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Folic-acid-conjugated pullulan/poly(DL-lactide-co-glycolide) graft copolymer nanoparticles for folate-receptor-mediated drug delivery.

Lee SJ, Shim YH, Oh JS, Jeong YI, Park IK, Lee HC - Nanoscale Res Lett (2015)

Bottom Line: However, fluorescence intensity was decreased by blocking folate receptors.Antitumor activity of FAPuLG nanoparticles against KB cells in vitro was also decreased by blocking folate receptors.In animal study using near-infrared dye-conjugated FAPuLG nanoparticles, fluorescence intensity was significantly higher at KB solid tumor than that of NIH3T3.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju, 501-746 Korea.

ABSTRACT

Background: Nanoparticles have been extensively investigated for targeted delivery of anticancer drugs. Since the folate receptor is universally over-expressed on the tumor cell membrane, folic acid is often used to modify the fate of nanoparticles in biologicals.

Methods: To fabricate targetable nanoparticles, folic acid was conjugated to a pullulan backbone and poly(DL-lactide-co-glycolide) (PLGA) (abbreviated as FAPuLG) was conjugated. KB cells and NIH3T3-cell-bearing mice were prepared to prove folate receptor targeting of FAPuLG nanoparticles.

Results and discussion: Nanoparticles of FAPuLG copolymer that self-assembled in water were small with diameters <200 nm. Doxorubicin (DOX) as a model drug was incorporated into the FAPuLG nanoparticles that were used to treat folate receptor over-expressing KB human carcinoma cells. Fluorescence microscopy revealed that DOX-incorporated FAPuLG nanoparticles induced strong red fluorescence in the KB cells in the absence of folic acid. However, fluorescence intensity was decreased by blocking folate receptors. Antitumor activity of FAPuLG nanoparticles against KB cells in vitro was also decreased by blocking folate receptors. In animal study using near-infrared dye-conjugated FAPuLG nanoparticles, fluorescence intensity was significantly higher at KB solid tumor than that of NIH3T3.

Conclusions: The results indicate that FAPuLG nanoparticles can target the folate receptor of tumor cells. FAPuLG nanoparticles are a promising candidate for active targeting of anticancer agents.

No MeSH data available.


Related in: MedlinePlus

Fluorence excitation and plots of intensity ratios. Fluorescence excitation of pyrene (6.0 × 10 − 7 M) vs. the concentration of PuLG (a), FAPuLG-1 (b), and FAPuLG-2 (c) nanoparticles in distilled water (λem = 390 nm). Plots of the intensity ratios, I338/I335, from the pyrene excitation spectra vs. log c of the PuLG (d), FAPuLG-1 (e), and FAPuLG-2 (f) nanoparticles in distilled water. Each point was derived from the fluorescence spectra curve. The arrows indicate the signal changes in the crossover region.
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Fig3: Fluorence excitation and plots of intensity ratios. Fluorescence excitation of pyrene (6.0 × 10 − 7 M) vs. the concentration of PuLG (a), FAPuLG-1 (b), and FAPuLG-2 (c) nanoparticles in distilled water (λem = 390 nm). Plots of the intensity ratios, I338/I335, from the pyrene excitation spectra vs. log c of the PuLG (d), FAPuLG-1 (e), and FAPuLG-2 (f) nanoparticles in distilled water. Each point was derived from the fluorescence spectra curve. The arrows indicate the signal changes in the crossover region.

Mentions: To make nanoparticles, FAPuLG was dissolved in DMSO and then added dropwise to deionized water. Organic solvent was removed by dialysis method. The average diameter of the formed nanoparticles was consistently <200 nm (Figure 2a, Table 2). Particle sizes of FAPuLG were slightly larger than PuLG, suggesting that the folic acid moiety may increase their average diameter. Furthermore, PuLG and FAPuLG nanoparticles were spherical (Figure 2b). Their sizes were not significantly different from the results of particle size measurement. Since PuLG and FAPuLG are amphiphilic polymers composed of the hydrophilic domain of pullulan and hydrophobic domain of PLGA, formation of nanoparticles occurred by self-aggregation process in the aqueous environment. To study the self-assembly of nanoparticles, fluorescence spectroscopy measured CAC using pyrene as a fluorescence probe. The fluorescence spectra showed a red shift according to the increase of copolymer concentration, indicating that the self-assembly of the copolymer was formed in water, and then, pyrene was preferentially partitioned into the core of the nanoparticles (Figure 3a,c). A flat region and a sigmoid change in the crossover region were observed at low concentrations of copolymer (Figure 3d,f). These crossover regions were known to be the CAC of the copolymer. The CAC of PuLG, FAPuLG-1, and FAPuLG-2 was 0.026 g/l, 0.011 g/l, and 0.01 g/l, respectively. DOX was used as a model anticancer drug. DOX was incorporated into the PuLG and FAPuLG nanoparticles. The results are summarized in Table 2. When DOX was incorporated into the nanoparticles, sizes were increased significantly compared to empty nanoparticles. The drug release kinetics was shown in Figure 4. The drug release rate was relatively fast until 36 h, after which release was continuous. The nanoparticles having larger diameter and higher drug contents induced a slower release rate of drugs.Figure 2


Folic-acid-conjugated pullulan/poly(DL-lactide-co-glycolide) graft copolymer nanoparticles for folate-receptor-mediated drug delivery.

Lee SJ, Shim YH, Oh JS, Jeong YI, Park IK, Lee HC - Nanoscale Res Lett (2015)

Fluorence excitation and plots of intensity ratios. Fluorescence excitation of pyrene (6.0 × 10 − 7 M) vs. the concentration of PuLG (a), FAPuLG-1 (b), and FAPuLG-2 (c) nanoparticles in distilled water (λem = 390 nm). Plots of the intensity ratios, I338/I335, from the pyrene excitation spectra vs. log c of the PuLG (d), FAPuLG-1 (e), and FAPuLG-2 (f) nanoparticles in distilled water. Each point was derived from the fluorescence spectra curve. The arrows indicate the signal changes in the crossover region.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4384989&req=5

Fig3: Fluorence excitation and plots of intensity ratios. Fluorescence excitation of pyrene (6.0 × 10 − 7 M) vs. the concentration of PuLG (a), FAPuLG-1 (b), and FAPuLG-2 (c) nanoparticles in distilled water (λem = 390 nm). Plots of the intensity ratios, I338/I335, from the pyrene excitation spectra vs. log c of the PuLG (d), FAPuLG-1 (e), and FAPuLG-2 (f) nanoparticles in distilled water. Each point was derived from the fluorescence spectra curve. The arrows indicate the signal changes in the crossover region.
Mentions: To make nanoparticles, FAPuLG was dissolved in DMSO and then added dropwise to deionized water. Organic solvent was removed by dialysis method. The average diameter of the formed nanoparticles was consistently <200 nm (Figure 2a, Table 2). Particle sizes of FAPuLG were slightly larger than PuLG, suggesting that the folic acid moiety may increase their average diameter. Furthermore, PuLG and FAPuLG nanoparticles were spherical (Figure 2b). Their sizes were not significantly different from the results of particle size measurement. Since PuLG and FAPuLG are amphiphilic polymers composed of the hydrophilic domain of pullulan and hydrophobic domain of PLGA, formation of nanoparticles occurred by self-aggregation process in the aqueous environment. To study the self-assembly of nanoparticles, fluorescence spectroscopy measured CAC using pyrene as a fluorescence probe. The fluorescence spectra showed a red shift according to the increase of copolymer concentration, indicating that the self-assembly of the copolymer was formed in water, and then, pyrene was preferentially partitioned into the core of the nanoparticles (Figure 3a,c). A flat region and a sigmoid change in the crossover region were observed at low concentrations of copolymer (Figure 3d,f). These crossover regions were known to be the CAC of the copolymer. The CAC of PuLG, FAPuLG-1, and FAPuLG-2 was 0.026 g/l, 0.011 g/l, and 0.01 g/l, respectively. DOX was used as a model anticancer drug. DOX was incorporated into the PuLG and FAPuLG nanoparticles. The results are summarized in Table 2. When DOX was incorporated into the nanoparticles, sizes were increased significantly compared to empty nanoparticles. The drug release kinetics was shown in Figure 4. The drug release rate was relatively fast until 36 h, after which release was continuous. The nanoparticles having larger diameter and higher drug contents induced a slower release rate of drugs.Figure 2

Bottom Line: However, fluorescence intensity was decreased by blocking folate receptors.Antitumor activity of FAPuLG nanoparticles against KB cells in vitro was also decreased by blocking folate receptors.In animal study using near-infrared dye-conjugated FAPuLG nanoparticles, fluorescence intensity was significantly higher at KB solid tumor than that of NIH3T3.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju, 501-746 Korea.

ABSTRACT

Background: Nanoparticles have been extensively investigated for targeted delivery of anticancer drugs. Since the folate receptor is universally over-expressed on the tumor cell membrane, folic acid is often used to modify the fate of nanoparticles in biologicals.

Methods: To fabricate targetable nanoparticles, folic acid was conjugated to a pullulan backbone and poly(DL-lactide-co-glycolide) (PLGA) (abbreviated as FAPuLG) was conjugated. KB cells and NIH3T3-cell-bearing mice were prepared to prove folate receptor targeting of FAPuLG nanoparticles.

Results and discussion: Nanoparticles of FAPuLG copolymer that self-assembled in water were small with diameters <200 nm. Doxorubicin (DOX) as a model drug was incorporated into the FAPuLG nanoparticles that were used to treat folate receptor over-expressing KB human carcinoma cells. Fluorescence microscopy revealed that DOX-incorporated FAPuLG nanoparticles induced strong red fluorescence in the KB cells in the absence of folic acid. However, fluorescence intensity was decreased by blocking folate receptors. Antitumor activity of FAPuLG nanoparticles against KB cells in vitro was also decreased by blocking folate receptors. In animal study using near-infrared dye-conjugated FAPuLG nanoparticles, fluorescence intensity was significantly higher at KB solid tumor than that of NIH3T3.

Conclusions: The results indicate that FAPuLG nanoparticles can target the folate receptor of tumor cells. FAPuLG nanoparticles are a promising candidate for active targeting of anticancer agents.

No MeSH data available.


Related in: MedlinePlus