An efficient Trojan delivery of tetrandrine by poly(N-vinylpyrrolidone)-block-poly(ε-caprolactone) (PVP-b-PCL) nanoparticles shows enhanced apoptotic induction of lung cancer cells and inhibition of its migration and invasion

Abstract

Earlier studies have demonstrated the promising antitumor effect of tetrandrine (Tet) against a series of cancers. However, the poor solubility of Tet limits its application, while its hydrophobicity makes Tet a potential model drug for nanodelivery systems. We report on a simple way of preparing drug-loaded nanoparticles formed by amphiphilic poly(N-vinylpyrrolidone)-block-poly(ε-caprolactone) (PVP-b-PCL) copolymers with Tet as a model drug. The mean diameters of Tet-loaded PVP-b-PCL nanoparticles (Tet-NPs) were between 110 nm and 125 nm with a negative zeta potential slightly below 0 mV. Tet was incorporated into PVP-b-PCL nanoparticles with high loading efficiency. Different feeding ratios showed different influences on sizes, zeta potentials, and the drug loading efficiencies of Tet-NPs. An in vitro release study shows the sustained release pattern of Tet-NPs. It is shown that the uptake of Tet-NPs is mainly mediated by the endocytosis of nanoparticles, which is more efficient than the filtration of free Tet. Further experiments including fluorescence activated cell sorting and Western blotting indicated that this Trojan strategy of delivering Tet in PVP-b-PCL nanoparticles via endocytosis leads to enhanced induction of apoptosis in the non-small cell lung cancer cell A549 line; enhanced apoptosis is achieved by inhibiting the expression of anti-apoptotic Bcl-2 and Bcl-xL proteins. Moreover, Tet-NPs more efficiently inhibit the ability of cell migration and invasion than free Tet by down-regulating matrix metalloproteinases (MMP)-2 and MMP-9, as well as up-regulating tissue inhibitor of MMP-3 (TIMP-3). Therefore, data from this study not only confirms the potential of Tet in treating lung cancer but also offers an effective way of improving the anticancer efficiency of Tet by nanodrug delivery systems.

A novel tetrandrine-loaded chitosan microsphere: characterization and in vivo evaluation

“… 9 In addition, TED has exhibited excellent pharmacological effects, especially in treating pulmonary hypertension. 10 – 13 Although it has potentially valuable clinical applications, some problems such as poor solubility contribute to its low and variable oral bioavailability 14 and have greatly inhibited its development.…”

“…In recent years, many pharmaceutical methods have been investigated to improve the bioavailability of TED, such as lipid nanocapsules, 3 nanoparticles, 14 ethosomes, 15 and microspheres. 16 Microsphere technology has been widely used in the preparation of sustained formulations in order to maintain targeted concentration in vivo for a sustained period of time.…”

Tetrandrine, a Chinese plant-derived alkaloid, is a potential candidate for cancer chemotherapy

“…Furthermore, delivering tetrandrine in PVP-b-PCL nanoparticles via endocytosis also leads to enhanced induction of apoptosis in the A549 non-small cell lung cancer cell line; this enhanced apoptosis is achieved by inhibiting the expression of anti-apoptotic proteins. Additionally, Tet-NPs more efficiently inhibit cell migration and invasion than free tetrandrine by down-regulating matrix metalloproteinase (MMP)-2 and MMP-9 as well as up-regulating tissue inhibitor of MMP-3 (TIMP-3) [118]. Therefore, nanodrug delivery systems are an effective way to improve the anticancer efficiency of tetrandrine alone or in combination with other agents.…”

Synthetic Polymer-Based Nanoparticles: Intelligent Drug Delivery Systems

“…The authors have paid particular attention to the biopharmaceutical application of the Trojan micro-particles. For example, an efficient Trojan delivery of tetrandrine by PVP-block-PCL NPs has shown enhanced apoptotic induction of lung cancer cells and inhibition of its migration and invasion [94].…”