Novel Ran-RCC1 Inhibitory Peptide-Loaded Nanoparticles Have Anti-Cancer Efficacy In Vitro and In Vivo

Abstract

The delivery of anticancer agents to their subcellular sites of action is a significant challenge for effective cancer therapy. Peptides, which are integral to several oncogenic pathways, have significant potential to be utilised as cancer therapeutics due to their selectivity, high potency and lack of normal cell toxicity. Novel Ras protein-Regulator of chromosome condensation 1 (Ran-RCC1) inhibitory peptides designed to interact with Ran, a novel therapeutic target in breast cancer, were delivered by entrapment into polyethylene glycol-poly (lactic-co-glycolic acid) PEG-PLGA polymeric nanoparticles (NPs). A modified double emulsion solvent evaporation technique was used to optimise the physicochemical properties of these peptide-loaded biodegradable NPs. The anti-cancer activity of peptide-loaded NPs was studied in vitro using Ran-expressing metastatic breast (MDA-MB-231) and lung cancer (A549) cell lines, and in vivo using Solid Ehrlich Carcinoma-bearing mice. The anti-metastatic activity of peptide-loaded NPs was investigated using migration, invasion and colony formation assays in vitro. A PEG-PLGA-nanoparticle encapsulating N-terminal peptide showed a pronounced antitumor and anti-metastatic action in lung and breast cancer cells in vitro and caused a significant reduction of tumor volume and associated tumor growth inhibition of breast cancer model in vivo. These findings suggest that the novel inhibitory peptides encapsulated into PEGylated PLGA NPs are delivered effectively to interact and deactivate Ran. This novel Ran-targeting peptide construct shows significant potential for therapy of breast cancer and other cancers mediated by Ran overexpression.

The association of RAN and RANBP2 gene polymerphisms with Wilms tumor risk in Chinese children

“…RAN has been shown to be implicated in carcinomas, such as breast cancer and lung cancer, by regulating cell adhesion, migration and invasion [31]. Several researches illustrated that RAN-inhibitory peptide-loaded PEG-PLGA NPs have great potential in curbing cancer through limiting the formation of active forms of RAN [32][33][34]. In addition, the expression level of RAN was significantly altered in glioblastoma, pancreatic cancer, neuroblastoma, melanoma [35][36][37][38][39][40].…”

<p>Design, Formulation and in vivo Evaluation of Novel Honokiol-Loaded PEGylated PLGA Nanocapsules for Treatment of Breast Cancer</p>

“…The linear regression equation of the dose-effect curve was used to calculate the IC 50. 20 The results showed that the blank NCs had no cytotoxicity on breast cancer cells. Treatment with honokiol showed a significant reduction in cell viability compared to control (p < 0.05, n=3).…”

“…Cytotoxicity was examined by MTT assay as previously reported by. 11,20 After treatment with 24, 48 and 72 h, media was removed and cells were treated by 500 μL of (15% v/v MTT solution). MCF-7 cells were incubated at 37°C and 5% CO 2 for 3 h. Afterward, formazan crystals formed were dissolved in DMSO (500 μL) and the plate was read at 570 nm in an FLUO star Omega microplate reader (BMG Labtech) and the results were expressed as the cell viability after treatment was compared to control cell viability.…”

“…The tumor developed as a palpable solid tumor mass which was achieved within 12 days postimplantation in all mice. 12,20 In vivo Anti-Tumor Activity…”

“…[17][18][19] These polymers are sufficiently stable in vitro and longcirculating in vivo besides they showed high cancer cell internalization by Enhanced Penetration Retention (EPR) effect to achieve passive targeting to tumor site. 12,20 Several attempts are described to develop different carriermediated drug delivery strategies for HK based on nanotechnology. These nano-drug delivery systems include nanosuspension, 21 nanoparticles, [22][23][24] microbubbles, 25 liposomes 26 and polymeric micelles.…”