Limits...
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

In vivo antitumor activity of DOX/DQA-DOX@DSPE-hyd-PEG-AA.A-the variation profiles of tumor volumes. B-body weights of tumor-bearing mice. C-the tumor inhibition of free DOX and DOX/DQA-DOX@DSPE-hyd-PEG-AA. Athymic nude mice xenografted with MDA-MB-231/ADR cells were treated with different doses of DOX/DQA-DOX@DSPE-hyd-PEG-AA (2.0, 10 μmol/kg DOX) and free DOX (10 μmol/kg) every 6 days (day 1, 6 and 12). Data are presented as mean ± SD, n = 4. **p < 0.01, *p < 0.05, vs normal saline; ##p < 0.01, #p < 0.05, vs free DOX.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4632084&req=5

f12: In vivo antitumor activity of DOX/DQA-DOX@DSPE-hyd-PEG-AA.A-the variation profiles of tumor volumes. B-body weights of tumor-bearing mice. C-the tumor inhibition of free DOX and DOX/DQA-DOX@DSPE-hyd-PEG-AA. Athymic nude mice xenografted with MDA-MB-231/ADR cells were treated with different doses of DOX/DQA-DOX@DSPE-hyd-PEG-AA (2.0, 10 μmol/kg DOX) and free DOX (10 μmol/kg) every 6 days (day 1, 6 and 12). Data are presented as mean ± SD, n = 4. **p < 0.01, *p < 0.05, vs normal saline; ##p < 0.01, #p < 0.05, vs free DOX.

Mentions: The in vivo antitumor activities of DOX/DQA-DOX@DSPE-hyd-PEG-AA are showed in Fig. 12. The tumor volume rapidly increased in normal saline treated and free DOX treated mice. However, compared with DOX treated group, same dose of DOX/DQA-DOX@DSPE-hyd-PEG-AA markedly delayed the tumor growth in dose-dependent manner. Besides, the tumor inhibition rate of DOX/DQA-DOX@DSPE-hyd-PEG-AA was higher than that of same dose of free DOX. Furthermore, histopathological analysis of tumor tissue was carried out to further evaluate the antitumor effect, and the representative H&E staining sections are showed in Fig. 13. Compared with tumor section from normal saline and free DOX treated nude mice, tumor section from DOX/DQA-DOX@DSPE-hyd-PEG-AA treated nude mice showed obvious vacuolation, inflammatory cell infiltration and nucleus lysis. This result indicated that DOX/DQA-DOX@DSPE-hyd-PEG-AA enhanced the toxicity of DOX to tumor tissue. The above data implied that simultaneous delivery of DOX to nucleus and mitochondria significantly increased the in vivo antitumor activity of DOX on DOX-resistant tumor.


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)

In vivo antitumor activity of DOX/DQA-DOX@DSPE-hyd-PEG-AA.A-the variation profiles of tumor volumes. B-body weights of tumor-bearing mice. C-the tumor inhibition of free DOX and DOX/DQA-DOX@DSPE-hyd-PEG-AA. Athymic nude mice xenografted with MDA-MB-231/ADR cells were treated with different doses of DOX/DQA-DOX@DSPE-hyd-PEG-AA (2.0, 10 μmol/kg DOX) and free DOX (10 μmol/kg) every 6 days (day 1, 6 and 12). Data are presented as mean ± SD, n = 4. **p < 0.01, *p < 0.05, vs normal saline; ##p < 0.01, #p < 0.05, vs free DOX.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f12: In vivo antitumor activity of DOX/DQA-DOX@DSPE-hyd-PEG-AA.A-the variation profiles of tumor volumes. B-body weights of tumor-bearing mice. C-the tumor inhibition of free DOX and DOX/DQA-DOX@DSPE-hyd-PEG-AA. Athymic nude mice xenografted with MDA-MB-231/ADR cells were treated with different doses of DOX/DQA-DOX@DSPE-hyd-PEG-AA (2.0, 10 μmol/kg DOX) and free DOX (10 μmol/kg) every 6 days (day 1, 6 and 12). Data are presented as mean ± SD, n = 4. **p < 0.01, *p < 0.05, vs normal saline; ##p < 0.01, #p < 0.05, vs free DOX.
Mentions: The in vivo antitumor activities of DOX/DQA-DOX@DSPE-hyd-PEG-AA are showed in Fig. 12. The tumor volume rapidly increased in normal saline treated and free DOX treated mice. However, compared with DOX treated group, same dose of DOX/DQA-DOX@DSPE-hyd-PEG-AA markedly delayed the tumor growth in dose-dependent manner. Besides, the tumor inhibition rate of DOX/DQA-DOX@DSPE-hyd-PEG-AA was higher than that of same dose of free DOX. Furthermore, histopathological analysis of tumor tissue was carried out to further evaluate the antitumor effect, and the representative H&E staining sections are showed in Fig. 13. Compared with tumor section from normal saline and free DOX treated nude mice, tumor section from DOX/DQA-DOX@DSPE-hyd-PEG-AA treated nude mice showed obvious vacuolation, inflammatory cell infiltration and nucleus lysis. This result indicated that DOX/DQA-DOX@DSPE-hyd-PEG-AA enhanced the toxicity of DOX to tumor tissue. The above data implied that simultaneous delivery of DOX to nucleus and mitochondria significantly increased the in vivo antitumor activity of DOX on DOX-resistant tumor.

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