Co-delivery of pemetrexed and miR-21 antisense oligonucleotide by lipid-polymer hybrid nanoparticles and effects on glioblastoma cells

Abstract

Combination therapy using anticancer drugs and nucleic acid is a more promising strategy to overcome multidrug resistance in cancer and to enhance apoptosis. In this study, lipid-polymer hybrid nanoparticles (LPNs), which contain both pemetrexed and miR-21 antisense oligonucleotide (anti-miR-21), have been developed for treatment of glioblastoma, the most aggressive type of brain tumor. Prepared LPNs have been well characterized by particle size distribution and zeta potential measurements, determination of encapsulation efficiency, and in vitro release experiments. Morphology of LPNs was determined by transmission electron microscopy. LPNs had a hydrodynamic size below 100 nm and exhibited sustained release of pemetrexed up to 10 h. Encapsulation of pemetrexed in LPNs increased cellular uptake from 6% to 78%. Results of confocal microscopy analysis have shown that co-delivery of anti-miR-21 significantly improved accumulation of LPNs in the nucleus of U87MG cells. Nevertheless, more effective cytotoxicity results could not be obtained due to low concentration of anti-miR-21, loaded in LPNs. We expect that the effective drug delivery systems can be obtained with higher concentration of anti-miR-21 for the treatment of glioblastoma.

Combining hydrophilic chemotherapy and hydrophobic phytotherapy via tumor-targeted albumin–QDs nano-hybrids: covalent coupling and phospholipid complexation approaches

“…However, the relative lack of PMT specificity resulted in toxic dose-related adverse effects that may limit its therapeutic effect such as myelosuppression, hepatic enzyme elevations, maculopapular rash, emesis and diarrhea. To reduce its toxicity, PMT was encapsulated into nanocarriers including PEG–peptide–PCL NPs [11] and lipid–polymer hybrid NPs [12]. The small size (below 100 nm)of NPs containing both PMT and miR-21 antisense oligonucleotide, enabled their passive tumor targeting and enhanced uptake into U87MG human glioblastoma cells [12].…”

“…To reduce its toxicity, PMT was encapsulated into nanocarriers including PEG–peptide–PCL NPs [11] and lipid–polymer hybrid NPs [12]. The small size (below 100 nm)of NPs containing both PMT and miR-21 antisense oligonucleotide, enabled their passive tumor targeting and enhanced uptake into U87MG human glioblastoma cells [12]. On the other hand, Resveratrol (RSV), a natural polyphenol and phytoalexin, demonstrated a strong anti-cancer activity.…”

RNA Nanoparticle-Based Targeted Therapy for Glioblastoma through Inhibition of Oncogenic miR-21

“…Since miR-21 inhibition can be cytotoxic, unwanted targeting of normal brain cells needs to be avoided to minimize off target adverse treatment effects. 9,[31][32][33] While LNA-miR21 was employed to target this onco-miR in a glioblastoma model system in this study, the pRNA-3WJ-based RNP-based therapy is not limited to miR-21. Since our pRNA-3WJ RNP allows for the flexibility of any sequence replacement, any miRNA or siRNA can be loaded as a cargo for targeted therapy of glioblastoma or other cancers.…”

“…These data indicate that the RNP delivered anti-miR-21 LNA specifically targeted and inhibited endogenous mature miR-21 sequences, which has been shown to increase glioblastoma cell killing via apoptotic induction pathways. 9,[31][32][33] Glioma cell killing was also assessed in U87EGFRvIII-Luc cells 72 hr post treatment with FA-3WJ-Alexa647-LNA-miR21 RNPs at a concentration between 0 and 1,000 nM. Cell viability was then determined using a standard MTS assay.…”

Multifunctional Polymeric Nanoplatforms for Brain Diseases Diagnosis, Therapy and Theranostics

“…These nanofibers released TMZ for 30 days and significantly decreased the cell viability and survival of glioblastoma cells. Küçüktürkmen et al examined the effects of pemetrexed-and miR-21 antisense oligonucleotide-loaded lipid-polymer hybrid NPs on glioblastoma cells [129]. These NPs gradually released pemetrexed over 10 h and the encapsulation of pemetrexed in lipid NPs increased the cellular uptake from 6% to 78%.…”