Targeted Dual pH‐Sensitive Lipid ECO/siRNA Self‐Assembly Nanoparticles Facilitate In Vivo Cytosolic sieIF4E Delivery and Overcome Paclitaxel Resistance in Breast Cancer Therapy

Abstract

Down-regulation of oncogenes associated with multidrug resistance with RNAi has the potential to enhance the efficacy of cancer chemotherapy. Here, we have designed and developed targeted dual pH-sensitive lipid siRNA self-assembly nanoparticles RGD-PEG(HZ)-ECO/siRNA to enhance cytosolic siRNA delivery via systemic administration, to regulate oncogene expression, and to improve the efficacy of cancer chemotherapy. The dual pH-sensitive function of RGD-PEG(HZ)-ECO/siRNA nanoparticles facilitates effective cytosolic siRNA delivery in cancer cells both in vitro and in vivo after systemic injection. Intravenous injection of RGD-PEG(HZ)-ECO/siRNA nanoparticles (1.0 mg-siRNA/kg) results in effective gene silencing for at least a week in MDA-MB-231 tumor. Intravenous injections of RGD-PEG(HZ)-ECO/siRNA specific to eukaryotic translation initiation factor 4E (eIF4E) every 6 days for 6 weeks down-regulate the overexpression eIF4E protein in tumor and resensitize a drug-resistant MDA-MB-231 breast cancer model to paclitaxel, resulting in significant tumor regression at a low dose, with negligible side effects. RGD-PEG(HZ)-ECO/siRNA nanoparticles also result in minimal immunogenicity after repeated injections in immunocompetent mice. Silencing eIF4E with the targeted dual pH-sensitive multifunctional lipid sieIF4E nanoparticles has the potential to re-sensitize drug-resistant breast cancer to chemotherapy.

Targeted Multifunctional Lipid ECO Plasmid DNA Nanoparticles as Efficient Non-viral Gene Therapy for Leber’s Congenital Amaurosis

“…In future work, we will address the transience of gene expression with these nanoparticles by modifying the DNA plasmid with sequences that prolong gene expression, such as scaffold/matrix attachment regions (S/MARs) 41 . The targeted ECO/pDNA nanoparticles can also be further optimized by introducing a pH-sensitive spacer between PEG and ECO to enhance endosomal escape of the ECO/pDNA nanoparticles 42 . Although modification of ECO/pDNA with Ret-PEG promoted cellular uptake of the nanoparticles, the PEG layer could hinder the pH-sensitive amphiphilic endosomal escape of the ECO/pDNA nanoparticles.…”

Extradomain-B Fibronectin is a molecular marker of invasive breast cancer cells

“…ECO/siRNA nanoparticles were formulated as previously described (Gujrati et al, 2016). Briefly, the cationic lipid ECO (5 mM stock in ethanol) was mixed with siEDB or siLuc (as negative control NC) at a final siRNA concentration of 100 nM and N/P = 10 for 30 min to enable self-assembly formation of ECO/siEDB or ECO/NC nanoparticles, respectively.…”

Role of eIF4E on epithelial‐mesenchymal transition, invasion, and chemoresistance of prostate cancer cells

“…Numerous oncogenes, such as eukaryotic translation initiation factor 4E ( eIF4E ), have been reported to be involved in epithelial‐mesenchymal transition (EMT) and/or drug resistance in PCa [4]. We previously demonstrated that eIF4E overexpression was involved in chemoresistance of triple‐negative breast cancer and silencing eIF4E significantly inhibited cancer cell proliferation and sensitized cancer cells to chemotherapy in a patient‐derived xenograft mouse model [5]. In addition, eIF4E phosphorylation is known to stimulate the translation of matrix metalloproteinase 3 (MMP3) and Snail mRNAs to promote EMT in PCa [6].…”