Tumor multidrug resistance (MDR) is a fatal obstacle to cancer chemotherapy. The combination of P-glycoprotein (P-gp) inhibitor and chemotherapeutic drugs is one of the effective strategies to reverse tumor MDR. Herein, a folate-decorated PCL-ss-PEG-ss-PCL based redox-responsive polymersome (FA-TQR-Co-PS) was constructed, which was loaded with P-gp inhibitor tariquidar (TQR), anticancer drugs doxorubicin (DOX) and paclitaxel (PTX). The results suggested that the FA-TQR-Co-PS with an apparent bilayered lamellar structure displayed good monodispersity, high drug loading capacity, superior stability and redox-stimulated drug release peculiarity. In vitro cellular uptake study demonstrated that FA-TQR-Co-PS increased drug accumulation into MCF-7/ADR cells via the TQR-induced P-gp efflux inhibition, and further improved targeting to tumor cells due to folate receptor-mediated endocytosis. Furthermore, the DOX and PTX cytotoxicity and proapoptotic activity against MCF-7/ADR was enhanced dramatically along with the administration of TQR, and the cell cycle was profoundly blocked in G2/M phase. The folate-targeted redox-responsive polymersomes loaded with chemotherapeutic drugs and P-gp inhibitor demonstrated noticeable synergistic effect against human MDR MCF-7 cells and successfully reversed drug resistance, which displayed high potential in overcoming tumor MDR as a novel drug delivery system.
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The cellular uptake and cytotoxicity results demonstrated that chemosensitizer (TQR) achieved a complete multidrug resistance reversal in the MCF-7/ADR cells. The cell accumulation of DOX and PTX increased either Co-PS co-deliver with TQR or folate, providing a premise for combination therapy. Our results demonstrated improved cellular internalization mediated by polymer-somes via the P-gp inhibition and folate-targeted effect. When we delve deeper, it is interesting to find the resistance index of TQR-Co-PS and FA-TQR-Co-PS was decreased to 0.70 and 0.71 respectively. In addition, as shown in Figure 7, the cell viability curves of MCF-7/ADR cells is lower than MCF-7 cells at a high drug concentra- tion. These results may be related to a number of elements as follows. (1) With the increment of PTX concentration, the extracellular signal regulated kinase (ERK) may be activated, which contribute to the cell proliferation and arouse drug resistance to drug-sensitive cells.53–55 (2) Pre-REFERENCES vious studies have explored that P-gp overexpressing cells Multidrug resistance:Physiologicalprinciplesand nanomedicalsolu-1.S.Kunjachan,B. Rychlik,G. Storm,F. Kiessling,andT. Lammers, seemed to accumulate 2 times more TQR than parental tions.Adv.DrugDeliv.Rev.65,1852(2013). cells.56 In addition, high concentration of TQR (higher R. Li and Y. Xie, Nanodrug delivery systems for targeting the than 100 nM) could inhibit both P-gp and BCRP,57 leading endogenous tumor microenvironment and simultaneously overcom- severer cytotoxicity to MCF-7/ADR cells compared with ing multidrug resistance properties. J. Control. Release 251, 49 MCF-7 cell at a high concentration of drugs. Hence, the (2017). cellular uptake and cytotoxicity assays demonstrated that J. Tian, C. Yao, W. L. Yang, L. Zhang, D. W. Zhang, H. Wang, the FA-TQR-Co-PS and TQR-Co-PS successfully reversed supramolecularorganicframeworkdrugdelivery systems (sof-F. Zhang,Y. Liu,and Z. T.Li,Insitu-preparedhomogeneous the MDR. DDSs): Overcoming cancer multidrug resistance and controlled The drug co-delivery polymersomes enhanced chemo-release. Chin. Chem. Lett. 28, 798 (2017). therapeutic drugs accumulation in tumor cells and enabled W. Li, H. Zhang, Y. G. Assaraf, K. Zhao, X. Xu, J. Xie, D. H. TQR to be effective in ensuring DOX and PTX to restrain Yang, and Z. S. Chen, Overcoming ABC transporter-mediated mul- proliferation, induce apoptosis and block cell cycle. PTX tidrug resistance: Molecular mechanisms and noveltherapeutic drug has a high affinity to -subunit of tubulin and could pro-G.Szakacs, J. K.Paterson,J.A.Ludwig,C. Booth-Genthe, andstrategies. DrugResist.Updat.27,14(2016). mote the polymerization of tubulin results in inhibition M.M.Gottesman,Targetingmultidrugresistanceincancer.Nat.Rev. of cell mitosis, which arrests cells in the late G2 and DrugDiscov.5,219(2006). M stages of cell cycle.58 59 DOX has a high affinity to J. Zhang, L. Wang, H. Fai Chan, W. Xie, S. Chen, C. He, Y. Wang, DNA and blocks cycle at a G2/M phase via activating the and M. Chen, Co-delivery of paclitaxel and tetrandrine via iRGD P53/Bax/Bcl-2, caspase-3, and PIP-J:N 2K03, .P5-6P.32841p.a1t2h8w aOyn.60: Mon, 01peptide Oct 2c0onjugated18 12:2lipid-polym0:17 er hybrid nanoparticles overcome The combinationof DOX and PTX blCopyright: American Scientific Publishersocks MCF-7/ADRmultidrug resistance in cancer cells. Sci. Rep. 7, 46057 (2017). Delivered by Ingenta7. R. G. Tuguntaev, S. Chen, A. S. Eltahan, A. Mozhi, S. Jin, J. Zhang, cells in G2/M phase. Both the folate-targeted and P-gp C.Li,P.C.Wang,andX.J.Liang,P-gpinhibitionandmitochon- inhibitive effect enhanced DOX and PTX induced G2/M drialimpairment bydual-functional nanostructure basedonvitamin phase arrest. E derivatives to overcome multidrug resistance. ACS Appl. Mater. In summary, we developed a multifunctional nano-Interfaces9,16900(2017). delivery system with co-delivery chemosensitizer TQR, T.Cheng, J. Liu, J. Ren, F. Huang, H.Ou, Y. Ding, Y. Zhang, folate-targeting molecule and combination of DOX and micellescombinedwithdoxorubicintoovercomecardiotoxicityandR.Ma,Y.An,J.Liu,andL.Shi,Greenteacatechin-basedcomplex PTX to reverse tumor drug resistance. This nanocarrier has multidrug resistance. Theranostics 6, 1277 (2016). and Science and Technology Support Program of Tianjin (14RCGFSY00146), Science Foundation for The Youth Teachers of Peking Union Medical College (grant number 2014zlgc0754), Scientific Research Foundation of the State Human Resource Ministry and the Education Ministry for Returned Chinese Scholars.
Acknowledgments: The work was supported, in part,
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- Combination Therapy
- Drug Resistance