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Liposomal n-butylidenephthalide protects the drug from oxidation and enhances its antitumor effects in glioblastoma multiforme.

Lin YL, Chang KF, Huang XF, Hung CL, Chen SC, Chao WR, Liao KW, Tsai NM - Int J Nanomedicine (2015)

Bottom Line: However, BP has an unstable structure that reduces its antitumor activity and half-life in vivo.The therapeutic effects of BP/LPPC were analyzed in xenograft mice following intratumoral and intravenous injections.LPPC encapsulation technology is able to protect BP's structural stability and enhance its antitumor effects, thus providing a better tool for use in cancer therapy.

View Article: PubMed Central - PubMed

Affiliation: College of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan ; Center for Bioinformatics Research, National Chiao Tung University, Hsinchu, Taiwan.

ABSTRACT

Background: The natural compound n-butylidenephthalide (BP) can pass through the blood-brain barrier to inhibit the growth of glioblastoma multiforme tumors. However, BP has an unstable structure that reduces its antitumor activity and half-life in vivo.

Objective: The aim of this study is to design a drug delivery system to encapsulate BP to enhance its efficacy by improving its protection and delivery.

Methods: To protect its structural stability against protein-rich and peroxide solutions, BP was encapsulated into a lipo-PEG-PEI complex (LPPC). Then, the cytotoxicity of BP/LPPC following preincubation in protein-rich, acid/alkaline, and peroxide solutions was analyzed by MTT. Cell uptake of BP/LPPC was also measured by confocal microscopy. The therapeutic effects of BP/LPPC were analyzed in xenograft mice following intratumoral and intravenous injections.

Results: When BP was encapsulated in LPPC, its cytotoxicity was maintained following preincubation in protein-rich, acid/alkaline, and peroxide solutions. The cytotoxic activity of encapsulated BP was higher than that of free BP (~4.5- to 8.5-fold). This increased cytotoxic activity of BP/LPPC is attributable to its rapid transport across the cell membrane. In an animal study, a subcutaneously xenografted glioblastoma multiforme mouse that was treated with BP by intratumoral and intravenous administration showed inhibited tumor growth. The same dose of BP/LPPC was significantly more effective in terms of tumor inhibition.

Conclusion: LPPC encapsulation technology is able to protect BP's structural stability and enhance its antitumor effects, thus providing a better tool for use in cancer therapy.

No MeSH data available.


Related in: MedlinePlus

BP/LPPC characteristics.Notes: BP solution (1 M) encapsulated in LPPC at various volume ratios. The (A) particle size, (B) zeta-potential, and (C) BP encapsulation of BP/LPPC were measured. (D) BP release from BP/LPPC in H2O at 4°C, 25°C, and 37°C. *P<0.05, compared with the 25°C group; #P<0.05, compared with the 37°C group. (E) BP release from BP/LPPC in protein-rich solution (containing 10% FBS) at 37°C. After the incubation, the percentage of BP in each supernatant was measured and compared with the total amount of BP (n=6). *P<0.05, compared with the control group.Abbreviations: BP, n-butylidenephthalide; FBS, fetal bovine serum; LPPC, lipo-PEG-PEI complex.
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f1-ijn-10-6009: BP/LPPC characteristics.Notes: BP solution (1 M) encapsulated in LPPC at various volume ratios. The (A) particle size, (B) zeta-potential, and (C) BP encapsulation of BP/LPPC were measured. (D) BP release from BP/LPPC in H2O at 4°C, 25°C, and 37°C. *P<0.05, compared with the 25°C group; #P<0.05, compared with the 37°C group. (E) BP release from BP/LPPC in protein-rich solution (containing 10% FBS) at 37°C. After the incubation, the percentage of BP in each supernatant was measured and compared with the total amount of BP (n=6). *P<0.05, compared with the control group.Abbreviations: BP, n-butylidenephthalide; FBS, fetal bovine serum; LPPC, lipo-PEG-PEI complex.

Mentions: The particle sizes of different BP/LPPC mixtures (volume ratios of BP/LPPC from 0.5:10 to 3:10) ranged from 200 nm to 280 nm (Figure 1A). The average zeta-potential of these different BP/LPPC mixtures was ~38 mV (Figure 1B). For BP encapsulation, the maximal encapsulation capacity of 1 mg of LPPC was ~830 µg of BP at 3:10 and 4:10 (v/v) ratios of BP/LPPC (Figure 1C). According to the results of particle size, zeta-potential, and BP encapsulation capacity assessments, a 3:10 ratio of BP/LPPC was chosen for the following experiments.


Liposomal n-butylidenephthalide protects the drug from oxidation and enhances its antitumor effects in glioblastoma multiforme.

Lin YL, Chang KF, Huang XF, Hung CL, Chen SC, Chao WR, Liao KW, Tsai NM - Int J Nanomedicine (2015)

BP/LPPC characteristics.Notes: BP solution (1 M) encapsulated in LPPC at various volume ratios. The (A) particle size, (B) zeta-potential, and (C) BP encapsulation of BP/LPPC were measured. (D) BP release from BP/LPPC in H2O at 4°C, 25°C, and 37°C. *P<0.05, compared with the 25°C group; #P<0.05, compared with the 37°C group. (E) BP release from BP/LPPC in protein-rich solution (containing 10% FBS) at 37°C. After the incubation, the percentage of BP in each supernatant was measured and compared with the total amount of BP (n=6). *P<0.05, compared with the control group.Abbreviations: BP, n-butylidenephthalide; FBS, fetal bovine serum; LPPC, lipo-PEG-PEI complex.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4592058&req=5

f1-ijn-10-6009: BP/LPPC characteristics.Notes: BP solution (1 M) encapsulated in LPPC at various volume ratios. The (A) particle size, (B) zeta-potential, and (C) BP encapsulation of BP/LPPC were measured. (D) BP release from BP/LPPC in H2O at 4°C, 25°C, and 37°C. *P<0.05, compared with the 25°C group; #P<0.05, compared with the 37°C group. (E) BP release from BP/LPPC in protein-rich solution (containing 10% FBS) at 37°C. After the incubation, the percentage of BP in each supernatant was measured and compared with the total amount of BP (n=6). *P<0.05, compared with the control group.Abbreviations: BP, n-butylidenephthalide; FBS, fetal bovine serum; LPPC, lipo-PEG-PEI complex.
Mentions: The particle sizes of different BP/LPPC mixtures (volume ratios of BP/LPPC from 0.5:10 to 3:10) ranged from 200 nm to 280 nm (Figure 1A). The average zeta-potential of these different BP/LPPC mixtures was ~38 mV (Figure 1B). For BP encapsulation, the maximal encapsulation capacity of 1 mg of LPPC was ~830 µg of BP at 3:10 and 4:10 (v/v) ratios of BP/LPPC (Figure 1C). According to the results of particle size, zeta-potential, and BP encapsulation capacity assessments, a 3:10 ratio of BP/LPPC was chosen for the following experiments.

Bottom Line: However, BP has an unstable structure that reduces its antitumor activity and half-life in vivo.The therapeutic effects of BP/LPPC were analyzed in xenograft mice following intratumoral and intravenous injections.LPPC encapsulation technology is able to protect BP's structural stability and enhance its antitumor effects, thus providing a better tool for use in cancer therapy.

View Article: PubMed Central - PubMed

Affiliation: College of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan ; Center for Bioinformatics Research, National Chiao Tung University, Hsinchu, Taiwan.

ABSTRACT

Background: The natural compound n-butylidenephthalide (BP) can pass through the blood-brain barrier to inhibit the growth of glioblastoma multiforme tumors. However, BP has an unstable structure that reduces its antitumor activity and half-life in vivo.

Objective: The aim of this study is to design a drug delivery system to encapsulate BP to enhance its efficacy by improving its protection and delivery.

Methods: To protect its structural stability against protein-rich and peroxide solutions, BP was encapsulated into a lipo-PEG-PEI complex (LPPC). Then, the cytotoxicity of BP/LPPC following preincubation in protein-rich, acid/alkaline, and peroxide solutions was analyzed by MTT. Cell uptake of BP/LPPC was also measured by confocal microscopy. The therapeutic effects of BP/LPPC were analyzed in xenograft mice following intratumoral and intravenous injections.

Results: When BP was encapsulated in LPPC, its cytotoxicity was maintained following preincubation in protein-rich, acid/alkaline, and peroxide solutions. The cytotoxic activity of encapsulated BP was higher than that of free BP (~4.5- to 8.5-fold). This increased cytotoxic activity of BP/LPPC is attributable to its rapid transport across the cell membrane. In an animal study, a subcutaneously xenografted glioblastoma multiforme mouse that was treated with BP by intratumoral and intravenous administration showed inhibited tumor growth. The same dose of BP/LPPC was significantly more effective in terms of tumor inhibition.

Conclusion: LPPC encapsulation technology is able to protect BP's structural stability and enhance its antitumor effects, thus providing a better tool for use in cancer therapy.

No MeSH data available.


Related in: MedlinePlus