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Phospholipid-modified PEI-based nanocarriers for in vivo siRNA therapeutics against multidrug-resistant tumors.

Essex S, Navarro G, Sabhachandani P, Chordia A, Trivedi M, Movassaghian S, Torchilin VP - Gene Ther. (2014)

Bottom Line: First, we studied the biodistribution of DOPE-PEI nanocarriers and the effect of PEG coating in a subcutaneous breast tumor model.Four hours postinjection, PEGylated carriers showed an 8% injected dose (ID) accumulation in solid tumor via the enhanced permeability and retention effect and 22% ID in serum due to a prolonged, PEG-mediated circulation.Second, we established the therapeutic efficacy and safety of DOPE-PEI/siRNA-mediated P-gp downregulation in combination with doxorubicin (Dox) chemotherapy in MCF-7/MDR xenografts.

View Article: PubMed Central - PubMed

Affiliation: Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115, USA.

ABSTRACT
Multidrug resistance (MDR) mediated by P-glycoprotein overexpression in solid tumors is a major factor in the failure of many forms of chemotherapy. Here we evaluated phospholipid-modified, low-molecular-weight polyethylenimine (DOPE-PEI) nanocarriers for intravenous delivery of anti-P-pg siRNA to tumors with the final goal of modulating MDR in breast cancer. First, we studied the biodistribution of DOPE-PEI nanocarriers and the effect of PEG coating in a subcutaneous breast tumor model. Four hours postinjection, PEGylated carriers showed an 8% injected dose (ID) accumulation in solid tumor via the enhanced permeability and retention effect and 22% ID in serum due to a prolonged, PEG-mediated circulation. Second, we established the therapeutic efficacy and safety of DOPE-PEI/siRNA-mediated P-gp downregulation in combination with doxorubicin (Dox) chemotherapy in MCF-7/MDR xenografts. Weekly injection of siRNA nanopreparations and Dox for up to 5 weeks sensitized the tumors to otherwise non-effective doses of Dox and decreased the tumor volume by threefold vs controls. This therapeutic improvement in response to Dox was attributed to the significant, sequence-specific P-gp downregulation in excised tumors mediated by the DOPE-PEI formulations.

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Levels of mRNA MDR1 in orthotopic and s.c. tumors measured 5 weeks after tumor implantation by qRT-PCR.
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Figure 4: Levels of mRNA MDR1 in orthotopic and s.c. tumors measured 5 weeks after tumor implantation by qRT-PCR.

Mentions: Due to the conflicting literature regarding the development of MCF-7/ADR tumors and the need for β-estradiol supplementation for the growth of MCF7/ADR xenografts 29-33, we decided to first optimize tumorigenic conditions for MCF7/ADR cells in female nude mice. Mice were injected orthotopically in the mammary fat pad or subcutaneously (s.c.) over the right flank with these cells as described in the methods section. The tumors were allowed to develop for five weeks after which the mice were sacrificed and their tumors excised. The tumors sizes in the two orthotopic tumors MCF-7/ADR were similar with or without estrogen supplementation (mean volume approx. 40 mm3). The qRT-PCR data clearly showed that the MDR1 levels in the MCF7/ADR orthotopic tumors in the presence or absence of the estradiol were very similar suggesting that, in contrast to orthotopic MCF7/S tumors, the growth of MCF7/ADR orthotopic tumors was estrogen-independent. The implantation of the estradiol pellet did not affect tumor volume or MDR1 gene expression five weeks post-tumor inoculation. On the other hand, the subcutaneous (s.c) tumors (about 100 mm3) had a lower MDR1 level compared to the MCF7/ADR orthotopic tumors, albeit they had significantly higher MDR1 levels than the orthotopic MCF7/S tumors (Fig. 4). The s.c. model was chosen for the final therapeutic efficacy experiments since larger tumors were obtained in a shorter period of time, and the tumors retained high MDR1 levels.


Phospholipid-modified PEI-based nanocarriers for in vivo siRNA therapeutics against multidrug-resistant tumors.

Essex S, Navarro G, Sabhachandani P, Chordia A, Trivedi M, Movassaghian S, Torchilin VP - Gene Ther. (2014)

Levels of mRNA MDR1 in orthotopic and s.c. tumors measured 5 weeks after tumor implantation by qRT-PCR.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4352110&req=5

Figure 4: Levels of mRNA MDR1 in orthotopic and s.c. tumors measured 5 weeks after tumor implantation by qRT-PCR.
Mentions: Due to the conflicting literature regarding the development of MCF-7/ADR tumors and the need for β-estradiol supplementation for the growth of MCF7/ADR xenografts 29-33, we decided to first optimize tumorigenic conditions for MCF7/ADR cells in female nude mice. Mice were injected orthotopically in the mammary fat pad or subcutaneously (s.c.) over the right flank with these cells as described in the methods section. The tumors were allowed to develop for five weeks after which the mice were sacrificed and their tumors excised. The tumors sizes in the two orthotopic tumors MCF-7/ADR were similar with or without estrogen supplementation (mean volume approx. 40 mm3). The qRT-PCR data clearly showed that the MDR1 levels in the MCF7/ADR orthotopic tumors in the presence or absence of the estradiol were very similar suggesting that, in contrast to orthotopic MCF7/S tumors, the growth of MCF7/ADR orthotopic tumors was estrogen-independent. The implantation of the estradiol pellet did not affect tumor volume or MDR1 gene expression five weeks post-tumor inoculation. On the other hand, the subcutaneous (s.c) tumors (about 100 mm3) had a lower MDR1 level compared to the MCF7/ADR orthotopic tumors, albeit they had significantly higher MDR1 levels than the orthotopic MCF7/S tumors (Fig. 4). The s.c. model was chosen for the final therapeutic efficacy experiments since larger tumors were obtained in a shorter period of time, and the tumors retained high MDR1 levels.

Bottom Line: First, we studied the biodistribution of DOPE-PEI nanocarriers and the effect of PEG coating in a subcutaneous breast tumor model.Four hours postinjection, PEGylated carriers showed an 8% injected dose (ID) accumulation in solid tumor via the enhanced permeability and retention effect and 22% ID in serum due to a prolonged, PEG-mediated circulation.Second, we established the therapeutic efficacy and safety of DOPE-PEI/siRNA-mediated P-gp downregulation in combination with doxorubicin (Dox) chemotherapy in MCF-7/MDR xenografts.

View Article: PubMed Central - PubMed

Affiliation: Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115, USA.

ABSTRACT
Multidrug resistance (MDR) mediated by P-glycoprotein overexpression in solid tumors is a major factor in the failure of many forms of chemotherapy. Here we evaluated phospholipid-modified, low-molecular-weight polyethylenimine (DOPE-PEI) nanocarriers for intravenous delivery of anti-P-pg siRNA to tumors with the final goal of modulating MDR in breast cancer. First, we studied the biodistribution of DOPE-PEI nanocarriers and the effect of PEG coating in a subcutaneous breast tumor model. Four hours postinjection, PEGylated carriers showed an 8% injected dose (ID) accumulation in solid tumor via the enhanced permeability and retention effect and 22% ID in serum due to a prolonged, PEG-mediated circulation. Second, we established the therapeutic efficacy and safety of DOPE-PEI/siRNA-mediated P-gp downregulation in combination with doxorubicin (Dox) chemotherapy in MCF-7/MDR xenografts. Weekly injection of siRNA nanopreparations and Dox for up to 5 weeks sensitized the tumors to otherwise non-effective doses of Dox and decreased the tumor volume by threefold vs controls. This therapeutic improvement in response to Dox was attributed to the significant, sequence-specific P-gp downregulation in excised tumors mediated by the DOPE-PEI formulations.

Show MeSH
Related in: MedlinePlus