Novel “Carrier-Free” Nanofiber Codelivery Systems with the Synergistic Antitumor Effect of Paclitaxel and Tetrandrine through the Enhancement of Mitochondrial Apoptosis

Abstract

Paclitaxel (Ptx), a type of microtubule depolymerization inhibitor, is one of the main components in gastric cancer chemotherapy. Some studies have demonstrated that tetrandrine (Tet), a bisbenzylisoquinoline alkaloid, has potential antitumor effects in several cancers. Aside from the direct anticancer effect, Tet is proved to synergistically enhance the antitumor effect of Ptx in gastric cancer. However, the application of the combinational strategy is limited by the poor solubility of both drugs. Nanodrug delivery systems including polymeric nanoparticles, selfassembled nanofibers, hydrogels, etc., hold the potential to meet the need. Here, a novel supramolecular nanomaterial, based on the concept of "carrier-free nanodrugs", is reported as a feasible platform for synergistic drug delivery. Ptx−SA−RGD is obtained through the conjugation of Ptx and the tumor-specific peptide RGD (arginine−glycine−aspartic acid) with succinic acid (SA) as a linker. Ptx−SA−RGD could self-assemble into Ptx nanofibers (P-NFs) with high drugloading efficiency. Tet was then encapsulated into P-NFs to acquire novel Ptx and Tet coloaded self-assembled nanofibers (P/T-NFs). The uptake study shows the dynamic internalization of P/T-NFs by the gastric cancer cell line MGC-803. P/T-NFs significantly triggered the accumulation of reactive oxygen species (ROS) in gastric cancer cells MGC803 and further decreased the mitochondrial membrane potential, which led to the induction of mitochondrial apoptosis with superior cytotoxicity against free drugs. Moreover, P/T-NFs suppressed the expressions of p-STAT3 and p-JAK, initiated cytochrome-C release, and promoted caspase protein expression. Furthermore, P/T-NFs demonstrated the strongest tumor-delaying effect as well as the lowest toxicity. Therefore, self-assembled nanofibers of P/T-NFs demonstrated an increase of the mitochondrial apoptosis level and a stronger antitumor effect both in vitro and in vivo, which could be a potential way to enhance the clinical efficacy and reduce the side-effects of Ptx in gastric cancer.

Hypericin Enhances Paclitaxel-Induced B16-F10 Cell Apoptosis by Activating a Cytochrome c Release–Dependent Pathway

“…ROS have been reported to play an important role in drug-induced apoptosis. The production of ROS is accompanied by inactivation of superoxide dismutase (SOD), cytochrome c release, caspase-3 activation, and PARP cleavage, leading to apoptosis of numerous types of cancer cells ( Lin et al, 2016b ; Li et al, 2020 ). High levels of ROS are accompanied by a decrease in GSH levels.…”

Development of Natural-Drugs-Based Low-Molecular-Weight Supramolecular Gels

“…For example, Luo et al [37] replaced GSH with RGD peptide and obtained a paclitaxel-based supramolecular hydrogel which could effectively release paclitaxel for more than one week. simultaneously coupling doxorubicin [30], folic acid [31], dexamethasone [32], or embedding vorinostat [33] and tetrandrine [34] on short peptides, the researchers can further regulate the properties of paclitaxel-based supramolecular gels and improve the therapeutic effect. At the same time, through the accurate molecular design of the charge of the short peptide and the type of amino acid, the stability or dissociation of the formed paclitaxel-based hydrogel can be adjusted, and then the release of paclitaxel can be controlled, which can improve the anti-tumor effect and reduce the systemic toxicity [35].…”

Nanotechnology-based strategies for gastric cancer imaging and treatment

“…21 RGD peptide-decorated nanoparticles achieved sufficiently satised performance benecial from targeting tumor site. 22 An integrin-targeting RGD-indocyanine green (RGD-ICG) molecular probe with a surgical navigation system was developed by Cheng et al 23 With this RGD decorated nanoprobe, the sensitivity and specicity of their diagnosis method raised to 93.93% and 100% respectively, with a diagnostic index (DI) of 193.93% and a diagnostic accuracy rate of 93.93%. Furthermore, compared with the conventionally-treated control group, the minimum tumor diameter measured was 1.8 mm during the surgery and the operative time was shortened by 3.26-fold.…”