Self-immolative Nanoparticles for Simultaneous Delivery of MicroRNA and Targeting of Polyamine Metabolism in Combination Cancer Therapy

Overview

Journal J Control Release

Specialty Pharmacology

Date 2016 Dec 27

PMID 28017891

Citations 47

Authors

Ying Xie

Tracy Murray-Stewart

Yazhe Wang

Fei Yu

Jing Li

Laurence J Marton

Robert A Casero Jr

David Oupicky

Affiliations

Soon will be listed here.

Abstract

Combination of anticancer drugs with therapeutic microRNA (miRNA) has emerged as a promising anticancer strategy. However, the promise is hampered by a lack of desirable delivery systems. We report on the development of self-immolative nanoparticles capable of simultaneously delivering miR-34a mimic and targeting dysregulated polyamine metabolism in cancer. The nanoparticles were prepared from a biodegradable polycationic prodrug, named DSS-BEN, which was synthesized from a polyamine analog N,N-bisethylnorspermine (BENSpm). The nanoparticles were selectively disassembled in the cytoplasm where they released miRNA. Glutathione (GSH)-induced degradation of self-immolative linkers released BENSpm from the DSS-BEN polymers. MiR-34a mimic was effectively delivered to cancer cells as evidenced by upregulation of intracellular miR-34a and downregulation of Bcl-2 as one of the downstream targets of miR-34a. Intracellular BENSpm generated from the degraded nanoparticles induced the expression of rate-limiting enzymes in polyamine catabolism (SMOX, SSAT) and depleted cellular natural polyamines. Simultaneous regulation of polyamine metabolism and miR-34a expression by DSS-BEN/miR-34a not only enhanced cancer cell killing in cultured human colon cancer cells, but also improved antitumor activity in vivo. The reported findings validate the self-immolative nanoparticles as delivery vectors of therapeutic miRNA capable of simultaneously targeting dysregulated polyamine metabolism in cancer, thereby providing an elegant and efficient approach to combination nanomedicines.

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References

Hermeking H . The miR-34 family in cancer and apoptosis. Cell Death Differ. 2009; 17(2):193-9. DOI: 10.1038/cdd.2009.56. View

Costa P, Cardoso A, Custodia C, Cunha P, de Almeida L, de Lima M . MiRNA-21 silencing mediated by tumor-targeted nanoparticles combined with sunitinib: A new multimodal gene therapy approach for glioblastoma. J Control Release. 2015; 207:31-9. DOI: 10.1016/j.jconrel.2015.04.002. View

Ren Y, Wang R, Gao L, Li K, Zhou X, Guo H . Sequential co-delivery of miR-21 inhibitor followed by burst release doxorubicin using NIR-responsive hollow gold nanoparticle to enhance anticancer efficacy. J Control Release. 2016; 228:74-86. DOI: 10.1016/j.jconrel.2016.03.008. View

Pegg A, Casero Jr R . Current status of the polyamine research field. Methods Mol Biol. 2011; 720:3-35. PMC: 3652263. DOI: 10.1007/978-1-61779-034-8_1. View

Piao J, Yan J, Wang M, Wu D, You Y . A new method to cross-link a polyplex for enhancing in vivo stability and transfection efficiency. Biomater Sci. 2020; 2(3):390-398. DOI: 10.1039/c3bm60204d. View

Zhang Q, Ran R, Zhang L, Liu Y, Mei L, Zhang Z . Simultaneous delivery of therapeutic antagomirs with paclitaxel for the management of metastatic tumors by a pH-responsive anti-microbial peptide-mediated liposomal delivery system. J Control Release. 2014; 197:208-18. DOI: 10.1016/j.jconrel.2014.11.010. View

Xie Y, Wehrkamp C, Li J, Wang Y, Wang Y, Mott J . Delivery of miR-200c Mimic with Poly(amido amine) CXCR4 Antagonists for Combined Inhibition of Cholangiocarcinoma Cell Invasiveness. Mol Pharm. 2016; 13(3):1073-80. PMC: 4924348. DOI: 10.1021/acs.molpharmaceut.5b00894. View

Streiff R, BENDER J . Phase 1 study of N1-N11-diethylnorspermine (DENSPM) administered TID for 6 days in patients with advanced malignancies. Invest New Drugs. 2001; 19(1):29-39. DOI: 10.1023/a:1006448516938. View

Lachelt U, Wagner E . Nucleic Acid Therapeutics Using Polyplexes: A Journey of 50 Years (and Beyond). Chem Rev. 2015; 115(19):11043-78. DOI: 10.1021/cr5006793. View

10.

Dai X, Tan C . Combination of microRNA therapeutics with small-molecule anticancer drugs: mechanism of action and co-delivery nanocarriers. Adv Drug Deliv Rev. 2014; 81:184-97. DOI: 10.1016/j.addr.2014.09.010. View

11.

Gerner E, Meyskens Jr F . Polyamines and cancer: old molecules, new understanding. Nat Rev Cancer. 2004; 4(10):781-92. DOI: 10.1038/nrc1454. View

12.

Li J, Wang Y, Zhu Y, Oupicky D . Recent advances in delivery of drug-nucleic acid combinations for cancer treatment. J Control Release. 2013; 172(2):589-600. PMC: 3783568. DOI: 10.1016/j.jconrel.2013.04.010. View

13.

Liu G, Zhang G, Hu J, Wang X, Zhu M, Liu S . Hyperbranched Self-Immolative Polymers (hSIPs) for Programmed Payload Delivery and Ultrasensitive Detection. J Am Chem Soc. 2015; 137(36):11645-55. DOI: 10.1021/jacs.5b05060. View

14.

Tan X, Li B, Lu X, Jia F, Santori C, Menon P . Light-triggered, self-immolative nucleic Acid-drug nanostructures. J Am Chem Soc. 2015; 137(19):6112-5. DOI: 10.1021/jacs.5b00795. View

15.

Wang Y, Kumar S, Rachagani S, Sajja B, Xie Y, Hang Y . Polyplex-mediated inhibition of chemokine receptor CXCR4 and chromatin-remodeling enzyme NCOA3 impedes pancreatic cancer progression and metastasis. Biomaterials. 2016; 101:108-120. PMC: 4921319. DOI: 10.1016/j.biomaterials.2016.05.042. View

16.

Minois N, Carmona-Gutierrez D, Madeo F . Polyamines in aging and disease. Aging (Albany NY). 2011; 3(8):716-32. PMC: 3184975. DOI: 10.18632/aging.100361. View

17.

Yao C, Liu J, Wu X, Tai Z, Gao Y, Zhu Q . Reducible self-assembling cationic polypeptide-based micelles mediate co-delivery of doxorubicin and microRNA-34a for androgen-independent prostate cancer therapy. J Control Release. 2016; 232:203-14. DOI: 10.1016/j.jconrel.2016.04.034. View

18.

Igarashi K, Kashiwagi K . Modulation of cellular function by polyamines. Int J Biochem Cell Biol. 2009; 42(1):39-51. DOI: 10.1016/j.biocel.2009.07.009. View

19.

Zhu Y, Li J, Kanvinde S, Lin Z, Hazeldine S, Singh R . Self-immolative polycations as gene delivery vectors and prodrugs targeting polyamine metabolism in cancer. Mol Pharm. 2014; 12(2):332-41. PMC: 4319695. DOI: 10.1021/mp500469n. View

20.

Kabra P, Lee H, Lubich W, Marton L . Solid-phase extraction and determination of dansyl derivatives of unconjugated and acetylated polyamines by reversed-phase liquid chromatography: improved separation systems for polyamines in cerebrospinal fluid, urine and tissue. J Chromatogr. 1986; 380(1):19-32. DOI: 10.1016/s0378-4347(00)83621-x. View