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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

LPPC protected BP against the loss of its antitumor activity in protein-rich, oxygenic, and acid/alkaline solutions.Notes: (A) IC50 of BP and BP/LPPC in DBTRG-05MG and RG2 cells. BP and BP/LPPC were preincubated in (B) H2O or (C) 10% FBS solution at 37°C, after which both GBM cell lines were treated with the preincubated BP or BP/LPPC. As the preincubation time increased, the IC50 values for BP and BP/LPPC were determined. *P<0.05, compared with DBTRG-BP in H2O; #P<0.05, compared with RG2-BP in H2O. BP and BP/LPPC were also preincubated in (D) H2O or (E) 10% FBS solutions ranging from pH 6 to 8 at 37°C, after which both GBM cell lines were treated with the preincubated BP or BP/LPPC. The IC50 values of BP and BP/LPPC were measured by MTT. BP and BP/LPPC were preincubated in (F) H2O with oxygen or (G) 10% FBS solution with oxygen for 24 hours, and their IC50 values in DBTRG-05MG cells were determined. *P<0.05, compared with nonencapsulated BP. (H) The cytotoxic activity of BP/LPPC in storage.Abbreviations: BP, n-butylidenephthalide; FBS, fetal bovine serum; GBM, glioblastoma multiforme; IC50, 50% inhibitory concentration; LPPC, lipo-PEG-PEI complex.
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f2-ijn-10-6009: LPPC protected BP against the loss of its antitumor activity in protein-rich, oxygenic, and acid/alkaline solutions.Notes: (A) IC50 of BP and BP/LPPC in DBTRG-05MG and RG2 cells. BP and BP/LPPC were preincubated in (B) H2O or (C) 10% FBS solution at 37°C, after which both GBM cell lines were treated with the preincubated BP or BP/LPPC. As the preincubation time increased, the IC50 values for BP and BP/LPPC were determined. *P<0.05, compared with DBTRG-BP in H2O; #P<0.05, compared with RG2-BP in H2O. BP and BP/LPPC were also preincubated in (D) H2O or (E) 10% FBS solutions ranging from pH 6 to 8 at 37°C, after which both GBM cell lines were treated with the preincubated BP or BP/LPPC. The IC50 values of BP and BP/LPPC were measured by MTT. BP and BP/LPPC were preincubated in (F) H2O with oxygen or (G) 10% FBS solution with oxygen for 24 hours, and their IC50 values in DBTRG-05MG cells were determined. *P<0.05, compared with nonencapsulated BP. (H) The cytotoxic activity of BP/LPPC in storage.Abbreviations: BP, n-butylidenephthalide; FBS, fetal bovine serum; GBM, glioblastoma multiforme; IC50, 50% inhibitory concentration; LPPC, lipo-PEG-PEI complex.

Mentions: To verify the stability of BP in BP/LPPC for cancer therapy, nonencapsulated BP and BP/LPPC were preincubated either in H2O at 4°C (storage condition) or in a 10% FBS solution at 37°C (bioactive condition), and changes in the IC50 values of BP and BP/LPPC were measured. The results, shown in Figure 2A, indicated that the IC50 values of freshly prepared BP and BP/LPPC in both cell lines were 55 µg/mL and 12 µg/mL, respectively. For BP preincubated in H2O at 4°C for 4 hours, the IC50 values dramatically increased (Figure 2B). A similar increase in IC50 was also observed for BP preincubated in 10% FBS solution at 37°C (Figure 2C). However, regardless of preincubation conditions, the IC50 value of BP/LPPC was similar to that of a freshly prepared BP/LPPC (Figure 2B and C).


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)

LPPC protected BP against the loss of its antitumor activity in protein-rich, oxygenic, and acid/alkaline solutions.Notes: (A) IC50 of BP and BP/LPPC in DBTRG-05MG and RG2 cells. BP and BP/LPPC were preincubated in (B) H2O or (C) 10% FBS solution at 37°C, after which both GBM cell lines were treated with the preincubated BP or BP/LPPC. As the preincubation time increased, the IC50 values for BP and BP/LPPC were determined. *P<0.05, compared with DBTRG-BP in H2O; #P<0.05, compared with RG2-BP in H2O. BP and BP/LPPC were also preincubated in (D) H2O or (E) 10% FBS solutions ranging from pH 6 to 8 at 37°C, after which both GBM cell lines were treated with the preincubated BP or BP/LPPC. The IC50 values of BP and BP/LPPC were measured by MTT. BP and BP/LPPC were preincubated in (F) H2O with oxygen or (G) 10% FBS solution with oxygen for 24 hours, and their IC50 values in DBTRG-05MG cells were determined. *P<0.05, compared with nonencapsulated BP. (H) The cytotoxic activity of BP/LPPC in storage.Abbreviations: BP, n-butylidenephthalide; FBS, fetal bovine serum; GBM, glioblastoma multiforme; IC50, 50% inhibitory concentration; LPPC, lipo-PEG-PEI complex.
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Related In: Results  -  Collection

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f2-ijn-10-6009: LPPC protected BP against the loss of its antitumor activity in protein-rich, oxygenic, and acid/alkaline solutions.Notes: (A) IC50 of BP and BP/LPPC in DBTRG-05MG and RG2 cells. BP and BP/LPPC were preincubated in (B) H2O or (C) 10% FBS solution at 37°C, after which both GBM cell lines were treated with the preincubated BP or BP/LPPC. As the preincubation time increased, the IC50 values for BP and BP/LPPC were determined. *P<0.05, compared with DBTRG-BP in H2O; #P<0.05, compared with RG2-BP in H2O. BP and BP/LPPC were also preincubated in (D) H2O or (E) 10% FBS solutions ranging from pH 6 to 8 at 37°C, after which both GBM cell lines were treated with the preincubated BP or BP/LPPC. The IC50 values of BP and BP/LPPC were measured by MTT. BP and BP/LPPC were preincubated in (F) H2O with oxygen or (G) 10% FBS solution with oxygen for 24 hours, and their IC50 values in DBTRG-05MG cells were determined. *P<0.05, compared with nonencapsulated BP. (H) The cytotoxic activity of BP/LPPC in storage.Abbreviations: BP, n-butylidenephthalide; FBS, fetal bovine serum; GBM, glioblastoma multiforme; IC50, 50% inhibitory concentration; LPPC, lipo-PEG-PEI complex.
Mentions: To verify the stability of BP in BP/LPPC for cancer therapy, nonencapsulated BP and BP/LPPC were preincubated either in H2O at 4°C (storage condition) or in a 10% FBS solution at 37°C (bioactive condition), and changes in the IC50 values of BP and BP/LPPC were measured. The results, shown in Figure 2A, indicated that the IC50 values of freshly prepared BP and BP/LPPC in both cell lines were 55 µg/mL and 12 µg/mL, respectively. For BP preincubated in H2O at 4°C for 4 hours, the IC50 values dramatically increased (Figure 2B). A similar increase in IC50 was also observed for BP preincubated in 10% FBS solution at 37°C (Figure 2C). However, regardless of preincubation conditions, the IC50 value of BP/LPPC was similar to that of a freshly prepared BP/LPPC (Figure 2B and C).

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