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Utilization of Glycosaminoglycans/Proteoglycans as Carriers for Targeted Therapy Delivery.

Misra S, Hascall VC, Atanelishvili I, Moreno Rodriguez R, Markwald RR, Ghatak S - Int J Cell Biol (2015)

Bottom Line: The outcome of patients with cancer has improved significantly in the past decade with the incorporation of drugs targeting cell surface adhesive receptors, receptor tyrosine kinases, and modulation of several molecules of extracellular matrices (ECMs), the complex composite of collagens, glycoproteins, proteoglycans, and glycosaminoglycans that dictates tissue architecture.In this review, we describe how the ECM components, proteoglycans and glycosaminoglycans, influence tumor cell signaling.In particular this review describes how the glycosaminoglycan hyaluronan (HA) and its major receptor CD44 impact invasive behavior of tumor cells, and provides useful insight when designing new therapeutic strategies in the treatment of cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA.

ABSTRACT
The outcome of patients with cancer has improved significantly in the past decade with the incorporation of drugs targeting cell surface adhesive receptors, receptor tyrosine kinases, and modulation of several molecules of extracellular matrices (ECMs), the complex composite of collagens, glycoproteins, proteoglycans, and glycosaminoglycans that dictates tissue architecture. Cancer tissue invasive processes progress by various oncogenic strategies, including interfering with ECM molecules and their interactions with invasive cells. In this review, we describe how the ECM components, proteoglycans and glycosaminoglycans, influence tumor cell signaling. In particular this review describes how the glycosaminoglycan hyaluronan (HA) and its major receptor CD44 impact invasive behavior of tumor cells, and provides useful insight when designing new therapeutic strategies in the treatment of cancer.

No MeSH data available.


Related in: MedlinePlus

Model for delivery of shRNA (adapted from [18]). This illustration depicts cellular uptake of plasmid Tf-PEG-PEI nanoparticles and the mechanism of action of shRNA. First, a pSico vector containing a U6 promoter-loxP-CMV-GFP-STOP signal-loxP-CD44vshRNA (gene of interest) is made. Second, an expression vector with the Cre-recombinase gene controlled by the tissue specific promoter is created. Third, the two vectors are packaged in transferrin (Tf) coated-PEG-PEI nanoparticles that bind with Tf-receptors (Tf-R) present at high levels in the targeted tumor cells. Delivery of the vectors in normal and malignant cells from the targeted tissue results in deletion of the Stop signal and transcription of Cre-recombinase driven by the tissue specific promoter. The target gene (CD44vshRNA) is then unlocked and transcribed through the strong U6 promoter for high expression. The normal tissue cells are not affected because they do not make the targeted CD44 variant. Tf-PEG-PEI nanoparticle coated plasmids (pSico-CD44v6shRNA/pFabpl-Cre) circulating in blood accumulate at tumor regions enhanced by the EPR effect. Endocytosis mediated by ligand-receptor interactions occurs because the nanoparticles are coated with the Tf-ligand for the Tf-R receptor on the tumor cell surface.
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fig6: Model for delivery of shRNA (adapted from [18]). This illustration depicts cellular uptake of plasmid Tf-PEG-PEI nanoparticles and the mechanism of action of shRNA. First, a pSico vector containing a U6 promoter-loxP-CMV-GFP-STOP signal-loxP-CD44vshRNA (gene of interest) is made. Second, an expression vector with the Cre-recombinase gene controlled by the tissue specific promoter is created. Third, the two vectors are packaged in transferrin (Tf) coated-PEG-PEI nanoparticles that bind with Tf-receptors (Tf-R) present at high levels in the targeted tumor cells. Delivery of the vectors in normal and malignant cells from the targeted tissue results in deletion of the Stop signal and transcription of Cre-recombinase driven by the tissue specific promoter. The target gene (CD44vshRNA) is then unlocked and transcribed through the strong U6 promoter for high expression. The normal tissue cells are not affected because they do not make the targeted CD44 variant. Tf-PEG-PEI nanoparticle coated plasmids (pSico-CD44v6shRNA/pFabpl-Cre) circulating in blood accumulate at tumor regions enhanced by the EPR effect. Endocytosis mediated by ligand-receptor interactions occurs because the nanoparticles are coated with the Tf-ligand for the Tf-R receptor on the tumor cell surface.

Mentions: Figures 5 and 6 illustrate the model for the uptake of Tf-PEG-PEI-nanoparticles carrying multiple functional domains. Nonviral vectors were once limited for their low gene transfer efficiency. However, the incorporation of various ligands, such as peptides, growth factors, and proteins, or antibodies for targets highly expressed on cancer cells, circumvented this obstacle [254]. Also, enhanced permeability due to aberrant vasculature in solid tumors and retention of ligand coated vectors around the receptors of tumor cells can increase chances for high probability of interaction with the cancer cells [43]. Thus, the nonviral vectors can acquire high gene transfer efficiency [43]. This concept was tested by preparing nonviral vector Tf-PEG-PEI-nanoparticles with plasmids packed inside an outer PEG-PEI layer coated with transferrin (Tf), an iron transporting protein [43, 254] that binds with Tf-receptors (Tf-R) with high affinity (depicted in the model in Figures 5 and 6). The Tf-R is present at much higher levels on the tumor cells [43] than on phenotypically normal epithelial cells. Association of transferrin with the Tf-PEG-PEI-nanoparticles significantly enhances transfection efficiency of shRNA generator-plasmids by promoting the internalization of Tf-PEG-PEI-nanoparticles in dividing and nondividing cells through receptor-mediated endocytosis [254]. The uptake of Tf-PEG-PEI-nanoparticles carrying multiple functional domains (surface shielding particles Tf-PEG-PEI, shRNA generator plasmids, tissue specific promoter driven-Cre-recombinase plasmids, and conditionally silenced plasmid) can overcome the intracellular barriers for successful delivery of the shRNA.


Utilization of Glycosaminoglycans/Proteoglycans as Carriers for Targeted Therapy Delivery.

Misra S, Hascall VC, Atanelishvili I, Moreno Rodriguez R, Markwald RR, Ghatak S - Int J Cell Biol (2015)

Model for delivery of shRNA (adapted from [18]). This illustration depicts cellular uptake of plasmid Tf-PEG-PEI nanoparticles and the mechanism of action of shRNA. First, a pSico vector containing a U6 promoter-loxP-CMV-GFP-STOP signal-loxP-CD44vshRNA (gene of interest) is made. Second, an expression vector with the Cre-recombinase gene controlled by the tissue specific promoter is created. Third, the two vectors are packaged in transferrin (Tf) coated-PEG-PEI nanoparticles that bind with Tf-receptors (Tf-R) present at high levels in the targeted tumor cells. Delivery of the vectors in normal and malignant cells from the targeted tissue results in deletion of the Stop signal and transcription of Cre-recombinase driven by the tissue specific promoter. The target gene (CD44vshRNA) is then unlocked and transcribed through the strong U6 promoter for high expression. The normal tissue cells are not affected because they do not make the targeted CD44 variant. Tf-PEG-PEI nanoparticle coated plasmids (pSico-CD44v6shRNA/pFabpl-Cre) circulating in blood accumulate at tumor regions enhanced by the EPR effect. Endocytosis mediated by ligand-receptor interactions occurs because the nanoparticles are coated with the Tf-ligand for the Tf-R receptor on the tumor cell surface.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4581573&req=5

fig6: Model for delivery of shRNA (adapted from [18]). This illustration depicts cellular uptake of plasmid Tf-PEG-PEI nanoparticles and the mechanism of action of shRNA. First, a pSico vector containing a U6 promoter-loxP-CMV-GFP-STOP signal-loxP-CD44vshRNA (gene of interest) is made. Second, an expression vector with the Cre-recombinase gene controlled by the tissue specific promoter is created. Third, the two vectors are packaged in transferrin (Tf) coated-PEG-PEI nanoparticles that bind with Tf-receptors (Tf-R) present at high levels in the targeted tumor cells. Delivery of the vectors in normal and malignant cells from the targeted tissue results in deletion of the Stop signal and transcription of Cre-recombinase driven by the tissue specific promoter. The target gene (CD44vshRNA) is then unlocked and transcribed through the strong U6 promoter for high expression. The normal tissue cells are not affected because they do not make the targeted CD44 variant. Tf-PEG-PEI nanoparticle coated plasmids (pSico-CD44v6shRNA/pFabpl-Cre) circulating in blood accumulate at tumor regions enhanced by the EPR effect. Endocytosis mediated by ligand-receptor interactions occurs because the nanoparticles are coated with the Tf-ligand for the Tf-R receptor on the tumor cell surface.
Mentions: Figures 5 and 6 illustrate the model for the uptake of Tf-PEG-PEI-nanoparticles carrying multiple functional domains. Nonviral vectors were once limited for their low gene transfer efficiency. However, the incorporation of various ligands, such as peptides, growth factors, and proteins, or antibodies for targets highly expressed on cancer cells, circumvented this obstacle [254]. Also, enhanced permeability due to aberrant vasculature in solid tumors and retention of ligand coated vectors around the receptors of tumor cells can increase chances for high probability of interaction with the cancer cells [43]. Thus, the nonviral vectors can acquire high gene transfer efficiency [43]. This concept was tested by preparing nonviral vector Tf-PEG-PEI-nanoparticles with plasmids packed inside an outer PEG-PEI layer coated with transferrin (Tf), an iron transporting protein [43, 254] that binds with Tf-receptors (Tf-R) with high affinity (depicted in the model in Figures 5 and 6). The Tf-R is present at much higher levels on the tumor cells [43] than on phenotypically normal epithelial cells. Association of transferrin with the Tf-PEG-PEI-nanoparticles significantly enhances transfection efficiency of shRNA generator-plasmids by promoting the internalization of Tf-PEG-PEI-nanoparticles in dividing and nondividing cells through receptor-mediated endocytosis [254]. The uptake of Tf-PEG-PEI-nanoparticles carrying multiple functional domains (surface shielding particles Tf-PEG-PEI, shRNA generator plasmids, tissue specific promoter driven-Cre-recombinase plasmids, and conditionally silenced plasmid) can overcome the intracellular barriers for successful delivery of the shRNA.

Bottom Line: The outcome of patients with cancer has improved significantly in the past decade with the incorporation of drugs targeting cell surface adhesive receptors, receptor tyrosine kinases, and modulation of several molecules of extracellular matrices (ECMs), the complex composite of collagens, glycoproteins, proteoglycans, and glycosaminoglycans that dictates tissue architecture.In this review, we describe how the ECM components, proteoglycans and glycosaminoglycans, influence tumor cell signaling.In particular this review describes how the glycosaminoglycan hyaluronan (HA) and its major receptor CD44 impact invasive behavior of tumor cells, and provides useful insight when designing new therapeutic strategies in the treatment of cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA.

ABSTRACT
The outcome of patients with cancer has improved significantly in the past decade with the incorporation of drugs targeting cell surface adhesive receptors, receptor tyrosine kinases, and modulation of several molecules of extracellular matrices (ECMs), the complex composite of collagens, glycoproteins, proteoglycans, and glycosaminoglycans that dictates tissue architecture. Cancer tissue invasive processes progress by various oncogenic strategies, including interfering with ECM molecules and their interactions with invasive cells. In this review, we describe how the ECM components, proteoglycans and glycosaminoglycans, influence tumor cell signaling. In particular this review describes how the glycosaminoglycan hyaluronan (HA) and its major receptor CD44 impact invasive behavior of tumor cells, and provides useful insight when designing new therapeutic strategies in the treatment of cancer.

No MeSH data available.


Related in: MedlinePlus