Tianjiao Ji

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.

Localized Electric Field of Plasmonic Nanoplatform Enhanced Photodynamic Tumor Therapy

Near-infrared plasmonic nanoparticles demonstrate great potential in disease theranostic applications. Herein a nanoplatform, composed of mesoporous silica-coated gold nanorods (AuNRs), is tailor-designed to optimize the photodynamic therapy (PDT) for tumor based on the plasmonic effect. The surface plasmon resonance of AuNRs was fine-tuned to overlap with the exciton absorption of indocyanine green (ICG), a near-infrared photodynamic dye with poor photostability and low quantum yield. Such overlap greatly increases the singlet oxygen yield of incorporated ICG by maximizing the local field enhancement, and protecting the ICG molecules against photodegradation by virtue of the high absorption cross section of the AuNRs. The silica shell strongly increased ICG payload with the additional benefit of enhancing ICG photostability by facilitating the formation of ICG aggregates. As-fabricated AuNR@SiO2-ICG nanoplatform enables trimodal imaging, near-infrared fluorescence from ICG, and two-photon luminescence/photoacoustic tomography from the AuNRs. The integrated strategy significantly improved photodynamic destruction of breast tumor cells and inhibited the growth of orthotopic breast tumors in mice, with mild laser irradiation, through a synergistic effect of PDT and photothermal therapy. Our study highlights the effect of local field enhancement in PDT and demonstrates the importance of systematic design of nanoplatform to greatly enhancing the antitumor efficacy.

Using Functional Nanomaterials to Target and Regulate the Tumor Microenvironment: Diagnostic and Therapeutic Applications

Malignant tumors remain a major health burden throughout the world and effective therapeutic strategies are urgently needed. Cancer nanotechnology, as an integrated platform, has the potential to dramatically improve cancer diagnosis, imaging, and therapy, while reducing the toxicity associated with the current approaches. Tumor microenvironment is an ensemble performance of various stromal cells and extracellular matrix. The recent progress in understanding the critical roles and the underlying mechanisms of the tumor microenvironment on tumor progression has resulted in emerging diagnostic and therapeutic nanomaterials designed and engineered specifically targeting the microenvironment components. Meanwhile, the bio-physicochemical differences between tumor and normal tissues have recently been exploited to achieve specific tumor-targeting for cancer diagnosis and treatment. Here, the major players in the tumor microenvironment and their biochemical properties, which can be utilized for the design of multifunctional nanomaterials with the potential to target and regulate this niche, are summarized. The recent progress in engineering intelligent and versatile nanomaterials for targeting and regulating the tumor microenvironment is emphasized. Although further investigations are required to develop robust methods for more specific tumor-targeting and well-controlled nanomaterials, the applications of tumor microenvironment regulation-based nanotechnology for safer and more effective anticancer nanomedicines have been proven successful and will eventually revolutionize the current landscape of cancer therapy.

Triple-punch strategy for triple negative breast cancer therapy with minimized drug dosage and improved antitumor efficacy.

Effective therapeutics against triple negative breast cancer (TNBC), which has no standard-of-care therapy, needs to be developed urgently. Here we demonstrated a strategy of integrating indocyanine green (ICG), paclitaxel (PTX), and survivin siRNA into one thermosensitive poly(2-(2-methoxyethoxy)ethyl methacrylate-co-oligo(ethylene glycol) methacrylate)-co-2-(dimethylamino)ethyl methacrylate-b-poly(D,L-lactide-co-glycolide) (P (MEO2MA-co-OEGMA-co-DMAEMA)-b-PLGA) nanoparticle (NP-IPS) for triple-punch strategy against TNBC. The NP-IPS significantly enhanced the stability of ICG. Controlled release of the PTX in tumor regions was triggered by the hyperthermia produced by laser irradiated ICG. The NP-IPS exhibited remarkable antitumor efficacy (almost complete ablation of the tumor xenografts) due to the combinational effects of chemotherapy, photothermal therapy, and gene therapy with low drug dose (ICG, 0.32 μmol/kg; PTX, 0.54 μmol/kg; siRNA, 1.5 mg/kg) and minimal side effects. Taken together, our current study demonstrates a nanoplatform for triple-therapy, which reveals a promising strategy for TNBC treatment.

Peptide Assembly Integration of Fibroblast‐Targeting and Cell‐Penetration Features for Enhanced Antitumor Drug Delivery

T. Ji, Dr. Y. Ding, Dr. Y. Zhao, J. Wang, H. Qin, J. Lang, R. Zhao, Y. Zhang, J. Shi, Prof. G. Nie CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST) 11 Beiyitiao, Zhongguancun Beijing 100190 , China E-mail: zhaoying@nanoctr.cn; niegj@nanoctr.cn X. Liu, Dr. N. Tao, Prof. Z. Qin CAS Key Laboratory of Protein and Peptide Pharmaceuticals Institute of Biophysics 15 Datun Road , Beijing 100101 , China E-mail: zhihai@ibp.ac.cn

Deciphering the underlying mechanisms of oxidation-state dependent cytotoxicity of graphene oxide on mammalian cells

The promising broad applications of graphene oxide (GO) derivatives in biomedicine have raised concerns about their safety on biological organisms. However, correlations between the physicochemical properties, especially oxidation degree of GOs and their toxicity, and the underlying mechanisms are not well understood. Herein, we evaluated the cytotoxicity of three GO samples with various oxidation degrees on mouse embryo fibroblasts (MEFs). Three samples can be internalized by MEFs observed via transmission electron microscopy (TEM), and were well tolerant by MEFs at lower doses (below 25μg/ml) but significantly toxic at 50 and 100μg/ml via Cytell Imaging System. More importantly, as the oxidation degree decreased, GO derivatives led to a higher degree of cytotoxicity and apoptosis. Meanwhile, three GOs stimulated dramatic enhancement in reactive oxygen species (ROS) production in MEFs, where the less oxidized GO produced a higher level of ROS, suggesting the major role of oxidative stress in the oxidation-degree dependent toxicity of GOs. Results from electron spin resonance (ESR) spectrometry showed a strong association of the lower oxidation degree of GOs with their stronger indirect oxidative damage through facilitating H2O2 decomposition into OH and higher direct oxidative abilities on cells. The theoretical simulation revealed the key contributions of carboxyl groups and aromatic domain size of nanosheets to varying the energy barrier of H2O2 decomposition reaction. These systematic explorations in the chemical mechanisms unravel the key physicochemical properties that would lead to the diverse toxic profiles of the GO nanosheets with different oxygenation levels, and offer us new clues in the molecular design of carbon nanomaterials for their safe applications in biomedicine.

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.

Photothermal Effect Enhanced Cascade-Targeting Strategy for Improved Pancreatic Cancer Therapy by Gold Nanoshell@Mesoporous Silica Nanorod

Pancreatic cancer, one of the leading causes of cancer-related mortality, is characterized by desmoplasia and hypovascular cancerous tissue, with a 5 year survival rate of <8%. To overcome the severe resistance of pancreatic cancer to conventional therapies, we synthesized gold nanoshell-coated rod-like mesoporous silica (GNRS) nanoparticles which integrated cascade tumor targeting (mediated by photothermal effect and molecular receptor binding) and photothermal treatment-enhanced gemcitabine chemotherapy, under mild near-infrared laser irradiation condition. GNRS significantly improved gemcitabine penetration and accumulation in tumor tissues, thus destroying the dense stroma barrier of pancreatic cancer and reinforcing chemosensitivity in mice. Our current findings strongly support the notion that further development of this integrated plasmonic photothermal strategy may represent a promising translational nanoformulation for effective treatment of pancreatic cancer with integral cascade tumor targeting strategy and enhanced drug delivery efficacy.

Fine-tuned h-ferritin nanocage with multiple gold clusters as near-infrared kidney specific targeting nanoprobe.

When stabilized and functionalized by biomolecules, noble metal (such as gold and silver) cluster-based hybrid nanocomposites have shown great promise for biomedical applications, due to their unique physiochemical properties originating from the inorganic elements and specific functionality and biocompatibility from their biological components. Although certain promise for bioimaging, biosensing, and biomimetic catalysis has been demonstrated, it is still a great challenge to integrate the defined functionality of the biomolecules with enhanced or novel physiochemical properties of the metal clusters, under control at the molecular level. Herein, based on molecular dynamics simulation of a gold (Au) cluster assembly, we designed near-infrared (NIR) fluorescent hybrid nanocomposites with multiple Au clusters within an apo H-ferritin (HFt) nanocage. The fluorescence quantum yield of near-infrared (NIR) Au-HFt is about 63.4% and the emission peak is 810 nm. The NIR Au-HFt is one of the first native protein-guided Au cluster-based nanomaterials for in vivo biowindow imaging. In vivo fluorescent imaging and quantification of Au element confirmed that Au-HFt not only retained the kidney targeting properties of HFt well (about 10 times higher Au concentration in kidney than in liver and spleen, the most common organs for nanoparticle accumulation), but also gained strong NIR imaging capability for live animals. The NIR Au-HFt showed powerful tissue penetrating ability, strong fluorescent efficiency, and excellent kidney targeting specificity. These results thus open new opportunities for kidney disease imaging and theranostic applications.