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Polymalic Acid-based Nano Biopolymers for Targeting of Multiple Tumor Markers: An Opportunity for Personalized Medicine?
Published on: June 13, 2014
Modulating versatile pathways using a cleavable PEG shell and EGFR-targeted nanoparticles to deliver CRISPR-Cas9 and
Yu-Li Lo1,2, Ci-Jheng Hong3,4, Chen-Shen Wang3
1Institute of Pharmacology, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan. yulilo@nycu.edu.tw.
Abstract:
Human antigen R (HuR), an RNA-binding protein, is implicated in regulating mRNA stability and translation in cancer, especially in triple-negative breast cancer (TNBC), a highly aggressive form. CRISPR/Cas9-mediated HuR knockout (HuR CRISPR) presents a promising genetic therapeutic approach, but it encounters transfection limitations. Docetaxel (DTX), an effective cytotoxic agent against metastatic breast cancer (BC), faces challenges related to vehicle-associated adverse events in DTX formulations. Therefore, we designed multifunctional nanoparticles with pH-sensitive PEG derivatives and targeting peptides to enable efficient HuR CRISPR and DTX delivery to human TNBC MDA-MB-231 cells and tumor-bearing mice. Our findings indicated that these nanoparticles displayed pH-responsive cytotoxicity, precise EGFR targeting, efficient tumor penetration, successful endosomal escape, and accurate nuclear and cytoplasmic localization. They also demonstrated the ability to spare normal cells and prevent hemolysis. Our study concurrently modulated multiple pathways, including EGFR, Wnt/β-catenin, MDR, and EMT, through the regulation of EGFR/PI3K/AKT, HuR/galectin-3/GSK-3β/β-catenin, and P-gp/MRPs/BCRP, as well as YAP1/TGF-β/ZEB1/Slug/MMPs. The combined treatment arrested the cell cycle at the G2 phase and inhibited EMT, effectively impeding tumor progression. Tissue distribution, biochemical assays, and histological staining revealed the enhanced safety profile of pH-responsive PEG- and peptide-modified nanoformulations in TNBC mice. The DTX-embedded and peptide-modified nanoparticles mitigated the side effects of DTX, enhanced cytotoxicity in TNBC MDA-MB-231 cells, and exhibited remarkable antitumor efficacy and safety in TNBC-bearing mice with HuR CRISPR deletion. Collectively, the combination therapy of DTX and CRISPR/Cas9 offers an effective platform for delivering antineoplastic agents and gene-editing systems to combat tumor resistance and progression in TNBC.
Insights
This study developed novel nanoparticles for combined gene therapy and chemotherapy delivery in triple-negative breast cancer (TNBC). The nanoparticles successfully delivered Human antigen R (HuR) CRISPR/Cas9 and docetaxel, showing significant antitumor efficacy and improved safety in TNBC models.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Therapeutics
Background:
- Human antigen R (HuR) is crucial in cancer progression, particularly in aggressive triple-negative breast cancer (TNBC).
- Existing therapies like CRISPR/Cas9 gene editing and docetaxel (DTX) face delivery challenges and side effects.
- Targeted delivery systems are needed to overcome these limitations for effective TNBC treatment.
Purpose of the Study:
- To design multifunctional nanoparticles for co-delivery of HuR CRISPR/Cas9 and DTX.
- To evaluate the nanoparticles' efficacy and safety in TNBC cells and tumor-bearing mice.
- To investigate the underlying molecular mechanisms of the combined therapy.
Main Methods:
- Development of pH-sensitive, PEGylated nanoparticles with targeting peptides for dual drug delivery.
- In vitro studies using human TNBC MDA-MB-231 cells to assess cytotoxicity, targeting, and cellular uptake.
- In vivo studies in TNBC tumor-bearing mice to evaluate tumor penetration, tissue distribution, safety, and antitumor efficacy.
Main Results:
- Nanoparticles demonstrated pH-responsive cytotoxicity, EGFR targeting, efficient tumor penetration, and endosomal escape.
- The combined therapy modulated multiple cancer-related pathways (EGFR, Wnt/β-catenin, MDR, EMT) and arrested cell cycle.
- In vivo studies showed enhanced safety, reduced DTX side effects, and significant tumor growth inhibition in TNBC mice.
Conclusions:
- Multifunctional nanoparticles provide an effective platform for co-delivering gene-editing systems and chemotherapeutics for TNBC.
- This combination therapy shows promise in overcoming tumor resistance and progression in TNBC.
- The developed nanoformulation offers an improved safety profile compared to conventional DTX treatments.
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