Bile acid profiles and classification model accuracy for inflammatory bowel disease diagnosis.

To investigate the utility of serum bile acid profiling for the diagnosis of inflammatory bowel disease (IBD). We analyzed 15 specific bile acids in the serum of 269 IBD patients, 200 healthy controls (HC), and 174 patients with other intestinal diseases (OID) using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Serum bile acid levels were compared between IBD group, HC group, and OID group. Binary logistic regression-based models were developed to model the bile acids and diagnose IBD. Furthermore, receiver operating characteristic (ROC) curve analysis was performed to assess the diagnostic accuracy of each bile acid and the model. Compared to HC group, IBD group exhibited significantly lower levels of chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), glycodeoxycholic acid (GDCA), taurodeoxycholic acid (TDCA), lithocholic acid (LCA), glycolithocholic acid (GLCA), taurolithocholic acid (TLCA), and an elevated primary-to-secondary bile acid ratio. DCA had an area under the curve (AUC) of 0.860 for diagnosing IBD, with a sensitivity of 80.67% and a specificity of 82.50%. A model Y0 combining DCA and CDCA to distinguish between IBD group and HC group further improved accuracy (AUC = 0.866, sensitivity = 76.28%, specificity = 89.37%). Compared to non-IBD group (which combined healthy controls and those with other intestinal diseases), IBD group had significantly lower levels of DCA, GDCA, TDCA, LCA, GLCA, and TLCA, and elevated levels of glycocholic acid (GCA) and glycochenodeoxycholic acid (GCDCA). A model Y1 incorporating GCDCA, DCA and TLCA to distinguish between IBD group and non-IBD group yielded an AUC of 0.792, with a sensitivity of 77.67% and specificity of 71.91%. IBD patients exhibit decreased serum secondary bile acid levels and an elevated primary-to-secondary bile acid ratio. Serum bile acid alterations are associated with the onset of IBD. A model consisting of CDCA and DCA has potential for distinguishing between IBD group and HC group, while a model incorporating GCDCA, DCA and TLCA may be suitable for distinguishing between IBD group and non-IBD group.

Exploration of the application potential of serum multi-biomarker model in colorectal cancer screening.

Analyzing blood lipid and bile acid profile changes in colorectal cancer (CRC) patients. Evaluating the integrated model's diagnostic significance for CRC. Ninety-one individuals with colorectal cancer (CRC group) and 120 healthy volunteers (HC group) were selected for comparison. Serum levels of total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and apolipoproteins (Apo) A1, ApoA2, ApoB, ApoC2, and ApoC3 were measured using immunoturbidimetric and colorimetric methods. Additionally, LC-MS/MS was employed to detect fifteen bile acids in the serum, along with six tumor markers: carcinoembryonic antigen (CEA), carbohydrate antigens (CA) 125, CA19-9, CA242, CA50, and CA72-4. Group comparisons utilized independent sample t-tests and Mann-Whitney U tests. A binary logistic regression algorithm was applied to fit the indicators and establish a screening model; the diagnostic accuracy of individual Indicators and the model was analyzed using receiver operating characteristic (ROC) curves. The CRC group showed significantly lower levels in eight serum lipid indicators and eleven bile acids compared to the HC group (P < 0.05). Conversely, serum levels of TG, CA19-9, and CEA were elevated (P < 0.05). Among the measured parameters, ApoA2 stands out for its strong correlation with the presence of CRC, showcasing exceptional screening efficacy with an area under the curve (AUC) of 0.957, a sensitivity of 85.71%, and a specificity of 93.33%. The screening model, integrating ApoA1, ApoA2, lithocholic acid (LCA), and CEA, attained an impressive AUC of 0.995, surpassing the diagnostic accuracy of individual lipids, bile acids, and tumor markers. CRC patients manifest noteworthy alterations in both blood lipids and bile acid profiles. A screening model incorporating ApoA1, ApoA2, LCA, and CEA provides valuable insights for detecting CRC.

TiN-Au/HfO2 -Au Multilayer Thin Films with Tunable Hyperbolic Optical Response.

Hyperbolic metamaterials (HMM) possess significant anisotropic physical properties and tunability and thus find many applications in integrated photonic devices. HMMs consisting of metal and dielectric phases in either multilayer or vertically aligned nanocomposites (VAN) form are demonstrated with different hyperbolic properties. Herein, self-assembled HfO2 -Au/TiN-Au multilayer thin films, combining both the multilayer and VAN designs, are demonstrated. Specifically, Au nanopillars embedded in HfO2 and TiN layers forming the alternative layers of HfO2 -Au VAN and TiN-Au VAN. The HfO2 and TiN layer thickness is carefully controlled by varying laser pulses during pulsed laser deposition (PLD). Interestingly, tunable anisotropic physical properties can be achieved by adjusting the bi-layer thickness and the number of the bi-layers. Type II optical hyperbolic dispersion can be obtained from high layer thickness structure (e.g., 20 nm), while it can be transformed into Type I optical hyperbolic dispersion by reducing the thickness to a proper value (e.g., 4 nm). This new nanoscale hybrid metamaterial structure with the three-phase VAN design shows great potential for tailorable optical components in future integrated devices.

Improved epitaxial growth and multiferroic properties of Bi3Fe2Mn2Ox using CeO2 re-seeding layers.

In ferroelectric and multiferroic-based devices, it is often necessary to grow thicker films for enhanced properties. For certain phases that rely on substrate strain for growth, such thicker film growths beyond the typical thin film regime could be challenging. As an example, the Bi3Fe2Mn2Ox (BFMO) Aurivillius supercell (SC) phase possesses highly desirable multiferroic (i.e., ferromagnetic and ferroelectric) properties and a unique layered structure but relies heavily on substrate strain. Beyond the thin film regime (approximately 100 nm), a less desirable pseudo-cubic (PC) phase is formed. In this work, a novel heterogeneous re-seeding method is applied to maintain the strained growth in this SC phase beyond the thin film regime, thus enabling the growth of thick BFMO SC phase films. The insertion of periodic CeO2 interlayers reintroduces the heteroepitaxial strain and effectively re-initiates the growth of the SC phase. The thick BFMO SC phase maintains the overall multiferroic and interesting anisotropic optical properties, even exceeding those of the typical 100 nm SC film. This re-seeding method can be effectively adopted with other SC systems or strain-dependent thin films, thus introducing practical applications of the new SC phases without thickness limitations.

Controlled Growth of Vertically Aligned Nanocomposites through a Au Seeding-Assisted Method.

Heteroepitaxial metal-oxide vertically aligned nanocomposites (VAN) have piqued significant interest due to their remarkable vertical interfacial coupling effects, strong structural and property anisotropy, and potential applications in magnetoelectrics, photocatalysts, and optical metamaterials. VANs present a unique pillar-in-matrix structure with uniform but rather random pillar distributions. Achieving a well-controlled pillar growth remains a major challenge in this field. Here, we use BaTiO3 (BTO)-Au as a model VAN system to demonstrate the effects of Au seedings on achieving such pillar-growth control with enhanced ordering and morphology tuning. The Au seedings are introduced using an anodic aluminum oxide (AAO) template through pulsed laser deposition (PLD). TEM characterization reveals that the Au seedings result in straighter and more evenly distributed Au pillars in the BTO matrix compared to those without seeding, with the diameter of the Au seedings increasing with the number of pulses. Additionally, spectroscopic ellipsometry demonstrates distinct permittivity dispersion for all samples. This demonstration lays a foundation for future controlled and selective growth of VAN systems for on-chip integration.

Controllable Phase Transition Properties in VO2 Films via Metal-Ion Intercalation.

VO2 has shown great promise for sensors, smart windows, and energy storage devices, because of its drastic semiconductor-to-metal transition (SMT) near 340 K coupled with a structural transition. To push its application toward room-temperature, effective transition temperature (Tc) tuning in VO2 is desired. In this study, tailorable SMT characteristics in VO2 films have been achieved by the electrochemical intercalation of foreign ions (e.g., Li ions). By controlling the relative potential with respect to Li/Li+ during the intercalation process, Tc of VO2 can be effectively and systematically tuned in the window from 326.7 to 340.8 K. The effective Tc tuning could be attributed to the observed strain and lattice distortion and the change of the charge carrier density in VO2 introduced by the intercalation process. This demonstration opens up a new approach in tuning the VO2 phase transition toward room-temperature device applications and enables future real-time phase change property tuning.

Identification of six hub genes and two key pathways in two rat renal fibrosis models based on bioinformatics and RNA-seq transcriptome analyses.

Renal fibrosis (RF) is the common pathological manifestation and central treatment target of multiple chronic kidney diseases with high morbidity and mortality. Currently, the molecular mechanisms underlying RF remain poorly understood, and exploration of RF-related hub targets and pathways is urgently needed. In this study, two classical RF rat models (adenine and UUO) were established and evaluated by HE, Masson and immunohistochemical staining. To clear molecular mechanisms of RF, differentially expressed genes (DEGs) were identified using RNA-Seq analysis, hub targets and pathways were screened by bioinformatics (functional enrichment analyses, PPI network, and co-expression analysis), the screening results were verified by qRT-PCR, and potential drugs of RF were predicted by network pharmacology and molecular docking. The results illustrated that renal structures were severely damaged and fibrotic in adenine- and UUO-induced models, as evidenced by collagen deposition, enhanced expressions of biomarkers (TGF-ß1 and α-SMA), reduction of E-cadherin biomarker, and severe renal function changes (significantly decreased UTP, CREA, Ccr, and ALB levels and increased UUN and BUN levels), etc. 1189 and 1253 RF-related DEGs were screened in the adenine and UUO models, respectively. Two key pathways (AGE-RAGE and NOD-like receptor) and their hub targets (Tgfb1, Col1a1, Nlrc4, Casp4, Trpm2, and Il18) were identified by PPI networks, co-expressed relationships, and qRT-PCR verification. Furthermore, various reported herbal ingredients (curcumin, resveratrol, honokiol, etc.) were considered as important drug candidates due to the strong binding affinity with these hub targets. Overall, this study mainly identified two key RF-related pathways (AGE-RAGE and NOD-like receptor), screened hub targets (Tgfb1, Col1a1, Nlrc4, Casp4, Trpm2, and Il18) that involved inflammation, ECM formation, myofibroblasts generation, and pyroptosis, etc., and provided referable drug candidates (curcumin, resveratrol, honokiol, etc.) in basic research and clinical treatment of RF.

Tunable physical properties in Bi-based layered supercell multiferroics embedded with Au nanoparticles.

Multiferroic materials are an interesting functional material family combining two ferroic orderings, e.g., ferroelectric and ferromagnetic orderings, or ferroelectric and antiferromagnetic orderings, and find various device applications, such as spintronics, multiferroic tunnel junctions, etc. Coupling multiferroic materials with plasmonic nanostructures offers great potential for optical-based switching in these devices. Here, we report a novel nanocomposite system consisting of layered Bi1.25AlMnO3.25 (BAMO) as a multiferroic matrix and well dispersed plasmonic Au nanoparticles (NPs) and demonstrate that the Au nanoparticle morphology and the nanocomposite properties can be effectively tuned. Specifically, the Au particle size can be tuned from 6.82 nm to 31.59 nm and the 6.82 nm one presents the optimum ferroelectric and ferromagnetic properties and plasmonic properties. Besides the room temperature multiferroic properties, the BAMO-Au nanocomposite system presents other unique functionalities including localized surface plasmon resonance (LSPR), hyperbolicity in the visible region, and magneto-optical coupling, which can all be effectively tailored through morphology tuning. This study demonstrates the feasibility of coupling single phase multiferroic oxides with plasmonic metals for complex nanocomposite designs towards optically switchable spintronics and other memory devices.

Self-assembled HfO2-Au nanocomposites with ultra-fine vertically aligned Au nanopillars.

Oxide-metal-based hybrid materials have gained great research interest in recent years owing to their potential for multifunctionality, property coupling, and tunability. Specifically, oxide-metal hybrid materials in a vertically aligned nanocomposite (VAN) form could produce pronounced anisotropic physical properties, e.g., hyperbolic optical properties. Herein, self-assembled HfO2-Au nanocomposites with ultra-fine vertically aligned Au nanopillars (as fine as 3 nm in diameter) embedded in a HfO2 matrix were fabricated using a one-step self-assembly process. The film crystallinity and pillar uniformity can be obviously improved by adding an ultra-thin TiN-Au buffer layer during the growth. The HfO2-Au hybrid VAN films show an obvious plasmonic resonance at 480 nm, which is much lower than the typical plasmonic resonance wavelength of Au nanostructures, and is attributed to the well-aligned ultra-fine Au nanopillars. Coupled with the broad hyperbolic dispersion ranging from 1050 nm to 1800 nm in wavelength, and unique dielectric HfO2, this nanoscale hybrid plasmonic metamaterial presents strong potential for the design of future integrated optical and electronic switching devices.

Bioreducible Micelles with Endosomal Buffering and Multidrug Resistance-Reversing Function Enhance Anti-Tumor Efficacy of Doxorubicin.

The clinical success of anthracyclines-containing chemotherapy for breast cancer is mainly restricted by cardiac damage and the development of multidrug resistance (MDR). For efficient reversal of drug resistance, doxorubicin (DOX) loaded multifunctional bioreducible micelles were constructed from a new amphiphilic copolymer consisting of polyethylene glycol and poly[bis(2-hydroxylethyl)-disulfide-diacrylate-ß-histamine and characterized. The introduction of imidazole group endowed the micelles with endosomal buffering capacity and improved the endosomal escape. The reduction-responsiveness of the micelles promoted DOX release. The activity of P-glycoprotein, one of the most well-described drug-efflux pumps, and glutathione S-transferase, an important detoxification enzyme, were also inhibited by the micelles. The accumulation of DOX in tumor after intravenous administration of the drug-loading micelles was increased in drug resistant tumor-bearing mice. These results indicated that the micelle was a promising drug delivery system for MDR cancer therapy.

Preparation of corn starch-g-polystyrene copolymer in ionic liquid: 1-ethyl-3-methylimidazolium acetate.

The copolymer of starch grafted with polystyrene (starch-g-PS) was synthesized with high grafting percentage by utilizing the ionic liquid 1-ethyl-3-methylimidazolium acetate ([EMIM]Ac) as solvent and potassium persulfate as initiator. The effect of various parameters upon the polymerization were studied including: initiator concentration, styrene:starch weight ratio, the reaction time and temperature. Grafting percentages were calculated using an FT-IR calibration method, with values up to 114%. The resulting copolymer was characterized using FT-IR, SEM, WAXD and TGA, which demonstrated that polystyrene side chains were evenly distributed on the starch backbone. Our results indicate that ionic liquid dissolution of starch, prior to polystyrene grafting, is a versatile methodology for the synthesis of amphiphilic, polysaccharide-based graft copolymers, having high grafting percent.

Simultaneous inhibition of tumor growth and angiogenesis for resistant hepatocellular carcinoma by co-delivery of sorafenib and survivin small hairpin RNA.

The development of multidrug resistance (MDR) in human hepatocellular carcinoma (HCC) is one of the major obstacles for successful chemotherapy of HCC. Co-delivery of sorafenib (SF) and survivin shRNA (shSur) was postulated to achieve synergistic effects in reversing MDR, suppressing tumor growth and angiogenesis. For this purpose, in this work, SF and shSur co-loaded pluronic P85-polyethyleneimine/d-α-tocopheryl polyethylene glycol 1000 succinate nanocomplexes (SSNs) were first designed and developed for the treatment of drug resistant HCC. The experimental results showed that SSNs could achieve effective cellular internalization and shSur transfection efficiency, induce significant downregulation of the survivin protein, and cause remarkable cell arrest and cell apoptosis. The tube formulation assay demonstrated that SSNs completely disrupted the enclosed capillary networks formed by human microvascular endothelial cells. The in vivo antitumor efficacy showed that SSNs were superior to that of other treatments on drug resistant hepatocellular tumor models. Therefore, it could be an efficient strategy to co-deliver SF and shSur for therapy of drug resistant HCC.

iRGD conjugated TPGS mediates codelivery of paclitaxel and survivin shRNA for the reversal of lung cancer resistance.

Multidrug resistance (MDR) is one of the major obstacles in tumor treatment. Herein, we reported an active targeting strategy with peptide-mediated nanoparticles deep into tumor parenchyma, which iRGD conjugated d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) mediated codelivery of paclitaxel (PTX) and survivin shRNA (shSur) for the reversal of lung cancer resistance. Pluronic P85-polyethyleneimine/TPGS complex nanoparticles incorporated with iRGD-TPGS conjugate codelivering PTX and shSur systems (iPTPNs) could induce effective cellular uptake, RNAi effects, and cytotoxicity on A549 and A549/T cells. In particular, iPTPNs showed superiority in biodistribution, survivin expression, tumor apoptosis, and antitumor efficacy by simultaneously exerting an enhanced permeability and retention (EPR) effect and iRGD mediated active targeting effects. iPTPNs significantly enhanced the accumulation of PTX and shSur, down-regulated survivin expression, and induced cell apoptosis in tumor tissue. The in vivo antitumor efficacy showed the tumor volume of iPTPNs group (10 mg/kg) was only 12.7% of the Taxol group. Therefore, the iRGD mediated PTX and shSur codelivery system could be a very powerful approach for the reversal and therapy of lung cancer resistance.

Synergistic inhibition of breast cancer metastasis by silibinin-loaded lipid nanoparticles containing TPGS.

Tumor metastasis is the leading cause of breast cancer-related mortality and remains to be the principal obstacle for the successful chemotherapy of breast cancer. To block metastasis of breast cancer, silibinin-loaded lipid nanoparticles (SLNs) containing TPGS and phosphatidylcholine were designed and prepared by a thin-film hydration method. The optimized SLNs were approximately 45 nm in particle size with high stability in serum, which were further demonstrated to be efficiently uptaken by MDA-MB-231 breast cancer cells. Importantly, the SLNs could accumulate within tumor tissues with high efficiency and amounts. Compared with free silibinin, SLNs exhibited much stronger inhibitory effects on the invasion and migration of MDA-MB-231 cells through the downregulation of MMP-9 and Snail. More importantly, systematic in vivo evaluations demonstrated that SLNs treatment group resulted in 67% and 39% less pulmonary metastases formation than saline treatment group in the spontaneous and blood vessel metastasis models, respectively. Interestingly, the blank lipid nanoparticles without silibinin were also found, for the first time, to possess the efficient anti-metastatic capabilities to some extent. The biocompatibility assay reveals that SLNs treatment did not exhibit obvious systemic toxicity in two mouse models. Therefore, SLNs are the promising delivery systems against metastasis of breast cancer cells.

Multifunctional nanoparticles improve therapeutic effect for breast cancer by simultaneously antagonizing multiple mechanisms of multidrug resistance.

For efficient reversal of multidrug resistance (MDR) in chemotherapy for breast cancer, multifunctional self-assembled nanoparticles (MSN) based on a new amphiphilic copolymer consisting of bioreducible poly[bis(2-hydroxylethyl)-disulfide-diacrylate-ß-tetraethylenepentamine] and polycaprolactone (PBD-PCL) were constructed and characterized. shRNA targeting the apoptosis-inhibiting gene, Survivin, was incorporated into the nanoparticles with high RNA interference efficiency. PBD-PCL significantly inhibited the activity of P-glycoprotein, one of the most well-described drug-efflux pumps, and glutathione S-transferase, an important detoxification enzyme. MSN achieved colocalization of RNA and doxorubicin in tumors after intravenous administration and showed remarkable antitumor efficacy in MDR tumor-bearing mice with less side-effect than drug combination therapy. This was a new attempt to overcome MDR against three different mechanisms of MDR simutaneously: overexpression of drug efflux protein, activation of detoxification system, and blockage of apoptosis. These results indicated that the PBD-PCL-based MSN had obvious potential for therapy of breast cancer.

Reversal of multidrug resistance by stimuli-responsive drug delivery systems for therapy of tumor.

Multidrug resistance (MDR) is a major obstacle to successful cancer therapy, especially for chemotherapy. The new drug delivery system (DDS) provides promising approaches to reverse MDR, for which the poor cellular uptake and insufficient intracellular drug release remain rate-limiting steps for reaching the drug concentration level within the therapeutic window. Stimulus-coupled drug delivery can control the drug-releasing pattern temporally and spatially, and improve the accumulation of chemotherapeutic agents at targeting sites. In this review, the applications of DDS which is responsive to different types of stimuli in MDR cancer therapy is introduced, and the design, construction, stimuli-sensitivity and the effect to reverse MDR of the stimuli-responsive DDS are discussed.

Simultaneous inhibition of metastasis and growth of breast cancer by co-delivery of twist shRNA and paclitaxel using pluronic P85-PEI/TPGS complex nanoparticles.

The metastasis of breast cancer is the leading cause of cancer death in women, and the lung is a common location of a secondary tumor that has metastasized from the primary source tumor. In this work, an attempt to simultaneously inhibit the metastasis and growth of tumor by co-delivering Twist shRNA (shTwi) and paclitaxel (PTX) using the conjugate of pluronic P85 (P85) and low molecular weight polyethyleneimine (PEI) (P85-PEI)/D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) complex nanoparticles (PTPNs) was performed on metastatic 4T1 breast cancer cell line and its pulmonary metastasis mice model. The experimental results demonstrated that PTPNs could effectively achieve cellular uptake and RNA interference. The down-regulation of Twist protein resulted in significant inhibitory effect of cell migration and invasion with the inhibition rate of 88.7% and 91.06%, respectively. The IC50 of PTPNs against 4T1 cells was 63-fold lower than that of free PTX. The prolonged circulation and increased accumulation of PTX and shTwi in lung and tumor were observed in in vivo biodistribution. The in vivo antitumor efficacy showed that PTPNs could not only inhibit the in situ tumor growth effectively, but also completely restrict the pulmonary metastasis in 4T1 pulmonary metastatic mice model. Therefore, co-delivering chemotherapy drugs with metastasis regulator by PTPNs to simultaneously inhibit metastasis and growth of tumor could achieve synergistic effect for the effective therapy of metastatic breast cancer.

Co-delivery of paclitaxel and survivin shRNA by pluronic P85-PEI/TPGS complex nanoparticles to overcome drug resistance in lung cancer.

Drug resistance is a main obstacle for the successful chemotherapy of lung cancer. In this work, a new co-delivery system, P85-PEI/TPGS/PTX/shSur complex nanoparticles (PTPNs), to overcome paclitaxel (PTX) resistance in A549 human lung cancer was designed and developed. The experimental results showed that PTPNs could facilitate drug into cells and induce survivin shRNA (shSur) into nuclei on A549 and A549/T cells, achieve efficient gene delivery and induce availably RNA interference on A549/T cells. The IC(50) of PTPNs against A549/T cells was 360-fold lower than that of free PTX. The enhanced efficacy of PTPNs against A549/T cells was associated with PTX-induced apoptosis and cell arrest in G2/M phase. Down-regulation of survivin protein by PTPNs could lower the apoptosis threshold of drug resistant cells and render chemotherapeutic agents more effective. Moreover, the inhibition of GST activity by P85 was found to increase PTX accumulation in A549/T cells. The in vivo antitumor efficacy showed that PTPNs were more effective than that of the Taxol. As a result, the co-delivery of PTX and shSur by PTPNs could be a very powerful approach to improve the therapeutic effect of PTX in resistant lung cancer.

Overcoming multidrug resistance by co-delivery of Mdr-1 and survivin-targeting RNA with reduction-responsible cationic poly(ß-amino esters).

Multidrug resistance (MDR) remains one of the main challenges in the successful chemotherapy of human cancer. RNA interference (RNAi) strategy aiming at only one cause of MDR was widely applied, nevertheless hardly obtained satisfactory tumor-suppressing effect. In this work, a new attempt to package two kinds of RNA with different functions into one vector and reverse MDR against two different mechanisms via RNAi was carried out. A new bioreducible poly (ß-amino esters) (PAEs), poly[bis(2-hydroxylethyl)-disulfide-diacrylate-ß-tetraethylenepentamine] (PAP) was synthesized by Michael addition reaction. The PAEs/RNA complex nanoparticles (PAEN) were prepared. The experimental results demonstrated that co-delivery of iMdr-1-shRNA and iSurvivin-shRNA could be achieved by a single vector, and interfering two genes simultaneously had a synergistic effect on overcoming MDR. PAEN lowered the IC(50) value of doxorubicin (DOX) in MDR tumor cells to a comparable level to that in the sensitive cell line through down-regulating the expression of P-gp and Survivin, and decreased the tumor volumes in mice xenograft model bearing DOX-resistant human breast cancer when combined with DOX. These results illustrated that PAEN could be applied as potential efficient non-viral RNA carriers for reversing MDR.

Mesoporous silica nanoparticles loading doxorubicin reverse multidrug resistance: performance and mechanism.

Multidrug resistance (MDR) is one of the major obstacles for successful chemotherapy in cancer. One of the effective approaches to overcome MDR is to use nanoparticle-mediated drug delivery to increase drug accumulation in drug resistant cancer cells. In this work, we first report that the performance and mechanism of an inorganic engineered delivery system based on mesoporous silica nanoparticles (MSNs) loading doxorubicin (DMNs) to overcome the MDR of MCF-7/ADR (a DOX-resistant and P-glycoprotein (P-gp) over-expression cancer cell line). The experimental results showed that DMNs could enhance the cellular uptake of doxorubicin (DOX) and increase the cell proliferation suppression effect of DOX against MCF-7/ADR cells. The IC(50) of DMNs against MCF-7/ADR cells was 8-fold lower than that of free DOX. However, an improved effect of DOX in DMNs against MCF-7 cells (a DOX-sensitive cancer cell line) was not found. The increased cellular uptake and nuclear accumulation of DOX delivered by DMNs in MCF-7/ADR cells was confirmed by confocal laser scanning microscopy, and could result from the down-regulation of P-gp and bypassing the efflux action by MSNs themselves. The cellular uptake mechanism of DMNs indicated that the macropinocytosis was one of the pathways for the uptake of DMNs by MCF-7/ADR cells. The in vivo biodistribution showed that DMNs induced a higher accumulation of DOX in drug resistant tumors than free DOX. These results suggested that MSNs could be an effective delivery system to overcome multidrug resistance.