Reduction-sensitive Paclitaxel Prodrug Self-assembled Nanoparticles with Tetrandrine Effectively Promote Synergistic Therapy Against Drug-sensitive and Multidrug-resistant Breast Cancer

Abstract

Codelivery of multiple drugs with complementary anticancer mechanisms by nanocarriers offers an effective strategy to treat cancers. Herein, conjugation (PTX-SS-VE) of paclitaxel (PTX) to vitamin E succinate (VE) self-assembled nanoparticles were used to load tetrandrine (TET) for combinational treatment against breast carcinoma. The ratio of PTX-SS-VE and TET was optimized. Compared with PTX, the TET/PTX-SS-VE coloaded nanoparticles (TPNPs) demonstrated superior cytotoxicity against both MCF-7 cells and MCF-7/Adr cells. TPNPs were facilitated to release PTX and TET under a highly reductive environment in tumor cells through the in vitro simulative release study. Cell apoptosis study and Western blotting analysis exhibited TPNPs could significantly increase cell apoptosis via modulating the levels of Bcl-2 protein and Caspase-3, which might be triggered by excess cellular reactive oxygen species (ROS) production through an intracellular ROS detection test. Cellular uptake study showed that TET could increase PTX accumulation in MCF-7/Adr cells but not in MCF-7 cells, which explained stronger synergetic efficacy of TPNPs on MCF-7/Adr cells. Overall, encapsulation of hydrophobic drugs, such as TET, in reduction-sensitive PTX-SS-VE nanoparticles provides a prospective strategy to effectively overcome the multidrug resistance of tumor cells in a synergistic manner. Such a uniquely small molecular weight prodrug-nanocarrier opens up new perspectives for the development of nanomedicines.

Tetrandrine: a review of its anticancer potentials, clinical settings, pharmacokinetics and drug delivery systems

“…Poly (lactic‐co‐glycolic acid) (PLGA) nanoparticles might provide an effective drug delivery system for tetrandrine as a basis for further preclinical and clinical investigations. [ 85,86 ] The recent investigations reported here firmly back tetrandrine as a potential candidate for cancer chemotherapy. Yet, the limitations involved in the use of tetrandrine as a potent chemotherapy drug have not yet been discussed comprehensively and systematically.…”

“…Results showed that Tet/Ptx‐SS‐VE‐co‐loaded nanoparticles (TPNPs) display prominent cytotoxicity against MCF‐7 and MCF‐7/Adr cells compared with the use of the drug alone. TPNPs can also be stimulated to release paclitaxel and tetrandrine under highly reductive environments in cancer cells in in vitro simulative release studies, [ 86 ] suggesting that the encapsulation of hydrophobic drugs, such as tetrandrine, by Ptx‐SS‐VE nanoparticles provides a prospective strategy to effectively overcome the multidrug resistance of tumour cells synergistically in the presence of reduction‐sensitive drugs.…”

iRGD‐paclitaxel conjugate nanoparticles for targeted paclitaxel delivery

“…Abraxane significantly increases the compliance of patients (Yardley, ) However, Abraxane may also cause neurotoxicity (Sahoo & Kumar, ). In order to obtain better clinical use of PTX, many PTX delivery systems have been developed and investigated, including micelles (Han et al, ; Luo, Han, Xu, Chen, & Zhang, ), nanoparticles (Jiang et al, ; Wang et al, ; Xiang et al, ; Xin et al, ), liposomes (Hong et al, ; Monteiro et al, ; Wang et al, ), PTX prodrugs (Han et al, ; Jiang et al, ; Jiang et al, ; Luo et al, ; Tam, Gao, & Kwon, ), and so on. Among these PTX delivery systems, PTX prodrugs, especially targeting peptide‐PTX conjugates (Bianchi et al, ; Colombo et al, ; Dal Corso et al, ; Zanella et al, ), achieved great attention because conjugating targeting peptide onto PTX can not only increase the water solubility of PTX, but also endow the conjugate with the capability of targeting tumor cells by ligand–receptor interactions.…”

Multifunctional redox-responsive and CD44 receptor targeting polymer-drug nanomedicine based curcumin and alendronate: synthesis, characterization and in vitro evaluation

“…Tumour microenvironment-responsive drug delivery system could minimalize undesired toxicity and maximum desired effect [8]. There was a research that the reducing substances (7-10-folds) higher in tumour cells than normal cells [9,10]. Thus, we could make use of tumour microenvironment designing a redox-responsive drug delivery system with the disulphide bond to achieve tumour targeting [11].…”