A curcumin-loaded polymeric micelle as a carrier of a microRNA-21 antisense-oligonucleotide for enhanced anti-tumor effects in a glioblastoma animal model

Abstract

A glioblastoma is a common primary brain tumor that expresses microRNA-21 (miR-21), which inhibits the expression of pro-apoptotic genes such as phosphatase and tensin homologue (PTEN) and programmed cell death 4 (PDCD4). Therefore, an antisense-oligonucleotide against miR-21 (miR21ASO) could have therapeutic effects for glioblastomas. In this study, curcumin was loaded into deoxycholic acid-conjugated polyethylenimine (DP) micelles. The curcumin-loaded DP micelle (DP-Cur) was evaluated as a carrier for the combined delivery of curcumin and miR21ASO. Gel retardation and heparin competition assays showed that DP-Cur formed stable complexes with miR21ASO. The anti-tumor effects of the combined delivery of curcumin and miR21ASO were evaluated in C6 glioblastoma cells. In vitro transfection showed that DP-Cur had an miR21ASO delivery efficiency similar to that of polyethylenimine (25 kDa, PEI25k) and DP. In the C6 cells, the delivery of miR21ASO using DP-Cur effectively reduced the miR21 level. The miR21ASO/DP-Cur complex induced apoptosis more effectively than the single delivery of curcumin or miR21ASO. The therapeutic effect of the miR21ASO/DP-Cur complex was also evaluated in an intracranial glioblastoma animal model. The miR21ASO/DP-Cur complex reduced the tumor volume more effectively than single therapy of curcumin or miR21ASO. Immunohistochemistry showed that PDCD4 and PTEN were induced in the miR21ASO/DP and miR21ASO/DP-Cur complex groups. Therefore, DP-Cur is an efficient carrier of miR21ASO and the combined delivery of miR21ASO and curcumin may be useful in the development of combination therapy for glioblastoma.

Lymphoid Organ Proteomes Identify Therapeutic Efficacy Biomarkers Following the Intracavitary Administration of Curcumin in a Highly Invasive Rat Model of Peritoneal Mesothelioma

“…Mudduluru et al [27] Rko and HCT116 human colorectal cancer cells Yang et al [28] DU145 human prostate cancer cells, B16 murine melanoma cells Chen et al [29] Review: microRNAs regulation Lelli et al [30] Review: melanoma Tan et al [31] C6 rat experimental glioblastoma Shakeri et al [32] Review Zhang et al [35] Lu1205 and A375 human melanoma cells Qin et al [36] HSC-T6 rat cells, rat liver fibrosis (in vivo) Wang et al [37] HMrSV5 human peritoneal mesothelial cells Gallardo et al [38] MCF…”

Immunoengineering in glioblastoma imaging and therapy

“…Deoxycholic acid‐conjugated polyethylenimine micelles laden with curcumin were evaluated for the combined delivery of curcumin and miR21ASO in an intracranial GBM animal model. This complex was more effective at decreasing the tumor volume compared with single therapy of curcumin or miR21ASO (Tan et al, ). In a recent study by Y. Zhu et al (), Angiopep‐2 and TAT peptides, as tumor‐targeting and cell‐penetrating peptides, were coupled on the surface of nanomicelles and resulted in BBB permeation enhancement, brain tumor targeting and improved survival rate in mice bearing orthotopic U87MG human glioma.…”

Two Worlds Colliding: The Interplay Between Natural Compounds and Non-Coding Transcripts in Cancer Therapy

“…Studies on breast cancer ( Wang X. et al, 2017 ; Esmatabadi et al, 2017 ) and glioma ( Yeh et al, 2015 ) have also reported curcumin down-regulating miR-21 expression, but without proposing a specific mechanism by which it does so, or possible targets of miR-21. Working with a GBM model, Tan et al (2018) designed a micelle loaded with curcumin and miR-21 antisense nucleotide and reported increased effects compared to both curcumin treatment and miR-21 antisense nucleotide treatment alone. This was found both in vitro and in vivo , as evidenced by increased apoptosis and lower tumor volume, respectively.…”