Construction of Hierarchical-Targeting PH-Sensitive Liposomes to Reverse Chemotherapeutic Resistance of Cancer Stem-like Cells

Overview

Journal Pharmaceutics

Publisher MDPI

Date 2021 Aug 28

PMID 34452166

Citations 3

Authors

Shuang Ba

Mingxi Qiao

Li Jia

Jiulong Zhang

Xiuli Zhao

Haiyang Hu

Dawei Chen

Affiliations

Soon will be listed here.

Abstract

Cancer stem-like cells (CSLCs) have been considered to be one of the main problems in tumor treatment owing to high tumorigenicity and chemotherapy resistance. In this study, we synthesized a novel mitochondria-target derivate, triphentlphosphonium-resveratrol (TPP-Res), and simultaneously encapsulated it with doxorubicin (Dox) in pH-sensitive liposomes (PSL (Dox/TPP-Res)), to reverse chemotherapeutic resistance of CSLCs. PSL (Dox/TPP-Res) was approximately 165 nm in size with high encapsulation efficiency for both Dox and TPP-Res. Cytotoxicity assay showed that the optimal synergistic effect was the drug ratio of 1:1 for TPP-Res and Dox. Cellular uptake and intracellular trafficking assay indicated that PSL (Dox/TPP-Res) could release drugs in acidic endosomes, followed by mitochondrial targeting of TPP-Res and nucleus transports for Dox. The mechanisms for reversing the resistance in CSLCs were mainly attributed to a synergistic effect for reduction of mitochondrial membrane potential, activation of caspase cascade reaction, reduction of ATP level and suppression of the Wnt/β-catenin pathway. Further, in vivo assay results demonstrated that the constructed liposomes could efficiently accumulate in the tumor region and possess excellent antineoplastic activity in an orthotopic xenograft tumor model with no evident systemic toxicity. The above experimental results determined that PSL (Dox/TPP-Res) provides a new method for the treatment of heterogenecity tumors.

Citing Articles

Sustained-release behavior and the antitumor effect of charge-convertible poly(amino acid)s drug-loaded nanoparticles.

Hu Z, Wang G, Zhang R, Yang Y, Wang J, Hu J Drug Deliv Transl Res. 2023; 13(9):2394-2406.

PMID: 36913103 DOI: 10.1007/s13346-023-01323-w.

Mitochondrial-Targeted Triphenylphosphonium-Hydroxycamptothecin Conjugate and Its Nano-Formulations for Breast Cancer Therapy: In Vitro and In Vivo Investigation.

Zhang K, Fu J, Liu X, Guo Y, Han M, Liu M Pharmaceutics. 2023; 15(2).

PMID: 36839710 PMC: 9961676. DOI: 10.3390/pharmaceutics15020388.

Methods of Liposomes Preparation: Formation and Control Factors of Versatile Nanocarriers for Biomedical and Nanomedicine Application.

Lombardo D, Kiselev M Pharmaceutics. 2022; 14(3).

PMID: 35335920 PMC: 8955843. DOI: 10.3390/pharmaceutics14030543.

References

Liu H, Guo N, Guo W, Huang-Fu M, Vakili M, Chen J . Delivery of mitochondriotropic doxorubicin derivatives using self-assembling hyaluronic acid nanocarriers in doxorubicin-resistant breast cancer. Acta Pharmacol Sin. 2018; 39(10):1681-1692. PMC: 6289358. DOI: 10.1038/aps.2018.9. View

Yao H, Ashihara E, Maekawa T . Targeting the Wnt/β-catenin signaling pathway in human cancers. Expert Opin Ther Targets. 2011; 15(7):873-87. DOI: 10.1517/14728222.2011.577418. View

Ishida T, Okada Y, Kobayashi T, Kiwada H . Development of pH-sensitive liposomes that efficiently retain encapsulated doxorubicin (DXR) in blood. Int J Pharm. 2005; 309(1-2):94-100. DOI: 10.1016/j.ijpharm.2005.11.010. View

Shen S, Xu X, Lin S, Zhang Y, Liu H, Zhang C . A nanotherapeutic strategy to overcome chemotherapeutic resistance of cancer stem-like cells. Nat Nanotechnol. 2021; 16(1):104-113. DOI: 10.1038/s41565-020-00793-0. View

Kim J, Chae M, Kim W, Kim Y, Kang H, Kim H . Salinomycin sensitizes cancer cells to the effects of doxorubicin and etoposide treatment by increasing DNA damage and reducing p21 protein. Br J Pharmacol. 2010; 162(3):773-84. PMC: 3041264. DOI: 10.1111/j.1476-5381.2010.01089.x. View

Saygin C, Matei D, Majeti R, Reizes O, Lathia J . Targeting Cancer Stemness in the Clinic: From Hype to Hope. Cell Stem Cell. 2019; 24(1):25-40. DOI: 10.1016/j.stem.2018.11.017. View

Li R, Ying X, Zhang Y, Ju R, Wang X, Yao H . All-trans retinoic acid stealth liposomes prevent the relapse of breast cancer arising from the cancer stem cells. J Control Release. 2010; 149(3):281-91. DOI: 10.1016/j.jconrel.2010.10.019. View

Han M, Vakili M, Soleymani Abyaneh H, Molavi O, Lai R, Lavasanifar A . Mitochondrial delivery of doxorubicin via triphenylphosphine modification for overcoming drug resistance in MDA-MB-435/DOX cells. Mol Pharm. 2014; 11(8):2640-9. DOI: 10.1021/mp500038g. View

Ma X, Zhou J, Zhang C, Li X, Li N, Ju R . Modulation of drug-resistant membrane and apoptosis proteins of breast cancer stem cells by targeting berberine liposomes. Biomaterials. 2013; 34(18):4452-65. DOI: 10.1016/j.biomaterials.2013.02.066. View

10.

Pham P, Phan N, Nguyen N, Truong N, Duong T, Le D . Differentiation of breast cancer stem cells by knockdown of CD44: promising differentiation therapy. J Transl Med. 2011; 9:209. PMC: 3251542. DOI: 10.1186/1479-5876-9-209. View

11.

Li H, Yan W, Suo X, Peng H, Yang X, Li Z . Nucleus-targeted nano delivery system eradicates cancer stem cells by combined thermotherapy and hypoxia-activated chemotherapy. Biomaterials. 2019; 200:1-14. DOI: 10.1016/j.biomaterials.2019.01.048. View

12.

Lai M, Vail W, Szoka F . Acid- and calcium-induced structural changes in phosphatidylethanolamine membranes stabilized by cholesteryl hemisuccinate. Biochemistry. 1985; 24(7):1654-61. DOI: 10.1021/bi00328a013. View

13.

Diaz A, Leon K . Therapeutic approaches to target cancer stem cells. Cancers (Basel). 2013; 3(3):3331-52. PMC: 3759198. DOI: 10.3390/cancers3033331. View

14.

Weissig V . DQAsomes as the prototype of mitochondria-targeted pharmaceutical nanocarriers: preparation, characterization, and use. Methods Mol Biol. 2015; 1265:1-11. DOI: 10.1007/978-1-4939-2288-8_1. View

15.

Hu Y, Smyth G . ELDA: extreme limiting dilution analysis for comparing depleted and enriched populations in stem cell and other assays. J Immunol Methods. 2009; 347(1-2):70-8. DOI: 10.1016/j.jim.2009.06.008. View

16.

Biasutto L, Mattarei A, Marotta E, Bradaschia A, Sassi N, Garbisa S . Development of mitochondria-targeted derivatives of resveratrol. Bioorg Med Chem Lett. 2008; 18(20):5594-7. DOI: 10.1016/j.bmcl.2008.08.100. View

17.

Zhang Y, Zhang C, Chen J, Liu L, Hu M, Li J . Trackable Mitochondria-Targeting Nanomicellar Loaded with Doxorubicin for Overcoming Drug Resistance. ACS Appl Mater Interfaces. 2017; 9(30):25152-25163. DOI: 10.1021/acsami.7b07219. View

18.

Han J, Park W, Park S, Na K . Photosensitizer-Conjugated Hyaluronic Acid-Shielded Polydopamine Nanoparticles for Targeted Photomediated Tumor Therapy. ACS Appl Mater Interfaces. 2016; 8(12):7739-47. DOI: 10.1021/acsami.6b01664. View

19.

Kawamura E, Yamada Y, Yasuzaki Y, Hyodo M, Harashima H . Intracellular observation of nanocarriers modified with a mitochondrial targeting signal peptide. J Biosci Bioeng. 2013; 116(5):634-7. DOI: 10.1016/j.jbiosc.2013.05.001. View

20.

Gledhill J, Montgomery M, Leslie A, Walker J . Mechanism of inhibition of bovine F1-ATPase by resveratrol and related polyphenols. Proc Natl Acad Sci U S A. 2007; 104(34):13632-7. PMC: 1948022. DOI: 10.1073/pnas.0706290104. View