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pH-responsive Virus-like Nanoparticles with Enhanced Tumour-targeting Ligands for Cancer Drug Delivery

View Article: PubMed Central - PubMed

ABSTRACT

Multifunctional nanocarriers harbouring specific targeting moieties and with pH-responsive properties offer great potential for targeted cancer therapy. Several synthetic drug carriers have been studied extensively as drug delivery systems but not much information is available on the application of virus-like nanoparticles (VLNPs) as multifunctional nanocarriers. Here, we describe the development of pH-responsive VLNPs, based on truncated hepatitis B virus core antigen (tHBcAg), displaying folic acid (FA) for controlled drug delivery. FA was conjugated to a pentadecapeptide containing nanoglue bound on tHBcAg nanoparticles to increase the specificity and efficacy of the drug delivery system. The tHBcAg nanoparticles loaded with doxorubicin (DOX) and polyacrylic acid (PAA) demonstrated a sustained drug release profile in vitro under tumour tissue conditions in a controlled manner and improved the uptake of DOX in colorectal cancer cells, leading to enhanced antitumour effects. This study demonstrated that DOX-PAA can be packaged into VLNPs without any modification of the DOX molecules, preserving the pharmacological activity of the loaded DOX. The nanoglue can easily be used to display a tumour-targeting molecule on the exterior surface of VLNPs and can bypass the laborious and time-consuming genetic engineering approaches.

No MeSH data available.


Related in: MedlinePlus

Internalization of tHBcAg nanoparticles conjugated with folic acid into HT29 cells.The cells were incubated with different tHBcAg nanoparticles (25 μg) for 16 h at 37 °C. The cells were then permeabilized with methanol and the internalized tHBcAg particles were detected by rabbit anti-tHBcAg serum, followed by anti-rabbit antibody conjugated to Alexa Fluor® 488. Nuclei were stained with Hoechst (blue). Non-transfected HT29 cells were used as a negative control. The samples are labelled on the left: Folic acid (FA)-conjugated tHBcAg nanoparticles (FA-tHBcAg), FA-conjugated tHBcAg nanoparticles using the nanoglue (FA-N-tHBcAg) and tHBcAg nanoparticles (tHBcAg).
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f3: Internalization of tHBcAg nanoparticles conjugated with folic acid into HT29 cells.The cells were incubated with different tHBcAg nanoparticles (25 μg) for 16 h at 37 °C. The cells were then permeabilized with methanol and the internalized tHBcAg particles were detected by rabbit anti-tHBcAg serum, followed by anti-rabbit antibody conjugated to Alexa Fluor® 488. Nuclei were stained with Hoechst (blue). Non-transfected HT29 cells were used as a negative control. The samples are labelled on the left: Folic acid (FA)-conjugated tHBcAg nanoparticles (FA-tHBcAg), FA-conjugated tHBcAg nanoparticles using the nanoglue (FA-N-tHBcAg) and tHBcAg nanoparticles (tHBcAg).

Mentions: The internalization of FA-conjugated tHBcAg nanoparticles into HT29 cells was studied by immuno-fluorescence microscopy, in which tHBcAg was detected by rabbit anti-tHBcAg antibody followed by anti-rabbit IgG conjugated to Alexa Fluor® 488. HT29 cells were used because they over-express the FR25. Figure 3 shows that the FA-tHBcAg nanoparticles translocated into HT29 cells, and the cells fluoresced. The green fluorescent signal increased considerably when FA-N-tHBcAg nanoparticles were used to transfect the cells (Fig. 3). This indicates that conjugation of FA to the pentadecapeptide bound to tHBcAg via the nanoglue enhanced the uptake of tHBcAg nanoparticles by HT29 cells. FA-tHBcAg and FA-N-tHBcAg nanoparticles accumulated in the cytoplasm of HT29 cells and no green fluorescent signal was detected in the nuclei of cells that were labelled with Hoechst (Fig. 3). This demonstrates that FA mediates the internalization of tHBcAg particles into the cytoplasm of HT29 cells but not into the nucleus. tHBcAg nanoparticles alone (tHBcAg) did not internalize HT29 cells.


pH-responsive Virus-like Nanoparticles with Enhanced Tumour-targeting Ligands for Cancer Drug Delivery
Internalization of tHBcAg nanoparticles conjugated with folic acid into HT29 cells.The cells were incubated with different tHBcAg nanoparticles (25 μg) for 16 h at 37 °C. The cells were then permeabilized with methanol and the internalized tHBcAg particles were detected by rabbit anti-tHBcAg serum, followed by anti-rabbit antibody conjugated to Alexa Fluor® 488. Nuclei were stained with Hoechst (blue). Non-transfected HT29 cells were used as a negative control. The samples are labelled on the left: Folic acid (FA)-conjugated tHBcAg nanoparticles (FA-tHBcAg), FA-conjugated tHBcAg nanoparticles using the nanoglue (FA-N-tHBcAg) and tHBcAg nanoparticles (tHBcAg).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5121657&req=5

f3: Internalization of tHBcAg nanoparticles conjugated with folic acid into HT29 cells.The cells were incubated with different tHBcAg nanoparticles (25 μg) for 16 h at 37 °C. The cells were then permeabilized with methanol and the internalized tHBcAg particles were detected by rabbit anti-tHBcAg serum, followed by anti-rabbit antibody conjugated to Alexa Fluor® 488. Nuclei were stained with Hoechst (blue). Non-transfected HT29 cells were used as a negative control. The samples are labelled on the left: Folic acid (FA)-conjugated tHBcAg nanoparticles (FA-tHBcAg), FA-conjugated tHBcAg nanoparticles using the nanoglue (FA-N-tHBcAg) and tHBcAg nanoparticles (tHBcAg).
Mentions: The internalization of FA-conjugated tHBcAg nanoparticles into HT29 cells was studied by immuno-fluorescence microscopy, in which tHBcAg was detected by rabbit anti-tHBcAg antibody followed by anti-rabbit IgG conjugated to Alexa Fluor® 488. HT29 cells were used because they over-express the FR25. Figure 3 shows that the FA-tHBcAg nanoparticles translocated into HT29 cells, and the cells fluoresced. The green fluorescent signal increased considerably when FA-N-tHBcAg nanoparticles were used to transfect the cells (Fig. 3). This indicates that conjugation of FA to the pentadecapeptide bound to tHBcAg via the nanoglue enhanced the uptake of tHBcAg nanoparticles by HT29 cells. FA-tHBcAg and FA-N-tHBcAg nanoparticles accumulated in the cytoplasm of HT29 cells and no green fluorescent signal was detected in the nuclei of cells that were labelled with Hoechst (Fig. 3). This demonstrates that FA mediates the internalization of tHBcAg particles into the cytoplasm of HT29 cells but not into the nucleus. tHBcAg nanoparticles alone (tHBcAg) did not internalize HT29 cells.

View Article: PubMed Central - PubMed

ABSTRACT

Multifunctional nanocarriers harbouring specific targeting moieties and with pH-responsive properties offer great potential for targeted cancer therapy. Several synthetic drug carriers have been studied extensively as drug delivery systems but not much information is available on the application of virus-like nanoparticles (VLNPs) as multifunctional nanocarriers. Here, we describe the development of pH-responsive VLNPs, based on truncated hepatitis B virus core antigen (tHBcAg), displaying folic acid (FA) for controlled drug delivery. FA was conjugated to a pentadecapeptide containing nanoglue bound on tHBcAg nanoparticles to increase the specificity and efficacy of the drug delivery system. The tHBcAg nanoparticles loaded with doxorubicin (DOX) and polyacrylic acid (PAA) demonstrated a sustained drug release profile in vitro under tumour tissue conditions in a controlled manner and improved the uptake of DOX in colorectal cancer cells, leading to enhanced antitumour effects. This study demonstrated that DOX-PAA can be packaged into VLNPs without any modification of the DOX molecules, preserving the pharmacological activity of the loaded DOX. The nanoglue can easily be used to display a tumour-targeting molecule on the exterior surface of VLNPs and can bypass the laborious and time-consuming genetic engineering approaches.

No MeSH data available.


Related in: MedlinePlus