Suping Li

A doxorubicin delivery platform using engineered natural membrane vesicle exosomes for targeted tumor therapy.

Targeted drug delivery vehicles with low immunogenicity and toxicity are needed for cancer therapy. Here we show that exosomes, endogenous nano-sized membrane vesicles secreted by most cell types, can deliver chemotherapeutics such as doxorubicin (Dox) to tumor tissue in BALB/c nude mice. To reduce immunogenicity and toxicity, mouse immature dendritic cells (imDCs) were used for exosome production. Tumor targeting was facilitated by engineering the imDCs to express a well-characterized exosomal membrane protein (Lamp2b) fused to αv integrin-specific iRGD peptide (CRGDKGPDC). Purified exosomes from imDCs were loaded with Dox via electroporation, with an encapsulation efficiency of up to 20%. iRGD exosomes showed highly efficient targeting and Dox delivery to αv integrin-positive breast cancer cells in vitro as demonstrated by confocal imaging and flow cytometry. Intravenously injected targeted exosomes delivered Dox specifically to tumor tissues, leading to inhibition of tumor growth without overt toxicity. Our results suggest that exosomes modified by targeting ligands can be used therapeutically for the delivery of Dox to tumors, thus having great potential value for clinical applications.

A DNA nanorobot functions as a cancer therapeutic in response to a molecular trigger in vivo

Nanoscale robots have potential as intelligent drug delivery systems that respond to molecular triggers. Using DNA origami we constructed an autonomous DNA robot programmed to transport payloads and present them specifically in tumors. Our nanorobot is functionalized on the outside with a DNA aptamer that binds nucleolin, a protein specifically expressed on tumor-associated endothelial cells, and the blood coagulation protease thrombin within its inner cavity. The nucleolin-targeting aptamer serves both as a targeting domain and as a molecular trigger for the mechanical opening of the DNA nanorobot. The thrombin inside is thus exposed and activates coagulation at the tumor site. Using tumor-bearing mouse models, we demonstrate that intravenously injected DNA nanorobots deliver thrombin specifically to tumor-associated blood vessels and induce intravascular thrombosis, resulting in tumor necrosis and inhibition of tumor growth. The nanorobot proved safe and immunologically inert in mice and Bama miniature pigs. Our data show that DNA nanorobots represent a promising strategy for precise drug delivery in cancer therapy.

An MMP-2 Responsive Liposome Integrating Antifibrosis and Chemotherapeutic Drugs for Enhanced Drug Perfusion and Efficacy in Pancreatic Cancer.

Fibrotic stroma, a critical character of pancreatic tumor microenvironment, provides a critical barrier against the penetration and efficacy of various antitumor drugs. Therefore, new strategies are urgently needed to alleviate the fibrotic mass and increase the drug perfusion within pancreatic cancer tissue. In our current work, we developed a β-cyclodextrin (β-CD) modified matrix metalloproteinase-2 (MMP-2) responsive liposome, integrating antifibrosis and chemotherapeutic drugs for regulation of pancreatic stellate cells (PSCs), a key source of the fibrosis, and targeted delivery of cytotoxic drugs for pancreatic cancer therapy. These liposomes disassembed into two functional parts upon MMP-2 cleavage at the tumor site. One part was constituted by the β-CDs and the antifibrosis drug pirfenidone, which was kept in the stroma and inhibited the expression of collagen I and TGF-β in PSCs, down-regulating the fibrosis and decreasing the stromal barrier. The other segment, the RGD peptide-modified-liposome loading the chemotherapeutic drug gemcitabine, targeted and killed pancreatic tumor cells. This integrated nanomedicine, showing an increased drug perfusion without any overt side effects, may provide a potential strategy for improvement of the pancreatic cancer therapy.

Self-assembled peptide nanoparticles as tumor microenvironment activatable probes for tumor targeting and imaging

Design of specific and sensitive imaging probes for targeting tumor microenvironment holds great promise to achieve precise detection and rapid responsiveness to neoplastic tissues. Dysregulated pH, one of the most remarkable hallmarks of tumor microenvironment, can be considered as a good specific trigger for the design of broad-spectrum and local-environment responsive imaging probes. However, the current existing design strategies for pH-responsive systems are insufficient to meet the needs for a rapid and tumor-specific diagnosis. Here we reported a novel biomimetic nanostructure based on oligopeptide self-assembly that can quickly switch into dissociated stage with active fluorescence property from self-assembled stage with quenched fluorescence activity when encountering a subtle pH-change in tumor microenvironment (pH 6.8 vs. 7.4). This oligopeptide-assembly is examined as tumor microenvironment activatable probes for both intratumoral and intravenous in vivo tumor imaging. Through the distinct fluorescent intensities, it is validated that the acidic tumor microenvironment can activate stronger fluorescence signals. The tailor-made self-assembled oligopeptide nanomaterials have the potential for efficient and specific in situ diagnosis of various solid tumors with a weakly acidic microenvironment, which is expected to be of crucial importance for clinical tumor diagnostics.

Nanotechnological strategies for therapeutic targeting of tumor vasculature

Neovascularization plays fundamental roles in tumor growth and metastasis. Tumor blood vessels are highly accessible and express various angiogenic markers that are either not present or are expressed at low levels in normal vessels, thereby serving as favorable targets for cancer therapy. Cancer nanotechnology, as an integrated platform, offers great opportunities for optimizing drug efficacy and pharmacokinetics while reducing side effects. Nanoparticles with tunable size, shape and surface modification have been exploited to achieve effective tumor vascular targeting. Here, we briefly introduce the signatures of tumor neovascularization and the review investigations on vascular-targeted anti-tumor nanomedicines. We also provide our perspectives on the promising fields of combination therapy and theranostic nanomedicines, as well as the challenges of nanotechnology-based cancer therapy. Furthermore, introducing new functionality would significantly consolidate the current development of nanomaterials based on tumor vasculature targeting.

Nanoparticle-mediated local depletion of tumour-associated platelets disrupts vascular barriers and augments drug accumulation in tumours

Limited intratumoural perfusion and nanoparticle retention remain major bottlenecks for the delivery of nanoparticle therapeutics into tumours. Here, we show that polymer–lipid–peptide nanoparticles delivering the antiplatelet antibody R300 and the chemotherapeutic agent doxorubicin can locally deplete tumour-associated platelets, thereby enhancing vascular permeability and augmenting the accumulation of the nanoparticles in tumours. R300 is specifically released in the tumour on cleavage of the lipid–peptide shell of the nanoparticles by matrix metalloprotease 2, which is commonly overexpressed in tumour vascular endothelia and stroma, thus facilitating vascular breaches that enhance tumour permeability. We also show that this strategy leads to substantial tumour regression and metastasis inhibition in mice.Polymer–lipid–peptide nanoparticles carrying an antiplatelet antibody and a chemotherapy drug deplete tumour-associated platelets to increase vascular permeability and augment the accumulation of the drug in tumours.

Deciphering an Underlying Mechanism of Differential Cellular Effects of Nanoparticles: An Example of Bach-1 Dependent Induction of HO-1 Expression by Gold Nanorod

Gold nanoparticles are extensively investigated for their potential biomedical applications. Therefore, it is pertinent to thoroughly evaluate their biological effects at different levels and their underlying molecular mechanism. Frequently, there are discrepancies about the biological effects of various gold nanoparticles among the reports dealing with different models. Most of the studies focused on the different biological effects of various nano-properties of the nanomaterials. We hypothesize that the biological models with different metabolic processes would be taken into account to explain the observed discrepancies of biological effects of nanomaterials. Herein, by using mouse embryo fibroblast cell line (MEF-1) and human embryonal lung fibroblast cell line (MRC-5) as in vitro models, we studied the cellular effects of gold nanorods (AuNRs) coated with poly (diallyldimethyl ammonium chloride) (PDDAC), polyethylene glycol and polystyrene sulfonae (PSS). We found that all three AuNRs had no effects on cellular viability at the concentration of 1xa0nM; however, AuNRs that coated with PDDAC and PSS induced significant up-regulation of heme oxygenase-1 (HO-1) which was believed to be involved in cellular defense activities in MEF-1 but not in MRC-5 cells. Further study showed that the low fundamental expression of transcription factor Bach-1, the major regulator of HO-1 expression, in MEF-1 was responsible for the up-regulation of HO-1 induced by the AuNRs. Our results indicate that although AuNRs we used are non-cytotoxic, they cell-specifically induce change of gene expression, such as HO-1. Our current study provides a good example to explain the molecular mechanisms of differential biological effects of nanomaterials in different cellular models. This finding raises a concern on evaluation of cellular effects of nanoparticles where the cell models should be critically considered.

Inhibition of platelet function using liposomal nanoparticles blocks tumor metastasis

Extensive evidence has shown that platelets support tumor metastatic progression by inducing epithelial-mesenchymal transition of cancer cells and by shielding circulating tumor cells from immune-mediated elimination. Therefore, blocking platelet function represents a potential new avenue for therapy focused on eliminating metastasis. Here we show that liposomal nanoparticles bearing the tumor-homing pentapeptide CREKA (Cys-Arg-Glu-Lys-Ala) can deliver a platelet inhibitor, ticagrelor, into tumor tissues to specifically inhibit tumor-associated platelets. The drug-loaded nanoparticles (CREKA-Lipo-T) efficiently blocked the platelet-induced acquisition of an invasive phenotype by tumor cells and inhibited platelet-tumor cell interaction in vitro. Intravenously administered CREKA-Lipo-T effectively targeted tumors within 24 h, and inhibited tumor metastasis without overt side effects. Thus, the CREKA-Lipo formulation provides a simple strategy for the efficient delivery of anti-metastatic drugs and shows considerable promise as a platform for novel cancer therapeutics.

Suppression of Tumor Energy Supply by Liposomal Nanoparticle-Mediated Inhibition of Aerobic Glycolysis

Aerobic glycolysis enables cancer cells to rapidly take up nutrients (e.g., nucleotides, amino acids, and lipids) and incorporate them into the biomass needed to produce a new cell. In contrast to existing chemotherapy/radiotherapy strategies, inhibiting aerobic glycolysis to limit the adenosine 5-triphosphate (ATP) yield is a highly efficient approach for suppressing tumor cell proliferation. However, most, if not all, current inhibitors of aerobic glycolysis cause significant adverse effects because of their nonspecific delivery and distribution to nondiseased organs, low bioavailability, and a narrow therapeutic window. New strategies to enhance the biosafety and efficacy of these inhibitors are needed for moving them into clinical applications. To address this need, we developed a liposomal nanocarrier functionalized with a well-validated tumor-targeting peptide to specifically deliver the aerobic glycolysis inhibitor 3-bromopyruvate (3-BP) into the tumor tissue. The nanoparticles effectively targeted tumors after systemic administration into tumor-bearing mice and suppressed tumor growth by locally releasing 3-BP to inhibit the ATP production of the tumor cells. No overt side effects were observed in the major organs. This report demonstrates the potential utility of the nanoparticle-enabled delivery of an aerobic glycolysis inhibitor as an anticancer therapeutic agent.

The critical role of the surface WO4 tetrahedron on the performance of Na-W-Mn/SiO2 catalysts for the oxidative coupling of methane

Abstract A series of M-W-Mn/SiO2 catalysts (M- Li, Na, K, Ba, Ca, Fe, Co, Ni, and A1) have been prepared and their catalytic performances for OCM were evaluated. The roles of the WO 4 tetrahedra and the WO 6 octahedra on the catalyst surface have been investigated using X-ray photoelectron spectroscopy (XPS) and laser Raman spectroscopy (LRS).