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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

Cellular uptakes of ATF–HSA:DOX (5 μM), HSA:DOX (5 μM), and DOX (5 μM) in H1299 cells and HELF cells after incubation for different time periods.Notes: The uptake amount of free DOX in both cell lines was much more than that of ATF–HSA:DOX. The amount of ATF–HSA:DOX was higher than that of HSA:DOX in H1299 at any time period, while there was almost no difference in the amount of ATF–HSA:DOX and DOX in HELF. *P<0.05. **P<0.01.Abbreviations: ATF, amino-terminal fragment of urokinase; DOX, doxorubicin; HELF, human embryo lung fibroblasts; HSA, human serum albumin.
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f2-ijn-10-5327: Cellular uptakes of ATF–HSA:DOX (5 μM), HSA:DOX (5 μM), and DOX (5 μM) in H1299 cells and HELF cells after incubation for different time periods.Notes: The uptake amount of free DOX in both cell lines was much more than that of ATF–HSA:DOX. The amount of ATF–HSA:DOX was higher than that of HSA:DOX in H1299 at any time period, while there was almost no difference in the amount of ATF–HSA:DOX and DOX in HELF. *P<0.05. **P<0.01.Abbreviations: ATF, amino-terminal fragment of urokinase; DOX, doxorubicin; HELF, human embryo lung fibroblasts; HSA, human serum albumin.

Mentions: As the DOX is buried inside the ATF–HSA:DOX, will it be able to enter the cells? We carried out the cellular uptake experiments of ATF–HSA:DOX in both H1299 and HELF cell lines with free DOX as a control. H1299, a lung cancer cell line, has a large amount of uPAR expressed on the cell surface, while fibroblast HELF cell line has little uPAR expression on the cell surface.37 In our experiment, cells were incubated with DOX, HSA:DOX, or ATF–HSA:DOX (all at a final concentration of 5 μM) for different time periods (0 hours, 4 hours, 8 hours, 16 hours, and 24 hours) followed by washing to remove the unbound DOX. The taken DOX was quantified by measuring the fluorescence of DOX. We noticed that the amount of ATF–HSA:DOX was higher than that of HSA:DOX in H1299 at any time periods, whereas there was almost no difference in the amount of ATF–HSA:DOX and DOX in HELF (Figure 2), presumably due to the higher level of uPAR expression on the cell surface of H1299 compared with HELF.


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)

Cellular uptakes of ATF–HSA:DOX (5 μM), HSA:DOX (5 μM), and DOX (5 μM) in H1299 cells and HELF cells after incubation for different time periods.Notes: The uptake amount of free DOX in both cell lines was much more than that of ATF–HSA:DOX. The amount of ATF–HSA:DOX was higher than that of HSA:DOX in H1299 at any time period, while there was almost no difference in the amount of ATF–HSA:DOX and DOX in HELF. *P<0.05. **P<0.01.Abbreviations: ATF, amino-terminal fragment of urokinase; DOX, doxorubicin; HELF, human embryo lung fibroblasts; HSA, human serum albumin.
© Copyright Policy
Related In: Results  -  Collection

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

f2-ijn-10-5327: Cellular uptakes of ATF–HSA:DOX (5 μM), HSA:DOX (5 μM), and DOX (5 μM) in H1299 cells and HELF cells after incubation for different time periods.Notes: The uptake amount of free DOX in both cell lines was much more than that of ATF–HSA:DOX. The amount of ATF–HSA:DOX was higher than that of HSA:DOX in H1299 at any time period, while there was almost no difference in the amount of ATF–HSA:DOX and DOX in HELF. *P<0.05. **P<0.01.Abbreviations: ATF, amino-terminal fragment of urokinase; DOX, doxorubicin; HELF, human embryo lung fibroblasts; HSA, human serum albumin.
Mentions: As the DOX is buried inside the ATF–HSA:DOX, will it be able to enter the cells? We carried out the cellular uptake experiments of ATF–HSA:DOX in both H1299 and HELF cell lines with free DOX as a control. H1299, a lung cancer cell line, has a large amount of uPAR expressed on the cell surface, while fibroblast HELF cell line has little uPAR expression on the cell surface.37 In our experiment, cells were incubated with DOX, HSA:DOX, or ATF–HSA:DOX (all at a final concentration of 5 μM) for different time periods (0 hours, 4 hours, 8 hours, 16 hours, and 24 hours) followed by washing to remove the unbound DOX. The taken DOX was quantified by measuring the fluorescence of DOX. We noticed that the amount of ATF–HSA:DOX was higher than that of HSA:DOX in H1299 at any time periods, whereas there was almost no difference in the amount of ATF–HSA:DOX and DOX in HELF (Figure 2), presumably due to the higher level of uPAR expression on the cell surface of H1299 compared with HELF.

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