Self-immolative nanoparticles for simultaneous delivery of microRNA and targeting of polyamine metabolism in combination cancer therapy

Abstract

Combination of anticancer drugs with therapeutic 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 N1,N11-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.

Biochemical evaluation of the anticancer potential of the polyamine-based nanocarrier Nano11047

“…Furthermore, the potential utility of Nano11047 as a delivery molecule for therapeutic nucleic acids, such as microRNA, is probable based on recent success using the closely related prodrug DSS-BENS [28]. As the antitumor targets of Nano11047 are multiple, the availability of this novel drug form will potentially benefit and encourage future clinical studies.…”

Synthesis and Evaluation of Chloroquine‐Containing DMAEMA Copolymers as Efficient Anti‐miRNA Delivery Vectors with Improved Endosomal Escape and Antimigratory Activity in Cancer Cells

“…MicroRNAs (miRNAs) are small noncoding RNAs that post‐transcriptionally regulate various signaling pathways and it is estimated that they are involved in the expression of more than 30% of all human proteins . Dysregulation of miRNA is prominently displayed in cancer due to the important role of miRNA in processes involved in tumorigenesis, tumor growth, angiogenesis, and metastasis . Anticancer treatments that use miRNA show great promise because single miRNA typically targets multiple genes simultaneously and is thus capable of regulating multiple biological pathways responsible for the cancer cell phenotype.…”

Synergistic effect of microRNA and albumin-bound nanoparticles for inhibition of glioblastoma cancer cell proliferation

“…A growing body of evidence has been suggested the potential use of tumor-suppressor miRNA in combination with chemotherapies or nanoparticles as "miRNA combination therapy" in the cancer therapy field Mishra, Mishra, Merlino, 2016;Xie et al, 2017;Zhao et al, 2016). In the current study, we investigated the anti-cancer effect of albumin-bound paclitaxel nanoparticles along with the some forced expression of miR-34a in U251 glioblastoma cell line in vitro.…”