Acetyl-CoA metabolic accumulation promotes hepatocellular carcinoma metastasis via enhancing CXCL1-dependent infiltration of tumor-associated neutrophils.

High levels of acetyl-CoA are considered a key metabolic feature of metastatic cancers. However, the impacts of acetyl-CoA metabolic accumulation on cancer microenvironment remodeling are poorly understood. In this study, using human hepatocellular carcinoma (HCC) tissues and orthotopic xenograft models, we found a close association between high acetyl-CoA levels in HCCs, increased infiltration of tumor-associated neutrophils (TANs) in the cancer microenvironment and HCC metastasis. Cytokine microarray and enzyme-linked immunosorbent assays (ELISA) revealed the crucial role of the chemokine (C-X-C motif) ligand 1(CXCL1). Mechanistically, acetyl-CoA accumulation induces H3 acetylation-dependent upregulation of CXCL1 gene expression. CXCL1 recruits TANs, leads to neutrophil extracellular traps (NETs) formation and promotes HCC metastasis. Collectively, our work linked the accumulation of acetyl-CoA in HCC cells and TANs infiltration, and revealed that the CXCL1-CXC receptor 2 (CXCR2)-TANs-NETs axis is a potential target for HCCs with high acetyl-CoA levels.

Longitudinal and quantitative assessment platform for concurrent analysis of anti-tumor efficacy and cardiotoxicity of nano-formulated medication in vivo.

Increasing nanomedicinal approaches have been developed to effectively inhibit tumor growth; however, critical questions such as whether a nanomedicinal approach can mitigate latent side effects are barely addressed. To this end, we established a zebrafish xenograft tumor model, combining pseudodynamic three-dimensional cardiac imaging and image analysis to enable simultaneous and quantitative determination of the change of tumor volume and cardiac function of zebrafish upon specific nanoformulation treatment. Doxorubicin (DOX), a well-known chemotherapeutic agent with cardiotoxicity, and a recently developed DOX-loaded nanocomposite were employed as two model drugs to demonstrate the effectiveness to utilize the proposed evaluation platform for rapid validation. The nanoformulation significantly mitigated DOX-associated cardiotoxicity, while retaining the efficacy of DOX in inhibiting tumor growth compared to administration of carrier-free DOX at the same dose. We anticipate that this platform possesses the potential as an efficient assessment system for nanoformulated cancer therapeutics with suspected toxicity and side effects to vital organs such as the heart.

Differential in situ sensing of extra- and intracellular glutathione by a novel redox-responsive silica matrix-Au nanoprobe.

We synthesized a biothiol-sensitive nanoprobe by assembling gold nanoparticles with a novel redox-responsive silica (ReSi) matrix using dithiobis (succinimidyl propionate) and (3-aminopropyl) trimethoxysilane. Thin layer disulfide-bonded networks of the ReSi could differentially respond to extra- and intracellular glutathione in cancer cells within 30 min; furthermore, targeted cellular uptake could be monitored in situ by fluorescence recovery. Sigmoidal dose-response pattern of the nanoprobes presented in this study were attributed to the buried disulfide-linked 3D nanostructure of the ReSi nanoshell, optimized at an appropriate thickness, enabling not only buffering of small redox disturbances in the extracellular milieu but also the satisfied sensitivity for rapid redox sensing. Such a ReSi-functionalized gold nanoparticle-based nanoconjugate possesses the potential to serve as an effective intracellular drug carrier for future cancer theranostics.

In vitro investigation of methylene blue-bearing, electrostatically assembled aptamer-silica nanocomposites as potential photodynamic therapeutics.

Photodynamic therapy, that is, excitation of a photosensitizer with light to generate reactive oxygen species such as singlet oxygen, has emerged as a noninvasive technique for cancer theranostics. However, the clinical use of many photosensitizers is impeded by their hydrophobicity, the nonspecific damage they cause to normal tissues, and their susceptibility to environmental degradation. In this study, we developed a simple electrostatic adsorption strategy to fabricate aptamer-silica nanocomposites by sequentially functionalizing nanocomposites with the cell surface-associated mucin 1 aptamer for tumor targeting and a hydrophilic photosensitizer, methylene blue, for photodynamic therapy applications. We investigated the relationship between the biophysical properties and cellular uptake of such nanocomposites to improve their formulation. Effective generation of singlet oxygen was achieved with a low photosensitizer dosage (0.5 µM) and a short, low-power irradiation (1 min, 10 mW/cm(2)). With the current strategy, the efficiency of photodynamic therapy was determined by the cellular uptake of nanocomposites and the targeting molecules used.

Non-metallic nanomaterials in cancer theranostics: a review of silica- and carbon-based drug delivery systems.

The rapid development in nanomaterials has brought great opportunities to cancer theranostics, which aims to combine diagnostics and therapy for cancer treatment and thereby improve the healthcare of patients. In this review we focus on the recent progress of several cancer theranostic strategies using mesoporous silica nanoparticles and carbon-based nanomaterials. Silicon and carbon are both group IV elements; they have been the most abundant and significant non-metallic substances in human life. Their intrinsic physical/chemical properties are of critical importance in the fabrication of multifunctional drug delivery systems. Responsive nanocarriers constructed using these nanomaterials have been promising in cancer-specific theranostics during the past decade. In all cases, either a controlled texture or the chemical functionalization is coupled with adaptive properties, such as pH-, light-, redox- and magnetic field- triggered responses. Several studies in cells and mice models have implied their underlying therapeutic efficacy; however, detailed and long-term in vivo clinical evaluations are certainly required to make these bench-made materials compatible in real bedside circumstances.

Aptamer-conjugated and drug-loaded acoustic droplets for ultrasound theranosis.

Tumor therapy requires multi-functional treatment strategies with specific targeting of therapeutics to reduce general toxicity and increase efficacy. In this study we fabricated and functionally tested aptamer-conjugated and doxorubicin (DOX)-loaded acoustic droplets comprising cores of liquid perfluoropentane compound and lipid-based shell materials. Conjugation of sgc8c aptamers provided the ability to specifically target CCRF-CEM cells for both imaging and therapy. High-intensity focused ultrasound (HIFU) was introduced to trigger targeted acoustic droplet vaporization (ADV) which resulted in both mechanical cancer cell destruction by inertial cavitation and chemical treatment through localized drug release. HIFU insonation showed a 56.8% decrease in cell viability with aptamer-conjugated droplets, representing a 4.5-fold increase in comparison to non-conjugated droplets. In addition, the fully-vaporized droplets resulted in the highest DOX uptake by cancer cells, compared to non-vaporized or partially vaporized droplets. Optical studies clearly illustrated the transient changes that occurred upon ADV of droplet-targeted CEM cells, and B-mode ultrasound imaging revealed contrast enhancement by ADV in ultrasound images. In conclusion, our fabricated droplets functioned as a hybrid chemical and mechanical strategy for the specific destruction of cancer cells upon ultrasound-mediated ADV, while simultaneously providing ultrasound imaging capability.

Release of photoactivatable drugs from plasmonic nanoparticles for targeted cancer therapy.

Chemotherapy is an important modality in cancer treatment. The major challenges of recent works are to improve drug loading, increase selectivity to target cells, and control the precise release of drugs. In the present study, we devised a smart drug carrier, an aptamer/hairpin DNA-gold nanoparticle (apt/hp-Au NP) conjugate for targeted delivery of drugs. The DNA aptamer sgc8c, which possesses strong affinity for protein tyrosine kinase 7 (PTK7), abundantly expressed on the surface of CCRF-CEM (T-cell acute lymphoblastic leukemia) cells, was assembled onto the surface of Au NPs. The repeated d(CGATCG) sequence within the hpDNA on the Au NP surface was used for the loading of the anticancer drug doxorubicin (Dox). After optimization, 25 (±3) sgc8c and 305 (±9) Dox molecules were successfully loaded onto the AuNP (13 nm) surface. The binding capability of apt/hp-Au NP conjugates toward targeted cells was investigated by flow cytometry and atomic absorption spectroscopy, which showed that the aptamer-functionalized nanoconjugates were selective for targeting of cancer cells. A cell toxicity (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, MTT) assay also demonstrated that these drug-loaded nanoconjugates could kill targeted cancer cells more effectively than nontargeted (control) cells. Most importantly, when illuminated with plasmon-resonant light (532 nm), Dox:nanoconjugates displayed enhanced antitumor efficacy with few side effects. The marked release of Dox from these nanoconjugates in living cells was monitored by increasing fluorescence signals upon light exposure. In vitro studies confirmed that aptamer-functionalized hp-Au NPs can be used as carriers for targeted delivery of drugs with remote control capability by laser irradiation with high spatial/temporal resolution.