Da Sun

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Long noncoding RNA (lncRNA) differentiation antagonizing noncoding RNA (DANCR) is overexpressed in human triple-negative breast cancer (TNBC) and promotes cell migration and proliferation. TNBC is limited in treatment options relative to hormone-receptor-positive breast cancer and is commonly treated with chemotherapy, which is often compromised by acquired resistance. DANCR has been implicated in the development of chemoresistance across multiple cancer types. Here, we applied magnetic resonance molecular imaging (MRMI) with a targeted contrast agent, MT218, specific to extradomain-B fibronectin (EDB-FN), a marker for epithelial-to-mesenchymal transition, to assess the therapeutic efficacy of the combination of paclitaxel and ZD2-PEG-ECO/siDANCR nanoparticles (ZD2-siDANCR-ELNP) to treat TNBC. The treatment of orthotopic MDA-MB-231 TNBC in mice with paclitaxel significantly suppressed tumor growth but with a significant increase of EDB-FN in the tumor, as revealed by MRMI and immunohistochemistry. Combining ZD2-siDANCR-ELNP with paclitaxel further reduced tumor sizes, along with reduced EDB-FN expression. Interestingly, MT218-MRMI revealed a lower reduction of tumor signal enhancement with the combination treatment than that with the siDANCR treatment alone, which was supported by higher cell density in the tumors treated with the combination therapy, as shown by histochemical analysis. MT218-MRMI clearly revealed the changes of the tumor microenvironment in response to various therapies and is effective to noninvasively assess the response of TNBC tumors to the therapies. Regulating oncogenic lncRNA DANCR is an effective strategy for improving the outcomes of chemotherapy in TNBC.

Differentiation antagonizing noncoding RNA (DANCR) is recognized as an oncogenic long noncoding RNA (lncRNA) overexpressed in triple negative breast cancer (TNBC). We showed in a previous study that RNAi with targeted multifunctional ionizable lipid ECO/siRNA nanoparticles was effective to regulate this undruggable target for effective treatment of TNBC. In this study, we developed dual-targeted ECO/siDANCR nanoparticles by targeting a tumor extracellular matrix oncoprotein, extradomain B fibronectin (EDB-FN), and integrins overexpressed on cancer cells for enhanced delivery of siDANCR. The treatment of Hs578T TNBC cells and MCF-7 estrogen receptor-positive cells in vitro resulted in significant down-regulation of DANCR and EDB-FN and suppressed invasion and 3D spheroid formation of the cells. Magnetic resonance molecular imaging (MRMI) with an EDB-FN-targeted contrast agent, MT218, was used to noninvasively evaluate tumor response to treatment with the targeted ECO/siDANCR nanoparticles in female nude mice bearing orthotopic Hs578T and MCF-7 xenografts. MRMI with MT218 was effective to differentiate between aggressive TNBC with high DANCR and EDB-FN expression and ER⁺ MCF-7 tumors with low expression of the targets. MRMI showed that the dual-targeted ECO/siDANCR nanoparticles resulted in more significant inhibition of tumor growth in both models than the controls and significantly reduced EDB-FN expression in the TNBC tumors. The combination of MRMI and dual-targeted ECO/siDANCR nanoparticles is a promising approach for image-guided treatment of TNBC by regulating the onco-lncRNA.

Nucleic acids are promising for a variety of therapies, such as cancer therapy and the gene therapy of genetic disorders. The therapeutic efficacy of nucleic acids is reliant on the ability of their efficient delivery to the cytosol of the target cells. Amino lipids have been developed to aid in the cytosolic delivery of nucleic acids. This work reports a new and efficient synthetic pathway for the lipid carrier, (1-aminoethyl) iminobis [N-(oleicylcysteinyl-1-amino-ethyl)propionamide] (ECO). The previous synthesis of the ECO was inefficient and presented poor product quality control. A solution-phase synthesis of the ECO was explored, and each intermediate product was characterized with better quality control. The ECO was synthesized with a relatively high yield and high purity. The formulations of the ECO nanoparticles were made with siRNA, miRNA, or plasmid DNA, and characterized. The transfection efficiency of the nanoparticles was evaluated in vitro over a range of N/P ratios. The nanoparticles were consistent in size with previous formulations and had primarily a positive zeta potential. The ECO/siLuc nanoparticles resulted in potent luciferase silencing with minimal cytotoxicity. The ECO/miR-200c nanoparticles mediated the efficient delivery of miR-200c into the target cells. The ECO/pCMV-GFP nanoparticles resulted in substantial GFP expression upon transfection. These results demonstrate that the solution-phase synthetic pathway produced pure ECO for the efficient intracellular delivery of nucleic acids without size limitation.

Safe and effective molecular therapeutics for prophylactic treatment of retinal degenerative diseases are greatly needed. Disruptions in the clearance of all-trans-retinal (atRAL) by the visual (retinoid) cycle of the retina can lead to the accumulation of atRAL and its condensation products known to initiate progressive retinal dystrophy. Retinylamine (Ret-NH₂) and its analogues are known to be effective in lowering the concentration of atRAL within the eye and thus preventing retinal degeneration in mouse models of human retinopathies. Here, we chemically modified Ret-NH₂ with amino acids and peptides to improve the stability and ocular bioavailability of the resulting derivatives and to minimize their side effects. Fourteen Ret-NH₂ derivatives were synthesized and tested in vitro and in vivo. These derivatives exhibited structure-dependent therapeutic efficacy in preventing light-induced retinal degeneration in Abca4^–/–Rdh8^–/– double-knockout mice, with the compounds containing glycine and/or L-valine generally exhibiting greater protective effects than Ret-NH₂ or other tested amino acid derivatives of Ret-NH₂. Ret-NH₂-L-valylglycine amide (RVG) exhibited good stability in storage; and effective uptake and prolonged retention in mouse eyes. RVG readily formed a Schiff base with atRAL and did not inhibit RPE65 enzymatic activity. Administered by oral gavage, this retinoid also provided effective protection against light-induced retinal degeneration in Abca4^–/–Rdh8^–/– mice. Notably, the treatment with RVG had minimal effects on the regeneration of 11-cis-retinal and recovery of retinal function. RVG holds promise as a lead therapy for effective and safe treatment of human retinal degenerative diseases.

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Nanoparticle based siRNA formulations often suffer from aggregation and loss of function during storage. We in this study report a frozen targeted RGD-polyethylene glycol (PEG)-ECO/siβ3 nanoparticle formulation with a prolonged shelf life and preserved nanoparticle functionality. The targeted RGD-PEG-ECO/siβ3 nanoparticles are formed by step-wised self-assembly of RGD-PEG-maleimide, ECO, and siRNA. The nanoparticles have a diameter of 224.5 ± 9.41 nm and a zeta potential to 45.96 ± 3.67 mV in water and a size of 234.34 ± 3.01 nm and a near neutral zeta potential in saline solution. The addition of sucrose does not affect their size and zeta potential and substantially preserves the integrity and biological activities of frozen and lyophilized formulations of the targeted nanoparticles. The frozen formulation with as low as 5% sucrose retains nanoparticle integrity (90% siRNA encapsulation), size distribution (polydispersity index [PDI] ≤20%), and functionality (at least 75% silencing efficiency) at −80°C for at least 1 year. The frozen RGD-PEG-ECO/siβ3 nanoparticle formulation exhibits excellent biocompatibility, with no adverse effects on hemocompatibility and minimal immunogenicity. As RNAi holds the promise in treating the previously untreatable diseases, the frozen nanoparticle formulation with the low sucrose concentration has the potential to be a delivery platform for clinical translation of RNAi therapeutics.

Long non-coding RNAs (lncRs), by virtue of their versatility and multilevel gene regulation, have emerged as attractive pharmacological targets for treating heterogenous and complex malignancies like triple-negative breast cancer (TNBC). Despite multiple studies on lncRNA functions in tumor pathology, systemic targeting of these “undruggable” macromolecules with conventional approaches remains a challenge. Here, we demonstrate effective TNBC therapy by nanoparticle-mediated RNAi of the oncogenic lncRNA DANCR, which is significantly overexpressed in TNBC. Tumor-targeting RGD-PEG-ECO/siDANCR nanoparticles were formulated via self-assembly of multifunctional amino lipid ECO, cyclic RGD peptide-PEG, and siDANCR for systemic delivery. MDA-MB-231 and BT549 cells treated with the therapeutic RGD-PEG-ECO/siDANCR nanoparticles exhibited 80-90% knockdown in the expression of DANCR for up to 7 days, indicating efficient intracellular siRNA delivery and sustained target silencing. The RGD-PEG-ECO/siDANCR nanoparticles mediated excellent in vitro therapeutic efficacy, reflected by the significant reduction in the invasion, migration, survival, tumor spheroid formation, and proliferation of the TNBC cell lines. At the molecular level, functional ablation of DANCR dynamically impacted the oncogenic nexus by downregulating PRC2-mediated H3K27-trimethylation and Wnt/EMT signaling, and altering the phosphorylation profiles of several kinases in the TNBC cells. Furthermore, systemic administration of the RGD-PEG-ECO/siDANCR nanoparticles at a dose of 1 mg/kg siRNA in nude mice bearing TNBC xenografts resulted in robust suppression of TNBC progression with no overt toxic side-effects, underscoring the efficacy and safety of the nanoparticle therapy. These results demonstrate that nanoparticle-mediated modulation of onco-lncRNAs and their molecular targets is a promising approach for developing curative therapies for TNBC and other cancers.

Few layer graphene (FLG) has been used to improve different properties of polymers. FLG‐modified waterborne epoxy dispersions were prepared using a hydrophilic epoxy oligomer (HEO‐144) as the surfactant, which was prepared using liquid epoxy resin and poly(ethylene glycol) (PEG4000) at a molar ratio of 1.0. To enhance the stability of FLG‐modified waterborne epoxy dispersions, fumed silica was added and best stability was reached at a fumed silica content of 1.5%. Thermogravimetric analyses demonstrated enhanced thermal stability of the epoxy films after FLG modification. With FLG content of 1.0%, T_5% of the modified epoxy films has been increased to 332 °C from 275 °C. Water contact angle and adsorption tests showed improved water resistance with FLG, the water contact angle increased from 49.5° to 76.2° and water adsorption decreased from 9.0% to 2.0%. Furthermore, electrochemical impedance spectroscopy tests and tafel analysis indicated that FLG greatly improved the anticorrosion performance of waterborne epoxy coatings. With a FLG content of 1.0%, modified waterborne epoxy coatings demonstrated significantly low corrosion rate, which was one eighth of that of the unmodified control. These results indicate that FLG modification can be an effective and low cost approach to enhance the anticorrosion performance of waterborne epoxy coatings. © 2018 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2018, 135, 46743.

In this study, nano-hydroxyapatite crystals (nHAs) were prepared in the presence of zwitterionic poly(3-carboxy-N,N-dimethyl-N-(3′-acrylamidopropyl) propanaminium inner salt) (PCBAA) at different concentrations and pH microenvironments, denoted as Z-nHAs. The phase, morphology, size of apatite, and interactions between nHAs and PCBAA were systemically characterized via XRD, TEM, FTIR, and TGA. The results showed that Z-nHAs could be formed at all pH ranges in the presence of PCBAA in our experiment. It was different from the case of pure nHAs that could not be formed under an acidic microenvironment without PCBAA. In addition, a higher pH value was beneficial for the formation of nHAs with a smaller size. Z-nHAs exhibited a fiber-like structure at the initial 2 h and became rod-like in shape after 5 h, whereas pure nHAs prepared in water had an irregular flake-like structure. Moreover, 14–20% PCBAA could be incorporated into Z-nHAs via interactions between the quaternary ammonium group (–R₃N⁺) and carboxyl group (–COO⁻) in the PCBAA chain and Ca²⁺/PO₄ ³⁻ of nHA. A possible mechanism for the formation of Z-nHAs in the presence of PCBAA was proposed based on the experimental results.