Combined Delivery of Let-7b MicroRNA and Paclitaxel via Biodegradable Nanoassemblies for the Treatment of KRAS Mutant Cancer

Abstract

In the present study, we synthesized a novel cationic copolymer composed of polyethylene glycol 5000 (PEG5K), vitamin E (VE), and diethylenetriamine (DET) at 1:4:20 molar ratio. The resulting PEG5K-VE4-DET20 copolymer formed nanoassemblies when mixed with the neutral PEG5K-VE4 copolymer at 1:8 weight ratio, which were investigated as the nanocarriers for combined delivery of paclitaxel and let-7b mimic. We found that the PEG5K-VE4-DET20 nanoassemblies could entrap paclitaxel for an extended period and burst release the drug in the presence of cathepsin B, demonstrating the biodegradability of the copolymers. At N/P ratio of 12:1, the PEG5K-VE4-DET20 nanoassemblies formed stable polyplexes with let-7b mimic, which were efficiently taken up by tumor cells and underwent endosomal escape. In non-small cell lung cancer A549 cells that harbor mutant KRAS, paclitaxel and let-7b mimic-loaded nanoassemblies (N-PTX/let-7b) markedly potentiated the cytotoxicity of paclitaxel, induced apoptosis, and diminished the invasiveness of tumor cells. In mice bearing subcutaneous A549 xenografts, intravenous administration of N-PTX/let-7b retarded tumor growth more efficaciously than Taxol. Our study demonstrates the promise of the PEG5K-VE4-DET20 nanoassemblies for concurrent delivery of hydrophobic drugs and miRNA mimics.

Current state of phenolic and terpenoidal dietary factors and natural products as non-coding RNA/microRNA modulators for improved cancer therapy and prevention

“…A pH-dependent liposomal formulation of a combination of antagomir-10b and paclitaxel released antagomir-10b and paclitaxel at lower pH values and inhibited lung metastasis formation and tumor growth inhibition of 4T1 breast tumors by suppression of miR-10b [327] . Another formulation of a special copolymer including polyethylene glycol 5000, vitamin E and diethylenetriamine (PEG 5K -VE 4 -DET 20 ) was loaded with a let-7b mimic and paclitaxel and exhibited increased anticancer activity (increased growth inhibition and apoptosis induction as well as reduced invasiveness) in KRAS-mutant lung cancer (A549) both in vitro and in vivo [328] . In gastric cancer cells (SGC7901), miR-21 expression mediated paclitaxel-resistance and inhibition of miR-21 restored paclitaxel activity in these cancer cells via suppression of the drug efflux transporter P-gp [329] .…”

Pharmacokinetics and biodistribution of polymeric micelles containing miRNA and small-molecule drug in orthotopic pancreatic tumor-bearing mice

“…Further, the KRAS-MEK-ERK cascade is known to noncanonically increase Gli1 transcriptional activity 13 . Dai et al demonstrated that let-7b restoration sensitizes KRAS mutant tumor cells of various tissue origins to paclitaxel and gemcitabine, suggesting that let-7b mimic has the potential to sensitize resistant tumor cells 14 , 15 . We previously demonstrated the synergistic effect of let-7b mimic and GDC-0449 using polymeric micelles in subcutaneous pancreatic tumor-bearing mice 4 .…”

MicroRNAs and Metastasis

“…In addition, multiple studies have been used combining miRNA modulators (mimics or anti-miRNAs) along with chemotherapy-most commonly, doxorubicin with miRNAs such as let-7a and miR-21 in breast cancer [159,160], miR-31 in cervical cancer [161] and miR-34a in prostate cancer [162]. Co-polymer nano-assemblies (PEG5K-VE4-DET20) were co-loaded with let-7b mimic and paclitaxel in NSCLC and demonstrated to potentiate the cytotoxicity of paclitaxel and induced apoptosis and inhibition of invasiveness in vivo [163]. Researchers developed a polymeric dual delivery nanoscale device (DDND) to delivery miR-345 mimic and gemcitabine for metastatic pancreatic cancer [164].…”