Xin Nie

Near Infrared Laser-Induced Targeted Cancer Therapy Using Thermoresponsive Polymer Encapsulated Gold Nanorods

External stimuli, such as ultrasound, magnetic field, and light, can be applied to activate in vivo tumor targeting. Herein, we fabricated polymer encapsulated gold nanorods to couple the photothermal properties of gold nanorods and the thermo- and pH-responsive properties of polymers in a single nanocomposite. The activation mechamism was thus transformed from heat to near-infrared (NIR) laser, which can be more easily controlled. Doxorubicin, a clinical anticancer drug, can be loaded into the nanocomposite through electrostatic interactions with high loading content up to 24%. The nanocomposites accumulation in tumor post systematic administration can be significantly enhanced by NIR laser irradiation, providing a prerequisite for their therapeutic application which almost completely inhibited tumor growth and lung metastasis. Since laser can be manipulated very precisely and flexibly, the nanocomposite provides an ideally versatile platform to simultaneously deliver heat and anticancer drugs in a laser-activation mechanism with facile control of the area, time, and dosage. The NIR laser-induced targeted cancer thermo-chemotherapy without using targeting ligands represents a novel targeted anticancer strategy with facile control and practical efficacy.

Efficient Delivery of Antitumor Drug to the Nuclei of Tumor Cells by Amphiphilic Biodegradable Poly(L‐Aspartic Acid‐co‐Lactic Acid)/DPPE Co‐Polymer Nanoparticles

The use of biodegradable polymeric nanoparticles (NPs) for controlled drug delivery has shown significant therapeutic potential. Polyaspartic acid and polylactic acid are the most intensively studied biodegradable polymers. In the present study, novel amphiphilic biodegradable co-polymer NPs, poly(L-aspartic acid-co-lactic acid) with 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE) (poly(AA-co-LA)/DPPE) is synthesized and subsequently used to encapsulate an antitumor drug doxorubicin (DOX). The formulation parameters of the NPs are optimized to improve encapsulation efficiency. The resulting drug-loaded NPs possess better size homogeneity (polydispersity) and exhibit pH-responsive drug release profiles. Cellular viability assays indicate that the poly(AA-co-LA)/DPPE NPs did not induce cell death, whereas doxorubicin encapsulated NPs were cytotoxic to various types of tumor cells. In addition, the free NPs could not enter the cell nuclei after internalized in tumor cells. The DOX-loaded NPs exhibit efficient intracellular delivery in tumor cells with co-localization in lysosome and delay entering into the nucleus, which suggests a time- and pH-dependent drug release profile within cells. When applied to deliver chemotherapeutics to a mouse xenograft model of human lung adenocarcinoma, DOX-loaded NPs have a comparable antitumor activity with free DOX, and greatly reduce systemic toxicity and mortality. The delivery of cytotoxic drugs directly to the nucleus specifically within tumor cells is of great interest. These results demonstrate the feasibility of the application of the amphiphilic polyaspartic acid derivative, poly(AA-co-LA)/DPPE, as a nanocarrier for cell nuclear delivery of potent antitumor drugs.

Multiwall carbon nanotubes mediate macrophage activation and promote pulmonary fibrosis through TGF-β/smad signaling pathway

Multiwall carbon nanotubes (MWCNTs) have been widely used in many disciplines due to their unique physical and chemical properties, but have also raised great concerns about their possible negative health impacts, especially through occupational exposure. Although recent studies have demonstrated that MWCNTs induce granuloma formation and/or fibrotic responses in the lungs of rats or mice, their cellular and molecular mechanisms remain largely unaddressed. Here, it is reported that the TGF-β/Smad signaling pathway can be activated by MWCNTs and play a critical role in MWCNT-induced pulmonary fibrosis. Firstly, in vivo data show that spontaneously hypertensive (SH) rats administered long MWCNTs (20-50 μm) but not short MWCNTs (0.5-2 μm) exhibit increased fibroblast proliferation, collagen deposition and granuloma formation in lung tissue. Secondly, the in vivo experiments also indicate that only long MWCNTs can significantly activate macrophages and increase the production of transforming growth factor (TGF)-β1, which induces the phosphorylation of Smad2 and then the expression of collagen I/III and extracellular matrix (ECM) protease inhibitors in lung tissues. Finally, the present in vitro studies further demonstrate that the TGF-β/Smad signaling pathway is indeed necessary for the expression of collagen III in fibroblast cells. Together, these data demonstrate that MWCNTs stimulate pulmonary fibrotic responses such as fibroblast proliferation and collagen deposition in a TGF-β/Smad-dependent manner. These observations also suggest that tube length acts as an important factor in MWCNT-induced macrophage activation and subsequent TGF-β1 secretion. These in vivo and in vitro studies further highlight the potential adverse health effects that may occur following MWCNT exposure and provide a better understanding of the cellular and molecular mechanisms by which MWCNTs induce pulmonary fibrotic reactions.

Multiwall Carbon Nanotubes Directly Promote Fibroblast–Myofibroblast and Epithelial–Mesenchymal Transitions through the Activation of the TGF-β/Smad Signaling Pathway

A number of studies have demonstrated that MWCNTs induce granuloma formation and fibrotic responses in vivo, and it has been recently reported that MWCNT-induced macrophage activation and subsequent TGF-β secretion contribute to pulmonary fibrotic responses. However, their direct effects against alveolar type-II epithelial cells and fibroblasts and the corresponding underlying mechanisms remain largely unaddressed. Here, MWCNTs are reported to be able to directly promote fibroblast-to-myofibroblast conversion and the epithelial-mesenchymal transition (EMT) through the activation of the TGF-β/Smad signaling pathway. Both of the cell transitions may play important roles in MWCNT-induced pulmonary fibrosis. Firstly, in-vivo and in-vitro data show that long MWCNTs can directly interact with fibroblasts and epithelial cells, and some of them may be uptaken into fibroblasts and epithelial cells by endocytosis. Secondly, long MWCNTs can directly activate fibroblasts and increase both the basal and TGF-β1-induced expression of the fibroblast-specific protein-1, α-smooth muscle actin, and collagen III. Finally, MWCNTs can induce the EMT through the activation of TGF-β/Smad2 signaling in alveolar type-II epithelial cells, from which some fibroblasts involved in pulmonary fibrosis are thought to originate. These observations suggest that the activation of the TGF-β/Smad2 signaling plays a critical role in the process of the fibroblast-to-myofibroblast transition and the EMT induced by MWCNTs.

Au nanostructures: an emerging prospect in cancer theranostics

Au nanoparticles have been used in biomedical applications since ancient times. However, the rapid development of nanotechnology over the past century has led to recognition of the great potential of Au nanoparticles in a wide range of applications. Advanced fabrication techniques allow us to synthesize a variety of Au nanostructures possessing physiochemical properties that can be exploited for different purposes. Functionalization of the surface of Au nanoparticles further eases their application in various roles. These advantages of Au nanoparticles make them particularly suited for cancer treatment and diagnosis. The small size of Au particles enables them to preferentially accumulate at tumor sites to achieve in vivo targeting after systemic administration. Efficient light absorption followed by rapid heat conversion makes them very promising in photothermal therapy. The facile surface chemistry of Au nanoparticles eases delivery of drugs, ligands or imaging contrast agents in vivo. In this review, we summarize recent development of Au nanoparticles in cancer theranostics including imaging-based detection, photothermal therapy, chemical therapy and drug delivery. The multifunctional nature of Au nanoparticles means they hold great promise as novel anti-cancer therapeutics.

Targeting peptide iRGD-conjugated amphiphilic chitosan-co-PLA/DPPE drug delivery system for enhanced tumor therapy

In this paper, we report a novel targeting drug delivery system, obtained using an amphiphilic chitosan-co-(d,l-lactide)/1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine copolymer (CS-co-PLA/DPPE) with the modification of an iRGD (CRGDKGPDC) peptide as the targeting module. Hydrophilic doxorubicin (DOX) was encapsulated and cell experiments were carried out to evaluate the anti-tumor efficacy of DOX-loaded nanoparticles (NPs) in vitro. Characterization data showed a favorable size distribution, high encapsulation efficiency and a pH-dependent release profile for the synthesized NPs. A cytotoxicity assay revealed the higher inhibitory effect of DOX-iRGD-NPs especially in cell lines with an abundant expression of αvβ3 integrin receptors. An increased cellular uptake of DOX-iRGD-NPs was observed and further confirmed to be a consequence of a specific endocytosis pathway mediated by ligand-receptor interactions. Visualization of the intracellular trafficking showed different distributions of DOX when delivered using DOX-NPs and DOX-iRGD-NPs, proving the targeting effect of iRGD. With the help of the iRGD targeting peptide, a chemotherapeutic drug can be delivered specifically to the cancer and endothelial cells expressing αvβ3 integrin receptors to achieve an enhanced anti-tumor efficacy and controlled drug release.

Fullerenol inhibits the cross-talk between bone marrow-derived mesenchymal stem cells and tumor cells by regulating MAPK signaling

The interaction between bone marrow-derived mesenchymal stem cells (BDMSCs) and tumor cells promotes tumor proliferation and metastasis. We found that 4T1 breast cancer cells induced malignant differentiation of BDMSCs and that BDMSCs also affected the growth and metastasis of 4T1 cells. However, when the interaction between BDMSCs and 4T1 cells was attenuated or blocked by C60(OH)22 nanoparticles, tumor growth and metastasis were significantly suppressed. The suppression of metastasis depended on the activation of MAPK signals in the BDMSCs, whereas the underlying pathways were related to a broad range of extracellular responses and were modulated by the secretion of multiple cytokines. Interestingly, C60(OH)22 regulated the malignantly differentiated BDMSCs via the Erk- and p38-MAPK and its downstream NF-κB signal pathway, but in normal BDMSCs regulation occurred only through Erk- and p38-MAPK and not by NF-κB activation. This study may provide a novel mechanism for C60(OH)22 nanoparticles as an anti-tumor drug.