Tumor pH Research Articles

Evaluation of a similarity anisotropic diffusion denoising approach for improving in vivo CEST-MRI tumor pH imaging.

Chemical exchange saturation transfer MRIprovides new approaches for investigating tumor microenvironment, including tumor acidosis that plays a key role in tumor progression and resistance to therapy. Following iopamidol injection, the detection of the contrast agent inside the tumor tissue allows measurements of tumor extracellular pH. However, accurate tumor pH quantifications are hampered by the low contrast efficiency of the CEST technique and by the low SNR of the acquired CEST images, hence in a reduced detectability of the injected agent. This work aims to investigate a novel denoising method for improving both tumor pH quantification and accuracy of CEST-MRI pH imaging. An hybrid denoising approach was investigated for CEST-MRI pH imaging based on the combination of the nonlocal mean filter and the anisotropic diffusion tensor method. The denoising approach was tested in simulated and in vitro data and compared with previously reported methods for CEST imaging and with established denoising approaches. Finally, it was validated with in vivo data to improve the accuracy of tumor pH maps. The proposed method outperforms current denoising methods in CEST contrast quantification and detection of the administered contrast agent at several increasing noise levels with simulated data. In addition, it achieved a better pH quantification in in vitro data and demonstrated a marked improvement in contrast detection and a substantial improvement in tumor pH accuracy in in vivo data. The proposed approach effectively reduces the noise in CEST images and increases the sensitivity detection in CEST-MRI pH imaging.

NIR‐II pH Sensor with a FRET Adjustable Transition Point for In Situ Dynamic Tumor Microenvironment Visualization

AbstractMonitoring the pH in tumor lesions provides abundant physiological information. However, currently developed pH sensors only achieve sensitive detection in the settled response region around the pH transition point (pHt). To realize tumor pH monitoring with high sensitivity within a wider response region, reported here are serial pHt adjustable sensors (pTAS) that simply regulate the component ratio of second near‐infrared (NIR‐II) emission aza‐BODIPY (NAB) donor and pH sensitive rhodamine‐based pre‐acceptor (NRh) in Förster resonance energy transfer system. Combining the pH response regions of pTAS, a twofold widened pH detection range (6.11–7.22) is obtained compared to the pHt settled sensor (6.38–6.94). With an adjustable pHt, in vivo tumor pH increase and decrease processes could be dynamically visualized through dual‐channel ratiometric bioimaging within the NIR‐II window, with a coefficient of variation under 1 % compared to the standard pH meter.

PEG Linker Length Strongly Affects Tumor Cell Killing by PEGylated Carbonic Anhydrase Inhibitors in Hypoxic Carcinomas Expressing Carbonic Anhydrase IX

Hypoxic tumors overexpress membrane-bound isozymes of carbonic anhydrase (CA) CA IX and CA XII, which play key roles in tumor pH homeostasis under hypoxia. Selective inhibition of these CA isozymes has the potential to generate pH imbalances that can lead to tumor cell death. Since these isozymes are dimeric, we designed a series of bifunctional PEGylated CA inhibitors (CAIs) through the attachment of our preoptimized CAI warhead 1,3,4-thiadiazole-2-sulfonamide to polyethylene glycol (PEG) backbones with lengths ranging from 1 KDa to 20 KDa via a succinyl linker. A detailed structure−thermal properties and structure–biological activity relationship study was conducted via differential scanning calorimetry (DSC) and via viability testing in 2D and 3D (tumor spheroids) cancer cell models, either CA IX positive (HT-29 colon cancer, MDA-MB 231 breast cancer, and SKOV-3 ovarian cancer) or CA IX negative (NCI-H23 lung cancer). We identified PEGylated CAIs DTP1K 28, DTP2K 23, and DTP3.4K 29, bearing short and medium PEG backbones, as the most efficient conjugates under both normoxic and hypoxic conditions, and in the tumor spheroid models. PEGylated CAIs did not affect the cell viability of CA IX-negative NCI-H23 tumor spheroids, thus confirming a CA IX-mediated cell killing for these potential anticancer agents.

A pH-responsive photoacoustic imaging probe for tumor pH imaging in vivo based on polyaniline–bovine serum albumin

Precise pH detection in tumors can guide the design of pH-responsive drugs and theranostic agents to improve treatment efficacy. However, most reported pH-responsive probes are fluorescent probes, for which in vivo application is limited by low probe penetration depth. In this study, a pH-responsive polyaniline–bovine serum albumin (BSA) probe was constructed for precise pH detection in tumors using photoacoustic imaging. The probe can be used to generate high-resolution images of deep biological tissues. The photoacoustic signal of the polyaniline–BSA probe exhibits a clear linear relationship with pH in the range of 5–6.8 both in vitro and in vivo, indicating that the probe is ideal for precise pH detection in most tumors. The polyaniline–BSA probe also exhibits satisfactory biocompatibility, low toxicity, fast response, and good reversibility. This work provides a useful in vivo pH detection probe for developing pH-responsive drugs and theranostic agents.

Impact of the acidic environment on gene expression and functional parameters of tumors in vitro and in vivo

BackgroundThe low extracellular pH (pHe) of tumors resulting from glycolytic metabolism is a stress factor for the cells independent from concomitant hypoxia. The aim of the study was to analyze the impact of acidic pHe on gene expression on mRNA and protein level in two experimental tumor lines in vitro and in vivo and were compared to hypoxic conditions as well as combined acidosis+hypoxia.MethodsGene expression was analyzed in AT1 prostate and Walker-256 mammary carcinoma of the rat by Next Generation Sequencing (NGS), qPCR and Western blot. In addition, the impact of acidosis on tumor cell migration, adhesion, proliferation, cell death and mitochondrial activity was analyzed.ResultsNGS analyses revealed that 147 genes were uniformly regulated in both cell lines (in vitro) and 79 genes in both experimental tumors after 24 h at low pH. A subset of 25 genes was re-evaluated by qPCR and Western blot. Low pH consistently upregulated Aox1, Gls2, Gstp1, Ikbke, Per3, Pink1, Tlr5, Txnip, Ypel3 or downregulated Acat2, Brip1, Clspn, Dnajc25, Ercc6l, Mmd, Rif1, Zmpste24 whereas hypoxia alone led to a downregulation of most of the genes. Direct incubation at low pH reduced tumor cell adhesion whereas acidic pre-incubation increased the adhesive potential. In both tumor lines acidosis induced a G1-arrest (in vivo) of the cell cycle and a strong increase in necrotic cell death (but not in apoptosis). The mitochondrial O2 consumption increased gradually with decreasing pH.ConclusionsThese data show that acidic pHe in tumors plays an important role for gene expression independently from hypoxia. In parallel, acidosis modulates functional properties of tumors relevant for their malignant potential and which might be the result of pH-dependent gene expression.

Gene-editing by CRISPR-Cas9 in combination with anthracycline therapy via tumor microenvironment-switchable, EGFR-targeted, and nucleus-directed nanoparticles for head and neck cancer suppression.

Head and neck cancer (HNC) has a high incidence and a poor prognosis. Epirubicin, a topoisomerase inhibitor, is a potential anthracycline chemotherapeutic for HNC treatment. HuR (ELAVL1), an RNA-binding protein, plays a critical role in promoting tumor survival, invasion, and resistance. HuR knockout via CRISPR/Cas9 (HuR CRISPR) is a possible strategy for the simultaneous modulation of the various pathways of tumor progression. Multifunctional nanoparticles modified with pH-sensitive epidermal growth factor receptor (EGFR)-targeting and nucleus-directed peptides were designed for the efficient delivery of HuR CRISPR and epirubicin to human tongue squamous carcinoma SAS cells and SAS tumor-bearing mice. The pH-sensitive nanoparticles responded to the acidic pH value as a switch to expose the targeting peptides. The cellular uptake and transfection efficiency of these nanoparticles in SAS cells increased via EGFR targeting, ligand-mediated endocytosis, and endosomal escape. These nanoparticles showed low cytotoxicity towards normal oral keratinocyte NOK cells. CRISPR/Cas9 was transported into the nucleus via the nuclear directing peptide and successfully knocked out HuR to suppress proliferation, metastasis, and resistance in SAS cells. The multiple inhibition of EGFR/β-catenin/epithelial-mesenchymal transition pathways was mediated through modulating the EGFR/PI3K/mTOR/AKT axis. The co-treatment of epirubicin and HuR CRISPR in SAS cells further facilitated apoptosis/necroptosis/autophagy and caused cancer cell death. In combination with HuR CRISPR nanoparticles, the efficacy and safety of epirubicin nanoparticles against cancer in SAS tumor-bearing mice improved significantly. Collectively, these nanoparticles showed a tumor pH response, active EGFR targeting, and nuclear localization and thus offered a combinatorial spatiotemporal platform for chemotherapy and the CRISPR/Cas gene-editing system.

Impact of Acidosis-Regulated MicroRNAs on the Expression of Their Target Genes in Experimental Tumors In Vivo.

In comparison to normal tissue, solid tumors show an acidic extracellular pH, which results from hypoxia-induced glycolytic metabolism and the Warburg effect. Since acidosis modulates the expression of different microRNAs (e.g., miR-7, miR-183, miR-203, miR-215), microRNAs and their targets might be mediators between tumor acidosis and malignant behavior. The aim of this study was to investigate how modulation of these microRNAs affects the expression of their targets (Crem, cAMP-responsive element modulator; Gls2, glutaminase 2; Txnip, thioredoxin-interacting protein) in experimental tumors in vivo and whether these changes are acidosis dependent. The study was performed in two experimental tumor lines of the rat (AT-1 prostate carcinoma, Walker-256 mammary carcinoma). The results showed that all three targets were regulated by acidosis in vivo, Crem and Gls2 being downregulated and Txnip upregulated in both models. In AT-1 tumors at normal tumor pH, miR-203 overexpression increased Txnip expression by about 75%, whereas in Walker-256 tumors, miR-7 reduced protein expression. In more acidic tumors, no impact of microRNAs on Txnip expression was seen. On the other hand, Gls2 was significantly increased in acidic tumors by miR-183 or miR-7 overexpression (cell line dependent). As this increase was not present under control conditions, an acidosis-dependent effect can be assumed. These results indicate that tumor acidosis modulates the expression of targets of pH-sensitive microRNAs in experimental tumors. Especially the protein expression of Gls2 might be regulated via changes of microRNAs, which then affects the malignant progression of tumors.

Polymer-conjugated glucosamine complexed with boric acid shows tumor-selective accumulation and simultaneous inhibition of glycolysis

We synthesized unique water-soluble synthetic-polymer, styrene-maleic acid copolymer (SMA) conjugated glucosamine (SG); which formed a stable complex with boric acid (BA). This complex had a mean particle size of 15 nm by light scattering, and single peak in gel permeation chromatography. The particles were taken up by tumor cells five times faster than free BA in vitro and liberated BA at acidic tumor pH (5–7). Liberated BA inhibited glycolysis and resulted in tumor suppression in vivo. Intravenously injected SGB-complex did bind with albumin, and plasma half-life was about 8 h in mice, and accumulated to tumor tissues about 10 times more than in normal organs. IC50 of SGB-complex for HeLa cells under pO2 of 6–9% was about 20 μg/ml (free BA equivalent), 150 times more potent than free BA. Neutron irradiation of human oral cancer cells with SGB-complex resulted in 16 times greater cell-killing than that without SGB-complex. In vivo antitumor effect was evaluated after neutron irradiation only once in SCC VII tumor bearing mice and significant tumor suppression was confirmed. These results indicate that SGB-complex is a unique multifunctional anticancer agent with much more potent activity under low pO2 conditions as in large advanced cancers.

Effective Eradication of Tumors by Enhancing Photoacoustic‐Imaging‐Guided Combined Photothermal Therapy and Ultrasonic Therapy

AbstractExploiting a comprehensive strategy that processes diagnosis and therapeutic functions is desired for eradicating tumors. In this study, two versatile nanoparticles are introduced: one is polyethylene glycol‐ and polyethyleneimine‐modified gold nanorods (mPEG–PEI–AuNRs), and the other is formed by electrostatic interactions between mPEG–PEI and calcium carbonate nanoparticles (mPEG–PEI/CaNPs). These two nanoparticles possess following favorable properties: 1) mPEG–PEI–AuNRs and mPEG–PEI/CaNPs show not only high cell uptake in acidic tumoral pH, but also efficient accumulation in tumors with prolonged circulation. 2) mPEG–PEI/CaNPs can generate carbon dioxide (CO2) bubbles in acidic tumoral environment and the photoacoustic (PA) signals from mPEG–PEI–AuNRs can be enhanced with the generation of CO2 bubbles. 3) The tumors can be eradicated by combining photothermal therapy (PTT) with ultrasonic therapy (UST) under the near‐infrared (NIR) laser and ultrasonic irradiation with the presence of mPEG–PEI–AuNRs and CO2 bubbles from mPEG–PEI/CaNPs. The detailed evaluation of cellular uptake, photothermal property of mPEG–PEI–AuNRs, CO2 bubbles’ generation from mPEG–PEI/CaNPs, imaging, and combined PTT and UST are carried out in vitro or in vivo. This work has great potential usage for diagnosis and treatment in the future.

Tumour acidosis evaluated in vivo by MRI-CEST pH imaging reveals breast cancer metastatic potential

BackgroundTumour acidosis is considered to play a central role in promoting cancer invasion and migration, but few studies have investigated in vivo how tumour pH correlates with cancer invasion. This study aims to determine in vivo whether tumour acidity is associated with cancer metastatic potential.MethodsBreast cancer cell lines with different metastatic potentials have been characterised for several markers of aggressiveness and invasiveness. Murine tumour models have been developed and assessed for lung metastases and tumour acidosis has been assessed in vivo by a magnetic resonance imaging-based chemical exchange saturation transfer (CEST) pH imaging approach.ResultsThe higher metastatic potential of 4T1 and TS/A primary tumours, in comparison to the less aggressive TUBO and BALB-neuT ones, was confirmed by the highest expression of cancer cell stem markers (CD44+CD24−), highlighting their propensity to migrate and invade, coinciding with the measurement obtained by in vitro assays. MRI-CEST pH imaging successfully discriminated the more aggressive 4T1 and TS/A tumours that displayed a more acidic pH. Moreover, the observed higher tumour acidity was significantly correlated with an increased number of lung metastases.ConclusionsThe findings of this study indicate that the extracellular acidification is associated with the metastatic potential.

CaCO3-Assisted Preparation of pH-Responsive Immune-Modulating Nanoparticles for Augmented Chemo-Immunotherapy

HighlightsCaCO3-assisted double emulsion method was developed to prepare pH-responsive nanoparticles enabling effective encapsulation of diverse molecules.The introducing of CaCO3 could enable deep intratumoral penetration of therapeutic agents and effective neutralization of acidic tumor pH to favor the reverse of immunosuppressive tumor microenvironment (TME).The reverse of immunosuppressive TME ascribing to NLG919-mediated IDO1 inhibition and CaCO3-mediated neutralization of acidic TME could collectively contribute to augmented chemo-immunotherapy of cancer.

Novel polyzwitterion shell with adaptable surface chemistry engineered to enhance anti-fouling and intracellular imaging of detonation nanodiamonds under tumor pHe

In this work, zwitterionic polymer (polyzwitterion) coating nanodiamonds (ND) with tumorous pH responsiveness were prepared for efficient application of commercial NDs in tumor cells imaging. Poly(carboxybetaine methacrylate) was firstly grafted on the pristine NDs (PCBMA-@-NDs) by surface-initiated reversible addition-fragmentation chain transfer (RAFT) polymerization. To achieve pH responsiveness and activated interaction with tumor cells, PCBMA-@-NDs were subsequently modified with benzene sulfonamide (PCBSA-@-NDs) via one step carbodiimide chemistry. The surface polymer functionalization was characterized by FTIR, 1H NMR and TGA, and PCBMA-@-NDs and PCBSA-@-NDs showed great dispersibility, enhanced fluorescence intensity and excellent antifouling property in contrast to pristine NDs. Moreover, PCBSA-@-NDs was able to switch zwitterionic surface (at pH 7.4) reversibly into positive charge (at pH 6.5) via protonated or deprotonated acylsulfonamide. As expected, PCBSA-@-NDs demonstrated higher cell affinity and better imaging performance than those of zwitterionic NDs at tumor slight acid environment, proven by fluorescence microscopy and flow cytometry. Overall, we provide a feasible and valuable strategy to construct smart NDs, thus encouraging the application of cost-effective fluorescence nanomaterials in biomedical fields.

Noninvasive Detection of Extracellular pH in Human Benign and Malignant Liver Tumors Using CEST MRI.

PurposeIn this study, we aimed to use 3T magnetic resonance imaging (MRI), which is clinically available, to determine the extracellular pH (pHe) of liver tumors and prospectively evaluate the ability of chemical exchange saturation transfer (CEST) MRI to distinguish between benign and malignant liver tumors.MethodsDifferent radiofrequency irradiation schemes were assessed for ioversol-based pH measurements at 3T. CEST effects were quantified in vitro using the asymmetric magnetization transfer ratio (MTRasym) at 4.3 ppm from the corrected Z spectrum. Generalized ratiometric analysis was conducted by rationing resolved ioversol CEST effects at 4.3 ppm at a flip angle of 60 and 350°. Fifteen patients recently diagnosed with hepatic carcinoma and five patients diagnosed with hepatic hemangioma [1 male; mean age, 48.6 (range, 37–59) years] were assessed.ResultsBy conducting dual-power CEST MRI, the pH of solutions was determined to be 6.0–7.2 at 3T in vitro. In vivo, ioversol signal intensities in the tumor region showed that the extracellular pH in hepatic carcinoma was acidic(mean ± standard deviation, 6.66 ± 0.19), whereas the extracellular pH was more physiologically neutral in hemangioma (mean ± standard deviation, 7.34 ± 0.09).The lesion size was similar between CEST pH MRI and T2-weighted imaging.Conclusiondual-power CEST MRI can detect extracellular pH in human liver tumors and can provide molecular-level diagnostic tools for differentiating benign and malignant liver tumors at 3T.

Variation in tumor pH affects pH-triggered delivery of peptide-modified magnetic nanoparticles

Acidification of the extracellular matrix, an intrinsic characteristic of many solid tumors, is widely exploited for physiologically triggered delivery of contrast agents, drugs, and nanoparticles to tumor. However, pH of tumor microenvironment shows intra- and inter-tumor variation. Herein, we investigate the impact of this variation on pH-triggered delivery of magnetic nanoparticles (MNPs) modified with pH-(low)-insertion peptide (pHLIP). Fluorescent flow cytometry, laser confocal scanning microscopy and transmission electron microscopy data proved that pHLIP-conjugated MNPs interacted with 4T1 cells in two-dimensional culture and in spheroids more effectively at pH 6.4 than at pH 7.2, and entered the cell via clathrin-independent endocytosis. The accumulation efficiency of pHLIP-conjugated MNPs in 4T1 tumors after their intravenous injection, monitored in vivo by magnetic resonance imaging, showed variation. Analysis of the tumor pH profiles recorded with implementation of original nanoprobe pH sensor, revealed obvious correlation between pH measured in the tumor with the amount of accumulated MNPs.

Increased Tumoral Microenvironmental pH Improves Cytotoxic Effect of Pharmacologic Ascorbic Acid in Castration-Resistant Prostate Cancer Cells

BackgroundThe anticancer potential of pharmacologic ascorbic acid (AA) has been detected in a number of cancer cells. However, in vivo study suggested a strongly reduced cytotoxic activity of AA. It was known that pH could be a critical influencing factor for multiple anticancer treatments. In this study, we explored the influence of pH on the cytotoxicity of ascorbic acid. We employed castration-resistant prostate cancer (CRPC) cell lines PC3 and DU145 to observe the therapeutic effect of AA on PCa cells that were cultured with different pH in vitro. We also analyzed the influence of pH and extracellular oxidation on cytotoxicity of AA in cancer cells using reactive oxygen species (ROS) assay, cellular uptake of AA, and NADPH assay. Male BALB/c nude mice bearing prostate carcinoma xenografts (PC3 or DU145) were used to assess treatment response to AA with or without bicarbonate in vivo. The cellular uptake of AA in PCa xenografts was detected using positron emission tomography (PET). Small animal PET/CT scans were performed on mice after the administration of 6-deoxy-6-[18F] fluoro-L-ascorbic acid (18F-DFA).ResultsOur in vitro studies demonstrate that acidic pH attenuates the cytotoxic activity of pharmacologic ascorbic acid by inhibiting AA uptake in PCa cells. Additionally, we found that the cancer cell-selective toxicity of AA depends on ROS. In vivo, combination of AA and bicarbonate could provide a significant better therapeutic outcome in comparison with controls or AA single treated mice. 18F-DFA PET imaging illustrated that the treatment with NaHCO3 could significantly increase the AA uptake in tumor.ConclusionsThe alkalinity of tumor microenvironment plays an important role in anticancer efficiency of AA in CRPC. 18F-DFA PET/CT imaging could predict the therapeutic response of PCa animal model through illustration of tumoral uptake of AA. 18F-DFA might be a potential PET tracer in clinical diagnosis and treatment for CRPC.

Photodynamic therapy using LCST polymers exerting pH-responsive isothermal phase transition

In photodynamic therapy (PDT), the inherent physicochemical properties of a photosensitizer (PS) critically affect its biodistribution and therapeutic outcome as well as side effect. Here, we developed a PS-polymer conjugate displaying isothermal hydrophilic-to-hydrophobic phase transition in response to tumorous acidic pH. The polymer backbone was poly(N-isopropylacrylamide (NIPAAm)/2-aminoisoprpylacrylamide (AIPAAm)) (P(NIPAAm/AIPAAm)), which shows lower critical solution temperature (LCST) of 30 °C. The amine groups in its side chains were converted to hydrophilic acid-labile 2-propionic-3-methylmaleic (PMM) amides, forming poly(NIPAAm/AIPAAm-PMM). The conjugation of PMM moieties drastically increased the LCST of the polymer to 40 °C and displayed hydrophilic character to minimalize unspecific interaction of PS-P(NIPAAm/AIPAAm-PMM) in bloodstream, diminishing potential photosensitivity. The detachment of PMM at tumorous pH lowered the LCST to that of original P(NIPAAm/AIPAAm), permitting hydrophilic-to-hydrophobic transition at a physiological temperature (37 °C). This pH-responsive isothermal phase transition facilitated interaction with the cultured cancer cells, accomplishing 8.1 times-enhanced cellular uptake and strong phototoxicity in a tumorous pH-selective manner. Even in subcutaneous tumor models, our polymer conjugates exhibited efficient tumor accumulation and significantly augmented PDT effect without inducing unfavorable photochemical toxicity to the skin. This study offers a novel concept of PS delivery systems targeting tumorous pH by the use of isothermal phase transition.

Cobalt Bis(dicarbollide) Alkylsulfonamides: Potent and Highly Selective Inhibitors of Tumor Specific Carbonic Anhydrase IX.

Carbonic anhydrase IX (CAIX) is an enzyme expressed on the surface of cells in hypoxic tumors. It plays a role in regulation of tumor pH and promotes thus tumor cell survival and occurrence of metastases. Here, derivatives of the cobalt bis(dicarbollide)(1-) anion are reported that are based on substitution at the carbon sites of the polyhedra by two alkylsulfonamide groups differing in the length of the aliphatic connector (from C1 to C4, n=1-4), which were prepared by cobalt insertion into the 7-sulfonamidoalkyl-7,8-dicarba-nido-undecaborate ions. Pure meso- and rac-diastereoisomeric forms were isolated. The series is complemented with monosubstituted species (n=2). Synthesis by a direct method furnished similar derivatives (n=2, 3), which are chlorinated at the B(8,8') boron sites. All compounds inhibited CAIX with subnanomolar inhibition constants and showed high selectivity for CAIX. The best inhibitory properties were observed for the compound with n= 3 and two substituents present in rac-arrangement with Ki =20 pM and a selectivity index of 668. X-ray crystallography was used to study interactions of these compounds with the active site of CAIX on the structural level.

Local strong acids: A driving force for metastasis

Carcinogenesis was postulated as the result of the local buildup of strong acids such as hydrogenchloride which may trigger metastasis. A previous study revealed that bicarbonate raised tumor pH and suppressed metastases. The phosphate groups in DNA on neutrophil extracellular traps possess hydrogen bonding capacity and can accept protons. The proteins commonly found in neutrophil extracellular traps such as CCDC25, myeloperoxidase (MPO), histone H3, peptidylarginine deiminase 4 (PAD4) possess basic amino acid content at about 20.2%, 12.8%, 24.3% and 13.0% respectively, which attracts anions such as chloride. The striking 20.2% basic amino acid content in CCDC25 is similar to that of typical oncoproteins. Local hydrogenchloride may be the dominant impetus for metastasis, accounting for the anticancer effects of virtually all weak organic acids, acetic acid and lactic acid in particular.

Synthesis of core-shell hybrid nanoparticles with pH responsive core and silica shell and their surface characterization

Herein, the preparation of pH-sensitive core-shell hybrid nanoparticles is reported. The core, prepared by emulsion polymerization, consisted of a copolymer of polyvinylimidazole (PVIm) and 3-(trimethoxysilyl) propylmethacrylate (TMSPMA). The silica shell, obtained by sol-gel synthesis, was anchored to the core at the TMSPMA moiety via silane linking. The pH response and the size of the nanoparticles were tuned by adjusting the quantity of VIm. The shell in the particles helps to decrease the drug release around tumoral pH (6.5–7.2).

T-cells produce acidic niches in lymph nodes to suppress their own effector functions

The acidic pH of tumors profoundly inhibits effector functions of activated CD8 + T-cells. We hypothesize that this is a physiological process in immune regulation, and that it occurs within lymph nodes (LNs), which are likely acidic because of low convective flow and high glucose metabolism. Here we show by in vivo fluorescence and MR imaging, that LN paracortical zones are profoundly acidic. These acidic niches are absent in athymic Nu/Nu and lymphodepleted mice, implicating T-cells in the acidifying process. T-cell glycolysis is inhibited at the low pH observed in LNs. We show that this is due to acid inhibition of monocarboxylate transporters (MCTs), resulting in a negative feedback on glycolytic rate. Importantly, we demonstrate that this acid pH does not hinder initial activation of naïve T-cells by dendritic cells. Thus, we describe an acidic niche within the immune system, and demonstrate its physiological role in regulating T-cell activation.