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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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Anti-tumor effect of siRNA targeting P-glycoprotein (siMDR1) in DOPE-PEI nanocarriers and Dox using nude mice bearing MCF-7/ADR tumors. Mice were intravenously injected once per week with BHG, free siRNA or different DOPE-PEI formulations followed by Dox injection (after 48 h) for 5 weeks. (A) Relative tumor volume (RTV) and (B) tumor weight ratio for the different treatments. Results are plotted as mean ± SD. (n=5). (C) Levels of mRNA MDR1 and (D) P-glycoprotein at the final time-point. Results are plotted as mean ± SD (n=5, C and D performed in duplicates and triplicates, respectively). *P < 0.001 vs BHG, free siMDR1 and DOPE-PEI/scramble siRNA.
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Figure 5: Anti-tumor effect of siRNA targeting P-glycoprotein (siMDR1) in DOPE-PEI nanocarriers and Dox using nude mice bearing MCF-7/ADR tumors. Mice were intravenously injected once per week with BHG, free siRNA or different DOPE-PEI formulations followed by Dox injection (after 48 h) for 5 weeks. (A) Relative tumor volume (RTV) and (B) tumor weight ratio for the different treatments. Results are plotted as mean ± SD. (n=5). (C) Levels of mRNA MDR1 and (D) P-glycoprotein at the final time-point. Results are plotted as mean ± SD (n=5, C and D performed in duplicates and triplicates, respectively). *P < 0.001 vs BHG, free siMDR1 and DOPE-PEI/scramble siRNA.

Mentions: The therapeutic effect of siRNA targeting P-glycoprotein (siMDR1) formulated in DOPE-PEI nanocarriers (PEGylated and non-PEGylated) in combination with Dox was evaluated in resistant breast MCF-7/ADR tumors (Fig. 5). The mice were randomized for treatment after the s.c. tumor volume reached 60 mm3. The dosing regimen was one naked siRNA or formulation containing siRNA injection followed by one Dox injection after 48 h (sequential regimen). This dosing regimen was carried on for 5 weeks. Five days after the final dose, the mice were sacrificed. The Dox effect was assessed by monitoring the tumor volume during the treatment and by the final weight of the post-mortem excised tumors. Although, in this study we aimed just to confirm the improved therapeutic outcome by using the suggested preparation rather than to analyze its detailed action mechanism, the P-gp downregulation is clearly be as shown by us and in similar setting by quantifying the levels of P-gp (mRNA and protein) in the experimental tumors as in 34-36.


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)

Anti-tumor effect of siRNA targeting P-glycoprotein (siMDR1) in DOPE-PEI nanocarriers and Dox using nude mice bearing MCF-7/ADR tumors. Mice were intravenously injected once per week with BHG, free siRNA or different DOPE-PEI formulations followed by Dox injection (after 48 h) for 5 weeks. (A) Relative tumor volume (RTV) and (B) tumor weight ratio for the different treatments. Results are plotted as mean ± SD. (n=5). (C) Levels of mRNA MDR1 and (D) P-glycoprotein at the final time-point. Results are plotted as mean ± SD (n=5, C and D performed in duplicates and triplicates, respectively). *P < 0.001 vs BHG, free siMDR1 and DOPE-PEI/scramble siRNA.
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Related In: Results  -  Collection

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Figure 5: Anti-tumor effect of siRNA targeting P-glycoprotein (siMDR1) in DOPE-PEI nanocarriers and Dox using nude mice bearing MCF-7/ADR tumors. Mice were intravenously injected once per week with BHG, free siRNA or different DOPE-PEI formulations followed by Dox injection (after 48 h) for 5 weeks. (A) Relative tumor volume (RTV) and (B) tumor weight ratio for the different treatments. Results are plotted as mean ± SD. (n=5). (C) Levels of mRNA MDR1 and (D) P-glycoprotein at the final time-point. Results are plotted as mean ± SD (n=5, C and D performed in duplicates and triplicates, respectively). *P < 0.001 vs BHG, free siMDR1 and DOPE-PEI/scramble siRNA.
Mentions: The therapeutic effect of siRNA targeting P-glycoprotein (siMDR1) formulated in DOPE-PEI nanocarriers (PEGylated and non-PEGylated) in combination with Dox was evaluated in resistant breast MCF-7/ADR tumors (Fig. 5). The mice were randomized for treatment after the s.c. tumor volume reached 60 mm3. The dosing regimen was one naked siRNA or formulation containing siRNA injection followed by one Dox injection after 48 h (sequential regimen). This dosing regimen was carried on for 5 weeks. Five days after the final dose, the mice were sacrificed. The Dox effect was assessed by monitoring the tumor volume during the treatment and by the final weight of the post-mortem excised tumors. Although, in this study we aimed just to confirm the improved therapeutic outcome by using the suggested preparation rather than to analyze its detailed action mechanism, the P-gp downregulation is clearly be as shown by us and in similar setting by quantifying the levels of P-gp (mRNA and protein) in the experimental tumors as in 34-36.

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