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Dual subcellular compartment delivery of doxorubicin to overcome drug resistant and enhance antitumor activity.

Song YF, Liu DZ, Cheng Y, Liu M, Ye WL, Zhang BL, Liu XY, Zhou SY - Sci Rep (2015)

Bottom Line: Drug released from DOX/DQA-DOX@DSPE-hyd-PEG-AA showed a pH-dependent manner.After DOX/DQA-DOX@DSPE-hyd-PEG-AA was injected to the tumor-bearing nude mice by the tail vein, DOX was mainly found in tumor tissue.But DOX was widely distributed in the whole body after the administration of free DOX.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China.

ABSTRACT
In order to overcome drug resistant and enhance antitumor activity of DOX, a new pH-sensitive micelle (DOX/DQA-DOX@DSPE-hyd-PEG-AA) was prepared to simultaneously deliver DOX to nucleus and mitochondria. Drug released from DOX/DQA-DOX@DSPE-hyd-PEG-AA showed a pH-dependent manner. DOX/DQA-DOX@DSPE-hyd-PEG-AA induced the depolarization of mitochondria and apoptosis in MDA-MB-231/ADR cells and A549 cells, which resulted in the high cytotoxicity of DOX/DQA-DOX@DSPE-hyd-PEG-AA against MDA-MB-231/ADR cells and A549 cells. Confocal microscopy confirmed that DOX/DQA-DOX@DSPE-hyd-PEG-AA simultaneously delivered DQA-DOX and DOX to the mitochondria and nucleus of tumor cell. After DOX/DQA-DOX@DSPE-hyd-PEG-AA was injected to the tumor-bearing nude mice by the tail vein, DOX was mainly found in tumor tissue. But DOX was widely distributed in the whole body after the administration of free DOX. Compared with free DOX, the same dose of DOX/DQA-DOX@DSPE-hyd-PEG-AA significantly inhibited the growth of DOX-resistant tumor in tumor-bearing mice without obvious systemic toxicity. Therefore, dual subcellular compartment delivery of DOX greatly enhanced the antitumor activity of DOX on DOX-resistant tumor. DOX/DQA-DOX@DSPE-hyd-PEG-AA has the potential in target therapy for DOX-resistant tumor.

No MeSH data available.


Related in: MedlinePlus

The effect of DOX and DQA-DOX on caspase3 activity in A549 cells (A) and MDA-MB-231/ADR cells (B) in 24 h. The effect of DOX/DQA-DOX@DSPE-hyd-PEG-AA and DOX@DSPE-hyd-PEG-AA on caspase3 activity in A549 cells (C) and MDA-MB-231/ADR cells (D) in 24 h. Data are presented as mean ± SD, n = 3. **p < 0.01, *p < 0.05, vs control; ##p < 0.01, #p < 0.05, vs the same dose of DOX or DOX@DSPE-hyd-PEG-AA.
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f7: The effect of DOX and DQA-DOX on caspase3 activity in A549 cells (A) and MDA-MB-231/ADR cells (B) in 24 h. The effect of DOX/DQA-DOX@DSPE-hyd-PEG-AA and DOX@DSPE-hyd-PEG-AA on caspase3 activity in A549 cells (C) and MDA-MB-231/ADR cells (D) in 24 h. Data are presented as mean ± SD, n = 3. **p < 0.01, *p < 0.05, vs control; ##p < 0.01, #p < 0.05, vs the same dose of DOX or DOX@DSPE-hyd-PEG-AA.

Mentions: A number of findings supported that cytotoxicity of DOX was resulted from inducing apoptosis5859. Caspase3 is a key executive molecule of apoptosis. In addition, it was reported when mitochondrial membrane potential were damaged, it led to the increase of caspase3 in the cell60. Thus, the effects of free DOX, DQA-DOX, DOX@DSPE-hyd-PEG-AA and DOX/DQA-DOX@DSPE-hyd-PEG-AA on the level of caspase3 in tumor cell were investigated. After A549 cells and MDA-MB-231/ADR cells were treated with different concentration of free DQA-DOX for 24 h, the cell apoptosis are showed in Fig. 7A,B, respectively. Compared with free DOX, free DQA-DOX induced less apoptosis on A549 cells. But free DQA-DOX induced much more apoptosis on MDA-MB-231/ADR cells as compared with free DOX. The above results were consistent with the cytotoxicity of free DQA-DOX on A549 cells and MDA-MB-231/ADR cells.


Dual subcellular compartment delivery of doxorubicin to overcome drug resistant and enhance antitumor activity.

Song YF, Liu DZ, Cheng Y, Liu M, Ye WL, Zhang BL, Liu XY, Zhou SY - Sci Rep (2015)

The effect of DOX and DQA-DOX on caspase3 activity in A549 cells (A) and MDA-MB-231/ADR cells (B) in 24 h. The effect of DOX/DQA-DOX@DSPE-hyd-PEG-AA and DOX@DSPE-hyd-PEG-AA on caspase3 activity in A549 cells (C) and MDA-MB-231/ADR cells (D) in 24 h. Data are presented as mean ± SD, n = 3. **p < 0.01, *p < 0.05, vs control; ##p < 0.01, #p < 0.05, vs the same dose of DOX or DOX@DSPE-hyd-PEG-AA.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4632084&req=5

f7: The effect of DOX and DQA-DOX on caspase3 activity in A549 cells (A) and MDA-MB-231/ADR cells (B) in 24 h. The effect of DOX/DQA-DOX@DSPE-hyd-PEG-AA and DOX@DSPE-hyd-PEG-AA on caspase3 activity in A549 cells (C) and MDA-MB-231/ADR cells (D) in 24 h. Data are presented as mean ± SD, n = 3. **p < 0.01, *p < 0.05, vs control; ##p < 0.01, #p < 0.05, vs the same dose of DOX or DOX@DSPE-hyd-PEG-AA.
Mentions: A number of findings supported that cytotoxicity of DOX was resulted from inducing apoptosis5859. Caspase3 is a key executive molecule of apoptosis. In addition, it was reported when mitochondrial membrane potential were damaged, it led to the increase of caspase3 in the cell60. Thus, the effects of free DOX, DQA-DOX, DOX@DSPE-hyd-PEG-AA and DOX/DQA-DOX@DSPE-hyd-PEG-AA on the level of caspase3 in tumor cell were investigated. After A549 cells and MDA-MB-231/ADR cells were treated with different concentration of free DQA-DOX for 24 h, the cell apoptosis are showed in Fig. 7A,B, respectively. Compared with free DOX, free DQA-DOX induced less apoptosis on A549 cells. But free DQA-DOX induced much more apoptosis on MDA-MB-231/ADR cells as compared with free DOX. The above results were consistent with the cytotoxicity of free DQA-DOX on A549 cells and MDA-MB-231/ADR cells.

Bottom Line: Drug released from DOX/DQA-DOX@DSPE-hyd-PEG-AA showed a pH-dependent manner.After DOX/DQA-DOX@DSPE-hyd-PEG-AA was injected to the tumor-bearing nude mice by the tail vein, DOX was mainly found in tumor tissue.But DOX was widely distributed in the whole body after the administration of free DOX.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China.

ABSTRACT
In order to overcome drug resistant and enhance antitumor activity of DOX, a new pH-sensitive micelle (DOX/DQA-DOX@DSPE-hyd-PEG-AA) was prepared to simultaneously deliver DOX to nucleus and mitochondria. Drug released from DOX/DQA-DOX@DSPE-hyd-PEG-AA showed a pH-dependent manner. DOX/DQA-DOX@DSPE-hyd-PEG-AA induced the depolarization of mitochondria and apoptosis in MDA-MB-231/ADR cells and A549 cells, which resulted in the high cytotoxicity of DOX/DQA-DOX@DSPE-hyd-PEG-AA against MDA-MB-231/ADR cells and A549 cells. Confocal microscopy confirmed that DOX/DQA-DOX@DSPE-hyd-PEG-AA simultaneously delivered DQA-DOX and DOX to the mitochondria and nucleus of tumor cell. After DOX/DQA-DOX@DSPE-hyd-PEG-AA was injected to the tumor-bearing nude mice by the tail vein, DOX was mainly found in tumor tissue. But DOX was widely distributed in the whole body after the administration of free DOX. Compared with free DOX, the same dose of DOX/DQA-DOX@DSPE-hyd-PEG-AA significantly inhibited the growth of DOX-resistant tumor in tumor-bearing mice without obvious systemic toxicity. Therefore, dual subcellular compartment delivery of DOX greatly enhanced the antitumor activity of DOX on DOX-resistant tumor. DOX/DQA-DOX@DSPE-hyd-PEG-AA has the potential in target therapy for DOX-resistant tumor.

No MeSH data available.


Related in: MedlinePlus