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Targeted antiepidermal growth factor receptor (cetuximab) immunoliposomes enhance cellular uptake in vitro and exhibit increased accumulation in an intracranial model of glioblastoma multiforme.

Mortensen JH, Jeppesen M, Pilgaard L, Agger R, Duroux M, Zachar V, Moos T - J Drug Deliv (2013)

Bottom Line: Therapeutic advances do not circumvent the devastating fact that the survival rate in glioblastoma multiforme (GBM) is less than 5%.The in vitro studies revealed significantly higher binding of α -hEGFR-ILs when compared with liposomes conjugated with isotypic nonimmune immunoglobulin.The data show that α -hEGFR-ILs significantly enhance the uptake and accumulation of liposomes in this experimental model of GBM suggestive of improved specific nanoparticle-based delivery.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Cancer Biology, Biomedicine, Institute of Medicine and Health Technology, Fredrik Bajers Vej 3B, 1.216, Aalborg University, 9220 Aalborg East, Denmark.

ABSTRACT
Therapeutic advances do not circumvent the devastating fact that the survival rate in glioblastoma multiforme (GBM) is less than 5%. Nanoparticles consisting of liposome-based therapeutics are provided against a variety of cancer types including GBM, but available liposomal formulations are provided without targeting moieties, which increases the dosing demands to reach therapeutic concentrations with risks of side effects. We prepared PEGylated immunoliposomes (ILs) conjugated with anti-human epidermal growth factor receptor (EGFR) antibodies Cetuximab ( α -hEGFR-ILs). The affinity of the α -hEGFR-ILs for the EGF receptor was evaluated in vitro using U87 mg and U251 mg cells and in vivo using an intracranial U87 mg xenograft model. The xenograft model was additionally analyzed with respect to permeability to endogenous albumin, tumor size, and vascularization. The in vitro studies revealed significantly higher binding of α -hEGFR-ILs when compared with liposomes conjugated with isotypic nonimmune immunoglobulin. The uptake and internalization of the α -hEGFR-ILs by U87 mg cells were further confirmed by 3D deconvolution analyses. In vivo, the α -hEGFR-ILs accumulated to a higher extent inside the tumor when compared to nonimmune liposomes. The data show that α -hEGFR-ILs significantly enhance the uptake and accumulation of liposomes in this experimental model of GBM suggestive of improved specific nanoparticle-based delivery.

No MeSH data available.


Related in: MedlinePlus

FACS analysis showing enhanced cellular binding of α-hEGFR-IL's in U87 mg (a) and U251 mg (b) cell lines. The targeting efficiency of the α-hEGFR-IL's (green histograms) was evaluated by comparing mean fluorescence intensities (MFI) with hIgG-IL's (orange histograms), or naked liposome (blue histograms) and cells not exposed to liposomes (black histograms). (c), (d) Comparison of the liposomal MFI of U87 mg (c) and U251 mg (d). *P < 0.05, Lp, liposome.
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fig4: FACS analysis showing enhanced cellular binding of α-hEGFR-IL's in U87 mg (a) and U251 mg (b) cell lines. The targeting efficiency of the α-hEGFR-IL's (green histograms) was evaluated by comparing mean fluorescence intensities (MFI) with hIgG-IL's (orange histograms), or naked liposome (blue histograms) and cells not exposed to liposomes (black histograms). (c), (d) Comparison of the liposomal MFI of U87 mg (c) and U251 mg (d). *P < 0.05, Lp, liposome.

Mentions: The findings from the FACS analyses revealed results consistent with those observed in the fluorescent microscopy analyses showing a significant uptake α-hEGFR-ILs (Figure 4). Hence, the binding and uptake of α-hEGFR-ILs were significantly higher as compared with those of nonimmune immunoglobulin conjugated liposomes or naked liposomes in both the U87 mg and U251 mg cell lines (P < 0.05).


Targeted antiepidermal growth factor receptor (cetuximab) immunoliposomes enhance cellular uptake in vitro and exhibit increased accumulation in an intracranial model of glioblastoma multiforme.

Mortensen JH, Jeppesen M, Pilgaard L, Agger R, Duroux M, Zachar V, Moos T - J Drug Deliv (2013)

FACS analysis showing enhanced cellular binding of α-hEGFR-IL's in U87 mg (a) and U251 mg (b) cell lines. The targeting efficiency of the α-hEGFR-IL's (green histograms) was evaluated by comparing mean fluorescence intensities (MFI) with hIgG-IL's (orange histograms), or naked liposome (blue histograms) and cells not exposed to liposomes (black histograms). (c), (d) Comparison of the liposomal MFI of U87 mg (c) and U251 mg (d). *P < 0.05, Lp, liposome.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3794561&req=5

fig4: FACS analysis showing enhanced cellular binding of α-hEGFR-IL's in U87 mg (a) and U251 mg (b) cell lines. The targeting efficiency of the α-hEGFR-IL's (green histograms) was evaluated by comparing mean fluorescence intensities (MFI) with hIgG-IL's (orange histograms), or naked liposome (blue histograms) and cells not exposed to liposomes (black histograms). (c), (d) Comparison of the liposomal MFI of U87 mg (c) and U251 mg (d). *P < 0.05, Lp, liposome.
Mentions: The findings from the FACS analyses revealed results consistent with those observed in the fluorescent microscopy analyses showing a significant uptake α-hEGFR-ILs (Figure 4). Hence, the binding and uptake of α-hEGFR-ILs were significantly higher as compared with those of nonimmune immunoglobulin conjugated liposomes or naked liposomes in both the U87 mg and U251 mg cell lines (P < 0.05).

Bottom Line: Therapeutic advances do not circumvent the devastating fact that the survival rate in glioblastoma multiforme (GBM) is less than 5%.The in vitro studies revealed significantly higher binding of α -hEGFR-ILs when compared with liposomes conjugated with isotypic nonimmune immunoglobulin.The data show that α -hEGFR-ILs significantly enhance the uptake and accumulation of liposomes in this experimental model of GBM suggestive of improved specific nanoparticle-based delivery.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Cancer Biology, Biomedicine, Institute of Medicine and Health Technology, Fredrik Bajers Vej 3B, 1.216, Aalborg University, 9220 Aalborg East, Denmark.

ABSTRACT
Therapeutic advances do not circumvent the devastating fact that the survival rate in glioblastoma multiforme (GBM) is less than 5%. Nanoparticles consisting of liposome-based therapeutics are provided against a variety of cancer types including GBM, but available liposomal formulations are provided without targeting moieties, which increases the dosing demands to reach therapeutic concentrations with risks of side effects. We prepared PEGylated immunoliposomes (ILs) conjugated with anti-human epidermal growth factor receptor (EGFR) antibodies Cetuximab ( α -hEGFR-ILs). The affinity of the α -hEGFR-ILs for the EGF receptor was evaluated in vitro using U87 mg and U251 mg cells and in vivo using an intracranial U87 mg xenograft model. The xenograft model was additionally analyzed with respect to permeability to endogenous albumin, tumor size, and vascularization. The in vitro studies revealed significantly higher binding of α -hEGFR-ILs when compared with liposomes conjugated with isotypic nonimmune immunoglobulin. The uptake and internalization of the α -hEGFR-ILs by U87 mg cells were further confirmed by 3D deconvolution analyses. In vivo, the α -hEGFR-ILs accumulated to a higher extent inside the tumor when compared to nonimmune liposomes. The data show that α -hEGFR-ILs significantly enhance the uptake and accumulation of liposomes in this experimental model of GBM suggestive of improved specific nanoparticle-based delivery.

No MeSH data available.


Related in: MedlinePlus