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

ECIS results for H1299 cells incubated with or without 50 μM ATF–HSA:DOX or DOX.Notes: Time course of the impedance values measured by ECIS at 16,000 Hz using H1299 cells treated with ATF–HSA:DOX (50 μM) or DOX (50 μM) for 12 hours, and the photographs of the cells at the end of the experiment. DOX shows a higher cytotoxicity on H1299 cells compared with ATF–HSA:DOX. Magnification ×200.Abbreviations: ATF, amino-terminal fragment of urokinase; DOX, doxorubicin; ECIS, electric cell-substrate impedance sensing; HSA, human serum albumin.
© Copyright Policy
Related In: Results  -  Collection

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

f4-ijn-10-5327: ECIS results for H1299 cells incubated with or without 50 μM ATF–HSA:DOX or DOX.Notes: Time course of the impedance values measured by ECIS at 16,000 Hz using H1299 cells treated with ATF–HSA:DOX (50 μM) or DOX (50 μM) for 12 hours, and the photographs of the cells at the end of the experiment. DOX shows a higher cytotoxicity on H1299 cells compared with ATF–HSA:DOX. Magnification ×200.Abbreviations: ATF, amino-terminal fragment of urokinase; DOX, doxorubicin; ECIS, electric cell-substrate impedance sensing; HSA, human serum albumin.

Mentions: To compare the cytotoxicities of ATF–HSA:DOX and free DOX on H1299 cells, we used a sensitive, noninvasive and in situ method named electric cell-substrate impedance sensing (ECIS) in our experiments. The cells were grown on the gold electrodes attached at the bottom of the ECIS plates. The electric impedance values measured are proportional to the number of live cells attached to the plate, while cells detaching from the gold electrodes will not contribute to impedance values. The results of ECIS for H1299 cells incubated with or without 50 μM ATF–HSA:DOX or DOX were shown in Figure 4. In the absence of DOX or ATF–HSA:DOX, H1299 cells continued to grow, leading to the rise of the impedance (Figure 4). In the presence of DOX, the cells started to die at the fifth hour, and after 12 hours only a few cells were alive and a large quantity of cell debris was visible (Figure 4). ATF–HSA:DOX showed some toxicity, but not as cytotoxic as DOX (Figure 4) at the same dosage (50 μM). This difference between DOX and ATF–HSA:DOX is in line with the different subcellular localization and the different amounts of cellular uptake stated in the section ATF-HSA:DOX reduces the cellular uptake of DOX and ATF-HSA:DOX distributes mainly in cytoplasm, DOX in nuclei.


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)

ECIS results for H1299 cells incubated with or without 50 μM ATF–HSA:DOX or DOX.Notes: Time course of the impedance values measured by ECIS at 16,000 Hz using H1299 cells treated with ATF–HSA:DOX (50 μM) or DOX (50 μM) for 12 hours, and the photographs of the cells at the end of the experiment. DOX shows a higher cytotoxicity on H1299 cells compared with ATF–HSA:DOX. Magnification ×200.Abbreviations: ATF, amino-terminal fragment of urokinase; DOX, doxorubicin; ECIS, electric cell-substrate impedance sensing; HSA, human serum albumin.
© Copyright Policy
Related In: Results  -  Collection

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

f4-ijn-10-5327: ECIS results for H1299 cells incubated with or without 50 μM ATF–HSA:DOX or DOX.Notes: Time course of the impedance values measured by ECIS at 16,000 Hz using H1299 cells treated with ATF–HSA:DOX (50 μM) or DOX (50 μM) for 12 hours, and the photographs of the cells at the end of the experiment. DOX shows a higher cytotoxicity on H1299 cells compared with ATF–HSA:DOX. Magnification ×200.Abbreviations: ATF, amino-terminal fragment of urokinase; DOX, doxorubicin; ECIS, electric cell-substrate impedance sensing; HSA, human serum albumin.
Mentions: To compare the cytotoxicities of ATF–HSA:DOX and free DOX on H1299 cells, we used a sensitive, noninvasive and in situ method named electric cell-substrate impedance sensing (ECIS) in our experiments. The cells were grown on the gold electrodes attached at the bottom of the ECIS plates. The electric impedance values measured are proportional to the number of live cells attached to the plate, while cells detaching from the gold electrodes will not contribute to impedance values. The results of ECIS for H1299 cells incubated with or without 50 μM ATF–HSA:DOX or DOX were shown in Figure 4. In the absence of DOX or ATF–HSA:DOX, H1299 cells continued to grow, leading to the rise of the impedance (Figure 4). In the presence of DOX, the cells started to die at the fifth hour, and after 12 hours only a few cells were alive and a large quantity of cell debris was visible (Figure 4). ATF–HSA:DOX showed some toxicity, but not as cytotoxic as DOX (Figure 4) at the same dosage (50 μM). This difference between DOX and ATF–HSA:DOX is in line with the different subcellular localization and the different amounts of cellular uptake stated in the section ATF-HSA:DOX reduces the cellular uptake of DOX and ATF-HSA:DOX distributes mainly in cytoplasm, DOX in nuclei.

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