Limits...
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 localization of ATF–HSA:DOX and DOX.Notes: ATF–HSA:DOX (5 μM) mainly distributes in cytoplasm, whereas DOX (5 μM) mainly localizes in nucleus in both H1299 cells and HELF cells after a 2 hours or 12 hours incubation period. The fluorescence of ATF–HSA:DOX and DOX excited at 488 nm is shown in red. The fluorescence of nucleus dye DAPI excited at 405 nm is shown in blue. The colocalization of ATF–HSA:DOX or DOX with DAPI is shown in magenta.Abbreviations: ATF, amino-terminal fragment of urokinase; DAPI, 4′,6-diamidino-2-phenylindole; DOX, doxorubicin; HELF, human embryo lung fibroblasts; HSA, human serum albumin; uPAR, urokinase-type plasminogen activator receptor.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4554405&req=5

f3-ijn-10-5327: Cellular localization of ATF–HSA:DOX and DOX.Notes: ATF–HSA:DOX (5 μM) mainly distributes in cytoplasm, whereas DOX (5 μM) mainly localizes in nucleus in both H1299 cells and HELF cells after a 2 hours or 12 hours incubation period. The fluorescence of ATF–HSA:DOX and DOX excited at 488 nm is shown in red. The fluorescence of nucleus dye DAPI excited at 405 nm is shown in blue. The colocalization of ATF–HSA:DOX or DOX with DAPI is shown in magenta.Abbreviations: ATF, amino-terminal fragment of urokinase; DAPI, 4′,6-diamidino-2-phenylindole; DOX, doxorubicin; HELF, human embryo lung fibroblasts; HSA, human serum albumin; uPAR, urokinase-type plasminogen activator receptor.

Mentions: It is important to study the subcellular localization of ATF–HSA:DOX, which helps to understand the molecular mechanism of DOX-induced cytotoxicity. We incubated DOX or ATF–HSA:DOX (both at 5 μM) with either H1299 or HELF cells in confocal chamber slides for two different time periods (2 hours and 12 hours). After the cells were fixed, a cell nucleus dye DAPI was applied. Cells were imaged by a laser scanning microscope under identical experimental conditions. ATF–HSA:DOX and DOX were found inside both H1299 and HELF cells after 2-hour incubation (Figure 3, red color). As expected, DOX was observed to localize in cell nuclei (Figure 3, blue color; magenta color is the mix of blue and red). Surprisingly, ATF–HSA:DOX was found to distribute mainly in cytoplasm, but not in nuclei at all. Such distribution pattern remained almost the same after 12-hour incubation for both DOX and ATF–HSA:DOX in both cell lines, except that a trace amount of ATF–HSA:DOX was observed to enter the nuclei in H1299 cells. Therefore, we concluded that DOX embedded into ATF–HSA had a subcellular distribution 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)

Cellular localization of ATF–HSA:DOX and DOX.Notes: ATF–HSA:DOX (5 μM) mainly distributes in cytoplasm, whereas DOX (5 μM) mainly localizes in nucleus in both H1299 cells and HELF cells after a 2 hours or 12 hours incubation period. The fluorescence of ATF–HSA:DOX and DOX excited at 488 nm is shown in red. The fluorescence of nucleus dye DAPI excited at 405 nm is shown in blue. The colocalization of ATF–HSA:DOX or DOX with DAPI is shown in magenta.Abbreviations: ATF, amino-terminal fragment of urokinase; DAPI, 4′,6-diamidino-2-phenylindole; DOX, doxorubicin; HELF, human embryo lung fibroblasts; HSA, human serum albumin; uPAR, urokinase-type plasminogen activator receptor.
© Copyright Policy
Related In: Results  -  Collection

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

f3-ijn-10-5327: Cellular localization of ATF–HSA:DOX and DOX.Notes: ATF–HSA:DOX (5 μM) mainly distributes in cytoplasm, whereas DOX (5 μM) mainly localizes in nucleus in both H1299 cells and HELF cells after a 2 hours or 12 hours incubation period. The fluorescence of ATF–HSA:DOX and DOX excited at 488 nm is shown in red. The fluorescence of nucleus dye DAPI excited at 405 nm is shown in blue. The colocalization of ATF–HSA:DOX or DOX with DAPI is shown in magenta.Abbreviations: ATF, amino-terminal fragment of urokinase; DAPI, 4′,6-diamidino-2-phenylindole; DOX, doxorubicin; HELF, human embryo lung fibroblasts; HSA, human serum albumin; uPAR, urokinase-type plasminogen activator receptor.
Mentions: It is important to study the subcellular localization of ATF–HSA:DOX, which helps to understand the molecular mechanism of DOX-induced cytotoxicity. We incubated DOX or ATF–HSA:DOX (both at 5 μM) with either H1299 or HELF cells in confocal chamber slides for two different time periods (2 hours and 12 hours). After the cells were fixed, a cell nucleus dye DAPI was applied. Cells were imaged by a laser scanning microscope under identical experimental conditions. ATF–HSA:DOX and DOX were found inside both H1299 and HELF cells after 2-hour incubation (Figure 3, red color). As expected, DOX was observed to localize in cell nuclei (Figure 3, blue color; magenta color is the mix of blue and red). Surprisingly, ATF–HSA:DOX was found to distribute mainly in cytoplasm, but not in nuclei at all. Such distribution pattern remained almost the same after 12-hour incubation for both DOX and ATF–HSA:DOX in both cell lines, except that a trace amount of ATF–HSA:DOX was observed to enter the nuclei in H1299 cells. Therefore, we concluded that DOX embedded into ATF–HSA had a subcellular distribution 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