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

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.

<p>Encapsulated <em>n</em>-Butylidenephthalide Efficiently Crosses the Blood–Brain Barrier and Suppresses Growth of Glioblastoma</p>

“…18 In addition, BP has low bioavailability and poor pharmacokinetics in vivo due to the water insolubility. To improve the anti-tumor efficiency of BP, drug delivery nanoparticles have been developed for BP encapsulation to overcome its poor stability and increase its aqueous solubility/dispersibility 9,19,20 .…”

“…22 LPPC can be administered through intravenous injection and/or transdermal treatment. 20,22,23 Both treatments display efficient tumor growth inhibition due to a large amount of drug accumulation. 20,22,23 The properties of LPPCs allow them to strongly capture antigens or immunomodulators on their surfaces and be used as an adjuvant to trigger Th2 immune responses and antibody class switch.…”

“…20,22,23 Both treatments display efficient tumor growth inhibition due to a large amount of drug accumulation. 20,22,23 The properties of LPPCs allow them to strongly capture antigens or immunomodulators on their surfaces and be used as an adjuvant to trigger Th2 immune responses and antibody class switch. 24 LPPCs also strongly captured antibodies for specific drug delivery 25 and captures proteins for intracellular protein therapy.…”

“…26 In our previous study, LPPC was shown to protect BP structure against protein adsorption in the blood to preserve the drug's stability and cytotoxicity during transportation. 20 However, BP/LPPC's anti-tumor mechanisms and transmission across the BBB have not yet been verified.…”

Inhibition of breast cancer with transdermal tamoxifen-encapsulated lipoplex

“…The cationic liposome-PEG-PEI complex (LPPC) had been developed for encapsulating drug and protected drugs’ structural stability [ 16 – 18 ]. LPPC helps the drugs rapidly penetrate into cell plasma to result in an excellent therapeutic effect in vitro and in vivo [ 17 , 18 ].…”