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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 cellular uptake of DOX@DSPE-hyd-PEG-AA (A), DOX/DQA-DOX@DSPE-hyd-PEG-AA (B) and DOX/DQA-DOX@DSPE-hyd-PEG-AA+AA (C) on A549 cell in 4 h. 60×oil immersion objective and 10×ocular lens. The quantitative analysis of DOX distribution in nucleus and cytoplasm on A549 cell (D). The pink region indicates the localization of DOX (red) in the nucleus (blue). **p < 0.01, vs nucleus of DOX/DQA-DOX@DSPE-hyd-PEG-AA+AA; &&p < 0.01, vs nucleus of DOX@DSPE-hyd-PEG-AA; ##p < 0.01 vs cytoplasm of DOX/DQA-DOX@DSPE-hyd-PEG-AA+AA; @@p < 0.01 vs cytoplasm of DOX@DSPE-hyd-PEG-AA.
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f9: The cellular uptake of DOX@DSPE-hyd-PEG-AA (A), DOX/DQA-DOX@DSPE-hyd-PEG-AA (B) and DOX/DQA-DOX@DSPE-hyd-PEG-AA+AA (C) on A549 cell in 4 h. 60×oil immersion objective and 10×ocular lens. The quantitative analysis of DOX distribution in nucleus and cytoplasm on A549 cell (D). The pink region indicates the localization of DOX (red) in the nucleus (blue). **p < 0.01, vs nucleus of DOX/DQA-DOX@DSPE-hyd-PEG-AA+AA; &&p < 0.01, vs nucleus of DOX@DSPE-hyd-PEG-AA; ##p < 0.01 vs cytoplasm of DOX/DQA-DOX@DSPE-hyd-PEG-AA+AA; @@p < 0.01 vs cytoplasm of DOX@DSPE-hyd-PEG-AA.

Mentions: The cellular uptake of DOX@DSPE-hyd-PEG-AA and DOX/DQA-DOX @DSPE-hyd-PEG-AA were evaluated by CLSM, the results are showed in Fig 9. When A549 cells were cultured with DOX@DSPE-hyd-PEG-AA, the red DOX fluorescence was mainly distributed in the nucleus. When A549 cells were cultured with DOX/DQA-DOX@DSPE-hyd-PEG-AA, large amount of red DOX fluorescence was found in the cytoplasm and nucleus. Compared with nucleus, the mean fluorescence intensity in cytoplasm was higher. This was due to the disassembly of DOX/DQA-DOX@DSPE-hyd-PEG-AA in endolysosomes, subsequently led to the burst release of DOX and DQA-DOX. Finally, DOX and DQA-DOX trafficked to the nucleus and mitochondria. When DOX/DQA-DOX@DSPE-hyd-PEG-AA and exogenous free AA were co-cultured with A549 cells, the mean fluorescence intensity in the cytoplasm and nucleus was significantly reduced. Moreover, MTT experiment indicated exogenous AA could reduce the cytotoxicity of DOX/DQA-DOX@DSPE-hyd-PEG-AA on tumor cells. These results indicated that the cellular uptake of DOX/DQA-DOX@DSPE-hyd-PEG-AA was mediated by sigma receptor.


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 cellular uptake of DOX@DSPE-hyd-PEG-AA (A), DOX/DQA-DOX@DSPE-hyd-PEG-AA (B) and DOX/DQA-DOX@DSPE-hyd-PEG-AA+AA (C) on A549 cell in 4 h. 60×oil immersion objective and 10×ocular lens. The quantitative analysis of DOX distribution in nucleus and cytoplasm on A549 cell (D). The pink region indicates the localization of DOX (red) in the nucleus (blue). **p < 0.01, vs nucleus of DOX/DQA-DOX@DSPE-hyd-PEG-AA+AA; &&p < 0.01, vs nucleus of DOX@DSPE-hyd-PEG-AA; ##p < 0.01 vs cytoplasm of DOX/DQA-DOX@DSPE-hyd-PEG-AA+AA; @@p < 0.01 vs cytoplasm of DOX@DSPE-hyd-PEG-AA.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f9: The cellular uptake of DOX@DSPE-hyd-PEG-AA (A), DOX/DQA-DOX@DSPE-hyd-PEG-AA (B) and DOX/DQA-DOX@DSPE-hyd-PEG-AA+AA (C) on A549 cell in 4 h. 60×oil immersion objective and 10×ocular lens. The quantitative analysis of DOX distribution in nucleus and cytoplasm on A549 cell (D). The pink region indicates the localization of DOX (red) in the nucleus (blue). **p < 0.01, vs nucleus of DOX/DQA-DOX@DSPE-hyd-PEG-AA+AA; &&p < 0.01, vs nucleus of DOX@DSPE-hyd-PEG-AA; ##p < 0.01 vs cytoplasm of DOX/DQA-DOX@DSPE-hyd-PEG-AA+AA; @@p < 0.01 vs cytoplasm of DOX@DSPE-hyd-PEG-AA.
Mentions: The cellular uptake of DOX@DSPE-hyd-PEG-AA and DOX/DQA-DOX @DSPE-hyd-PEG-AA were evaluated by CLSM, the results are showed in Fig 9. When A549 cells were cultured with DOX@DSPE-hyd-PEG-AA, the red DOX fluorescence was mainly distributed in the nucleus. When A549 cells were cultured with DOX/DQA-DOX@DSPE-hyd-PEG-AA, large amount of red DOX fluorescence was found in the cytoplasm and nucleus. Compared with nucleus, the mean fluorescence intensity in cytoplasm was higher. This was due to the disassembly of DOX/DQA-DOX@DSPE-hyd-PEG-AA in endolysosomes, subsequently led to the burst release of DOX and DQA-DOX. Finally, DOX and DQA-DOX trafficked to the nucleus and mitochondria. When DOX/DQA-DOX@DSPE-hyd-PEG-AA and exogenous free AA were co-cultured with A549 cells, the mean fluorescence intensity in the cytoplasm and nucleus was significantly reduced. Moreover, MTT experiment indicated exogenous AA could reduce the cytotoxicity of DOX/DQA-DOX@DSPE-hyd-PEG-AA on tumor cells. These results indicated that the cellular uptake of DOX/DQA-DOX@DSPE-hyd-PEG-AA was mediated by sigma receptor.

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