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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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Biodistribution of fluorescein-labeled siRNA either naked or complexed in formulations 4 h post injection. Results are expressed as mean percentage of injected dose (%ID)g of tissue or mL of serum ± SD (n=5); *P<0.05, ***P<0.001 vs the naked siRNA group.
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Figure 3: Biodistribution of fluorescein-labeled siRNA either naked or complexed in formulations 4 h post injection. Results are expressed as mean percentage of injected dose (%ID)g of tissue or mL of serum ± SD (n=5); *P<0.05, ***P<0.001 vs the naked siRNA group.

Mentions: For biodistribution studies, 4T1 murine breast cancer cells were chosen to induce tumors since this is a well-established animal model closely mimicking human metastatic breast cancer 28, and it is fairly simple to induce these tumors quickly in female Balb/c mice. Figure 3 depicts the biodistribution 4 h post-injection of fluorescently labeled siRNA loading with different formulations. Our data indicate an enhanced blood circulation for DOPE-PEI/PEG/siRNA complexes when compared to DOPE-PEI/siRNA complexes (22%ID vs 9% ID) and naked siRNA, for which no detectable fluorescence signal was measured. PEGylated formulations had significantly better tumor accumulation as compared to naked siRNA (8% ID vs 4% ID). DOPE-PEI nanocarriers delivered higher siRNA doses in lung and liver as compared to PEGylated formulations (14% ID vs 6% ID and 19% ID vs 13% ID, respectively). Inclusion of PEG-PE in formulations shielded the non-specific interactions with these organs and led to % ID values similar to those of the naked siRNA. The highest fluorescent signal of about 20% ID was detected in kidney where no difference between formulated and non-formulated siRNA accumulation was observed.


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)

Biodistribution of fluorescein-labeled siRNA either naked or complexed in formulations 4 h post injection. Results are expressed as mean percentage of injected dose (%ID)g of tissue or mL of serum ± SD (n=5); *P<0.05, ***P<0.001 vs the naked siRNA group.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 3: Biodistribution of fluorescein-labeled siRNA either naked or complexed in formulations 4 h post injection. Results are expressed as mean percentage of injected dose (%ID)g of tissue or mL of serum ± SD (n=5); *P<0.05, ***P<0.001 vs the naked siRNA group.
Mentions: For biodistribution studies, 4T1 murine breast cancer cells were chosen to induce tumors since this is a well-established animal model closely mimicking human metastatic breast cancer 28, and it is fairly simple to induce these tumors quickly in female Balb/c mice. Figure 3 depicts the biodistribution 4 h post-injection of fluorescently labeled siRNA loading with different formulations. Our data indicate an enhanced blood circulation for DOPE-PEI/PEG/siRNA complexes when compared to DOPE-PEI/siRNA complexes (22%ID vs 9% ID) and naked siRNA, for which no detectable fluorescence signal was measured. PEGylated formulations had significantly better tumor accumulation as compared to naked siRNA (8% ID vs 4% ID). DOPE-PEI nanocarriers delivered higher siRNA doses in lung and liver as compared to PEGylated formulations (14% ID vs 6% ID and 19% ID vs 13% ID, respectively). Inclusion of PEG-PE in formulations shielded the non-specific interactions with these organs and led to % ID values similar to those of the naked siRNA. The highest fluorescent signal of about 20% ID was detected in kidney where no difference between formulated and non-formulated siRNA accumulation was observed.

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