment of urokinase; DOX, doxorubicin; H&E, hematoxylin and eosin; HSA, human serum albumin; iv, intravenous.
Mentions: To investigate the antitumor efficacy of ATF–HSA:DOX in H22 tumor-bearing mice, we measured the tumor volumes of mice (eight per group) for 6 continuous days after one bolus injection of ATF–HSA:DOX (5 μmol/kg), DOX (5 μmol/kg or 2.9 mg/kg), or saline (as a control) through the caudal vein. The DOX treatment inhibited the tumor growth rate (Figure 7A) compared with the untreated group. In contrast, ATF–HSA:DOX treatment further reduced the tumor growth rate compared to the group treated with DOX (~60% of the tumor size from the DOX-treated group at day 6). These data showed that ATF–HSA:DOX had an enhanced antitumor efficacy compared with 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