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Magnetically Controllable Polymer Nanotubes from a Cyclized Crosslinker for Site-Specific Delivery of Doxorubicin.

Newland B, Leupelt D, Zheng Y, Thomas LS, Werner C, Steinhart M, Wang W - Sci Rep (2015)

Bottom Line: Externally controlled site specific drug delivery could potentially provide a means of reducing drug related side effects whilst maintaining, or perhaps increasing therapeutic efficiency.Using a single, commercially available monomer and a simple one-pot reaction process, a polymer was synthesized and crosslinked within the pores of an anodized aluminum oxide template.Using an external magnetic field the nanotubes could be regionally concentrated, leaving areas devoid of nanotubes.

View Article: PubMed Central - PubMed

Affiliation: Leibniz Institute of Polymer Research Dresden, Max Bergmann Centre for Biomaterials Dresden, Hohe Straße. 6, Dresden 01069, Germany.

ABSTRACT
Externally controlled site specific drug delivery could potentially provide a means of reducing drug related side effects whilst maintaining, or perhaps increasing therapeutic efficiency. The aim of this work was to develop a nanoscale drug carrier, which could be loaded with an anti-cancer drug and be directed by an external magnetic field. Using a single, commercially available monomer and a simple one-pot reaction process, a polymer was synthesized and crosslinked within the pores of an anodized aluminum oxide template. These polymer nanotubes (PNT) could be functionalized with iron oxide nanoparticles for magnetic manipulation, without affecting the large internal pore, or inherent low toxicity. Using an external magnetic field the nanotubes could be regionally concentrated, leaving areas devoid of nanotubes. Lastly, doxorubicin could be loaded to the PNTs, causing increased toxicity towards neuroblastoma cells, rendering a platform technology now ready for adaptation with different nanoparticles, degradable pre-polymers, and various therapeutics.

No MeSH data available.


Related in: MedlinePlus

The polymer nanotubes show far lower cytotoxicity than MWNTs.The viability of primary astrocytes (a predominant cell type of the brain) extracted from the newborn rat midbrain is unaffected by the incubation with polymer nanotubes (a). Light microscopy analysis shows a heavy coverage of the nanotubes on the astrocytes ((b) = MWNT, (c) = “Small” polymer nanotubes, (d) = “Large” polymer nanotubes) at the highest concentration analyzed (240 μg/ml) (scale bars = 100 μm, n = 4).
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f4: The polymer nanotubes show far lower cytotoxicity than MWNTs.The viability of primary astrocytes (a predominant cell type of the brain) extracted from the newborn rat midbrain is unaffected by the incubation with polymer nanotubes (a). Light microscopy analysis shows a heavy coverage of the nanotubes on the astrocytes ((b) = MWNT, (c) = “Small” polymer nanotubes, (d) = “Large” polymer nanotubes) at the highest concentration analyzed (240 μg/ml) (scale bars = 100 μm, n = 4).

Mentions: The rationale for developing wide pore, polymer based nanotubes, is that they may be more suitable for drug delivery applications than carbon nanotubes, via enhanced drug loading and perhaps reduced toxicity. High risk neuroblastoma currently has poor prognosis following diagnosis so was chosen as the model system to investigate the use of these nanotubes as a drug delivery system. However, to investigate the cytotoxicity of the biomaterial itself (ie. nanotubes in their unloaded form), in vitro assessment was carried out using astrocytes: a non-cancerous cell type. The cytotoxicity of the nanotubes was measured using the PrestoBlue® assay, after 24 hours of incubation of various concentrations of nanotubes on either primary cortical astrocytes (Fig. 4) or an astrocyte cell line (Supplementary Information Fig. 9) developed by the Fawcett lab25. These studies showed that both sizes of polymer nanotubes retained over 80% astrocyte viability up to a concentration of 240 μg/mL, whereas multi-walled carbon nanotubes (MWNT) of large diameter (170 nm by manufacturer’s definition) caused a dose dependent loss in viability. Brightfield images of the nanotube/cell incubations (Fig. 4b–d) show that 240 μg/mL is still a high enough concentration to result in a thick layer of nanotubes over the cell and well surface, with large aggregations also visible. The nanotubes themselves disperse well in solution (Supplementary Information Fig. 8) as measured by DLS and via visual observations over time. Since poly(ethylene glycol) is often used to functionalize materials for reduced aggregation, the fact that these tubes are predominantly ethylene glycol based may explain this good dispersion. However, the dispersion is concentration dependent as high concentrations such as 4 mg/ml will aggregate throughout the day. The difference in cytotoxicity caused by the polymer nanotubes compared to the MWNTs may be due to a number of factors, with the obvious starting point of differing material compositions (EGDMA vs graphitic carbon). In addition, the aspect ratio is much smaller for the polymer nanotubes, which is likely to explain the reduced toxicity. However, during transmission electron microscopy (TEM) analysis an interesting observation made showing the flexible nature of the polymer nanotubes. Where an area of the carbon film contained a tear the nanotubes either followed the contour of the curling film, or, if they spanned the film tear, they would stretch as the electron beam caused a widening of the tear (Supplementary Information Fig. 10). This purely qualitative analysis may however give an insight into the reduced toxicity. One could speculatively say that the combination of low aspect ratio and nanotube flexibility renders the material less toxic to cells at the concentrations analyzed.


Magnetically Controllable Polymer Nanotubes from a Cyclized Crosslinker for Site-Specific Delivery of Doxorubicin.

Newland B, Leupelt D, Zheng Y, Thomas LS, Werner C, Steinhart M, Wang W - Sci Rep (2015)

The polymer nanotubes show far lower cytotoxicity than MWNTs.The viability of primary astrocytes (a predominant cell type of the brain) extracted from the newborn rat midbrain is unaffected by the incubation with polymer nanotubes (a). Light microscopy analysis shows a heavy coverage of the nanotubes on the astrocytes ((b) = MWNT, (c) = “Small” polymer nanotubes, (d) = “Large” polymer nanotubes) at the highest concentration analyzed (240 μg/ml) (scale bars = 100 μm, n = 4).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4664922&req=5

f4: The polymer nanotubes show far lower cytotoxicity than MWNTs.The viability of primary astrocytes (a predominant cell type of the brain) extracted from the newborn rat midbrain is unaffected by the incubation with polymer nanotubes (a). Light microscopy analysis shows a heavy coverage of the nanotubes on the astrocytes ((b) = MWNT, (c) = “Small” polymer nanotubes, (d) = “Large” polymer nanotubes) at the highest concentration analyzed (240 μg/ml) (scale bars = 100 μm, n = 4).
Mentions: The rationale for developing wide pore, polymer based nanotubes, is that they may be more suitable for drug delivery applications than carbon nanotubes, via enhanced drug loading and perhaps reduced toxicity. High risk neuroblastoma currently has poor prognosis following diagnosis so was chosen as the model system to investigate the use of these nanotubes as a drug delivery system. However, to investigate the cytotoxicity of the biomaterial itself (ie. nanotubes in their unloaded form), in vitro assessment was carried out using astrocytes: a non-cancerous cell type. The cytotoxicity of the nanotubes was measured using the PrestoBlue® assay, after 24 hours of incubation of various concentrations of nanotubes on either primary cortical astrocytes (Fig. 4) or an astrocyte cell line (Supplementary Information Fig. 9) developed by the Fawcett lab25. These studies showed that both sizes of polymer nanotubes retained over 80% astrocyte viability up to a concentration of 240 μg/mL, whereas multi-walled carbon nanotubes (MWNT) of large diameter (170 nm by manufacturer’s definition) caused a dose dependent loss in viability. Brightfield images of the nanotube/cell incubations (Fig. 4b–d) show that 240 μg/mL is still a high enough concentration to result in a thick layer of nanotubes over the cell and well surface, with large aggregations also visible. The nanotubes themselves disperse well in solution (Supplementary Information Fig. 8) as measured by DLS and via visual observations over time. Since poly(ethylene glycol) is often used to functionalize materials for reduced aggregation, the fact that these tubes are predominantly ethylene glycol based may explain this good dispersion. However, the dispersion is concentration dependent as high concentrations such as 4 mg/ml will aggregate throughout the day. The difference in cytotoxicity caused by the polymer nanotubes compared to the MWNTs may be due to a number of factors, with the obvious starting point of differing material compositions (EGDMA vs graphitic carbon). In addition, the aspect ratio is much smaller for the polymer nanotubes, which is likely to explain the reduced toxicity. However, during transmission electron microscopy (TEM) analysis an interesting observation made showing the flexible nature of the polymer nanotubes. Where an area of the carbon film contained a tear the nanotubes either followed the contour of the curling film, or, if they spanned the film tear, they would stretch as the electron beam caused a widening of the tear (Supplementary Information Fig. 10). This purely qualitative analysis may however give an insight into the reduced toxicity. One could speculatively say that the combination of low aspect ratio and nanotube flexibility renders the material less toxic to cells at the concentrations analyzed.

Bottom Line: Externally controlled site specific drug delivery could potentially provide a means of reducing drug related side effects whilst maintaining, or perhaps increasing therapeutic efficiency.Using a single, commercially available monomer and a simple one-pot reaction process, a polymer was synthesized and crosslinked within the pores of an anodized aluminum oxide template.Using an external magnetic field the nanotubes could be regionally concentrated, leaving areas devoid of nanotubes.

View Article: PubMed Central - PubMed

Affiliation: Leibniz Institute of Polymer Research Dresden, Max Bergmann Centre for Biomaterials Dresden, Hohe Straße. 6, Dresden 01069, Germany.

ABSTRACT
Externally controlled site specific drug delivery could potentially provide a means of reducing drug related side effects whilst maintaining, or perhaps increasing therapeutic efficiency. The aim of this work was to develop a nanoscale drug carrier, which could be loaded with an anti-cancer drug and be directed by an external magnetic field. Using a single, commercially available monomer and a simple one-pot reaction process, a polymer was synthesized and crosslinked within the pores of an anodized aluminum oxide template. These polymer nanotubes (PNT) could be functionalized with iron oxide nanoparticles for magnetic manipulation, without affecting the large internal pore, or inherent low toxicity. Using an external magnetic field the nanotubes could be regionally concentrated, leaving areas devoid of nanotubes. Lastly, doxorubicin could be loaded to the PNTs, causing increased toxicity towards neuroblastoma cells, rendering a platform technology now ready for adaptation with different nanoparticles, degradable pre-polymers, and various therapeutics.

No MeSH data available.


Related in: MedlinePlus