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Improving the anticancer effect of afatinib and microRNA by using lipid polymeric nanoparticles conjugated with dual pH-responsive and targeting peptides.

ABSTRACT: BACKGROUND:The emergence of resistance to chemotherapy or target therapy, tumor metastasis, and systemic toxicity caused by available anticancer drugs hamper the successful colorectal cancer (CRC) treatment. The rise in epidermal growth factor receptor (EGFR; human epidermal growth factor receptor 1; HER1) expression and enhanced phosphorylation of HER2 and HER3 are associated with tumor resistance, metastasis and invasion, thus resulting in poor outcome of anti-CRC therapy. The use of afatinib, a pan-HER inhibitor, is a potential therapeutic approach for resistant CRC. Additionally, miR-139 has been reported to be negatively correlated with chemoresistance, metastasis, and epithelial-mesenchymal transition (EMT) of CRC. Hence, we develop a nanoparticle formulation consisting of a polymer core to carry afatinib or miR-139, which is surrounded by lipids modified with a targeting ligand and a pH-sensitive penetrating peptide to improve the anticancer effect of cargos against CRC cells. RESULTS:Our findings show that this formulation displays a spherical shape with core/shell structure, homogeneous particle size distribution and negative zeta potential. The prepared formulations demonstrate a pH-sensitive release profile and an enhanced uptake of cargos into human colorectal adenocarcinoma Caco-2 cells in response to the acidic pH. This nanoparticle formulation incorporating afatinib and miR-139 exhibits low toxicity to normal cells but shows a better inhibitory effect on Caco-2 cells than other formulations. Moreover, the encapsulation of afatinib and miR-139 in peptide-modified nanoparticles remarkably induces apoptosis and inhibits migration and resistance of Caco-2 cells via suppression of pan-HER tyrosine kinase/multidrug resistance/metastasis pathways. CONCLUSION:This study proposes a multifunctional nanoparticle formulation for targeted modulation of apoptosis/EGFR/HER/EMT/resistance/progression pathways to increase the sensitivity of colon cancer cells to afatinib.

SUBMITTER: Hong ST

PROVIDER: S-EPMC6699136 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Improving the anticancer effect of afatinib and microRNA by using lipid polymeric nanoparticles conjugated with dual pH-responsive and targeting peptides.

Hong Shu-Ting ST Lin Huaching H Wang Chen-Shen CS Chang Chih-Hsien CH Lin Anya Maan-Yuh AM Yang James Chih-Hsin JC Lo Yu-Li YL

Journal of nanobiotechnology 20190819 1

<h4>Background</h4>The emergence of resistance to chemotherapy or target therapy, tumor metastasis, and systemic toxicity caused by available anticancer drugs hamper the successful colorectal cancer (CRC) treatment. The rise in epidermal growth factor receptor (EGFR; human epidermal growth factor receptor 1; HER1) expression and enhanced phosphorylation of HER2 and HER3 are associated with tumor resistance, metastasis and invasion, thus resulting in poor outcome of anti-CRC therapy. The use of a ...[more]

PMID: 31426807

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Project description:The ability of small interfering RNA (siRNA) to efficiently silence the expression of specific genes provides the basis for exciting new therapies based on RNA interference (RNAi). The efficient intracellular delivery of siRNA from cell uptake through the endosomal trafficking pathways into the cytoplasm remains a significant challenge. Previously we described the synthesis of a new family of diblock copolymer siRNA carriers using controlled reversible addition-fragmentation chain transfer (RAFT) polymerization. The carriers were composed of a positively charged block of dimethylaminoethyl methacrylate (DMAEMA) to mediate siRNA binding and a second pH-responsive endosome releasing block composed of DMAEMA and propylacrylic acid (PAA) in roughly equimolar ratios and butyl methacylate (BMA). Here we describe the development of a new generation of siRNA delivery polymers based on this design that exhibit enhanced transfection efficiency and low cytotoxicity. This design incorporates a longer endosomolytic block with increased hydrophobic content to induce micelle formation. These polymers spontaneously form spherical micelles in the size range of 40 nm with CMC (critical micelle concentration) values of approximately 2 μg/mL based on dynamic light scattering (DLS), (1)H NMR, electron microscopy, and selective partitioning of the small molecule pyrene into the hydrophobic micelle core. The siRNA binding to the cationic shell block did not perturb micelle stability or significantly increase particle size. The self-assembly of the diblock copolymers into particles was shown to provide a significant enhancement in mRNA knockdown at siRNA concentrations as low as 12.5 nM. Under these conditions, the micelle-based systems showed an 89% reduction in GAPDH mRNA levels as compared to only 23% (10 nM siRNA) for the nonmicelle system. The reduction in mRNA levels becomes nearly quantitative as the siRNA concentration is increased to 25 nM and higher. Flow cytometry analysis of fluorescent-labeled siRNA showed uptake in 90% of cells and a 3-fold increase in siRNA per cell compared to a standard lipid transfection agent. These results demonstrate the potential utility of this carrier design for siRNA drug delivery.

Dataset Information

Improving the anticancer effect of afatinib and microRNA by using lipid polymeric nanoparticles conjugated with dual pH-responsive and targeting peptides.

Publications

Improving the anticancer effect of afatinib and microRNA by using lipid polymeric nanoparticles conjugated with dual pH-responsive and targeting peptides.

Similar Datasets

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