Tumor Tissue pH Research Articles

Anti-tumor effect of pH-sensitive drug-loaded nanoparticles optimized via an integrated computational/experimental approach.

The acidic pH of tumor tissue has been used to trigger drug release from nanoparticles. However, dynamic interactions between tumor pH and vascularity present challenges to optimize therapy to particular microenvironment conditions. Despite recent development of pH-sensitive nanomaterials that can accurately quantify drug release from nanoparticles, tailoring release to maximize tumor response remains elusive. This study hypothesizes that a computational modeling-based platform that simulates the heterogeneously vascularized tumor microenvironment can enable evaluation of the complex intra-tumoral dynamics involving nanoparticle transport and pH-dependent drug release, and predict optimal nanoparticle parameters to maximize the response. To this end, SPNCD nanoparticles comprising superparamagnetic cores of iron oxide (Fe3O4) and a poly(lactide-co-glycolide acid) shell loaded with doxorubicin (DOX) were fabricated. Drug release was measured in vitro as a function of pH. A 2D model of vascularized tumor growth was calibrated to experimental data and used to evaluate SPNCD effect as a function of drug release rate and tissue vascular heterogeneity. Simulations show that pH-dependent drug release from SPNCD delays tumor regrowth more than DOX alone across all levels of vascular heterogeneity, and that SPNCD significantly inhibit tumor radius over time compared to systemic DOX. The minimum tumor radius forecast by the model was comparable to previous in vivo SPNCD inhibition data. Sensitivity analyses of the SPNCD pH-dependent drug release rate indicate that slower rates are more inhibitory than faster rates. We conclude that an integrated computational and experimental approach enables tailoring drug release by pH-responsive nanomaterials to maximize the tumor response.

Low-Power Magnetic Resonance-Guided Focused Ultrasound Tumor Ablation upon Controlled Accumulation of Magnetic Nanoparticles by Cascade-Activated DNA Cross-Linkers.

Magnetic resonance-guided focused ultrasound (MRgFUS) is a promising non-invasive surgical technique with spatial specificity and minimal off-target effects. Despite the expanding clinical applications, the major obstacles associated with MRgFUS still lie in low magnetic resonance imaging (MRI) sensitivity and safety issues. High ultrasound power is required to resist the energy attenuation during the delivery to the tumor site and may cause damage to the surrounding healthy tissues. Herein, a surface modification strategy is developed to simultaneously strengthen MRI and ultrasound ablation of MRgFUS by prolonging Fe3O4 nanoparticles' blood circulation and tumor-environment-triggered accumulation and retention at the tumor site. Specifically, reactive oxygen species-labile methoxy polyethylene glycol and pH-responsive DNA cross-linkers are modified on the surface of Fe3O4 nanoparticles, which can transform nanoparticles into aggregations through the cascade responsive reactions at the tumor site. Notably, DNA is selected as the pH-responsive cross-linker because of its superior biocompatibility as well as the fast and sensitive response to the weak acidity of 6.5-6.8, corresponding to the extracellular pH of tumor tissues. Due to the significantly enhanced delivery and retention amount of Fe3O4 nanoparticles at the tumor site, the MRI sensitivity was enhanced by 1.7-fold. In addition, the ultrasound power was lowered by 35% to reach a sufficient thermal ablation effect. Overall, this investigation demonstrates a feasible resolution to promote the MRgFUS treatment by enhancing the therapeutic efficacy and reducing the side effects, which will be helpful to guide the clinical practice in the future.

Improving the Therapeutic Efficiency of Hypoxic-Activated Prodrugs by Enhancing Hypoxia in Solid Tumors.

The low sensitivity of hypoxic regions in solid tumors to radiotherapy and chemotherapy remains a major obstacle to cancer treatment. By taking advantage of hypoxic-activated prodrugs, tirapazamine (TPZ), generating cytotoxic reductive products and the glucose oxidase (GOx)-based glucose oxidation reaction, we designed a nanodrug-loading system that combined TPZ-induced chemotherapy with GOx-mediated cancer-orchestrated starvation therapy and cancer oxidation therapy. In this work, we first prepared mesoporous silica (MSN) loaded with TPZ. Then, in order to prevent the leakage of TPZ in advance, the surface was coated with a layer of carMOF formed by Fe3+ and carbenicillin (car), and GOx was adsorbed on the outermost layer to form the final nanosystem MSN-TPZ@carMOF-GOx (MT@c-G). GOx could effectively consume oxygen and catalyzed glucose into gluconic acid and hydrogen peroxide. First, the generated gluconic acid lowered the pH of tumor tissues, promoted the decomposition of carMOF, and released TPZ. Second, oxygen consumption could improve the degree of hypoxia in tumor tissues, so that enhanced the activity of TPZ. Furthermore, GOx could generate cancer-orchestrated starvation/oxidation therapy. Therefore, our study provided a new strategy that TPZ combined with GOx achieved starvation/oxidation/chemotherapy for enhancing anticancer effects in hypoxic regions.

A reciprocal feedback of miR-548ac/YB-1/Snail induces EndMT of HUVECs during acidity microenvironment

BackgroundResearches indicated the process of Endothelial-Mesenchymal-Transition (EndMT) of vascular endothelial cells (ECs) was critically involved in the progression of tumor. ECs demonstrated functional and phenotypic heterogeneity when located under different microenvironments. The extracellular pH of tumor tissues was acidic compared to that of normal tissues. However, there was still unclear whether the acidic microenvironment affected the EndMT of vascular ECs.MethodsHuman Umbilical Vein Endothelial Cell (HUVECs) was cultured under the normal or acidic medium to evaluate the alteration of morphology, migration, permeability, and EndMT markers. Microarray assay was adopted to analyze the differential expression of miRNAs in the acidity-treated HUVECs. Gain- and loss- of function experiments were performed to evaluate the functional role of miRNA-548ac on acidity-induced EndMT of HUVECs. Luciferase reporter and Chromatin-immunoprecipitation assays were conducted to assess the downstream pathway of miRNA-548ac in acidity-induced EndMT of HUVECs.ResultsOur results showed that HUVECs demonstrated mesenchymal transition under acidic conditions with the increase of migration, permeability, and expression of α-SMA and Vimentin, but the expression of vascular endothelial cadherin (VE-cadherin) and CD31 were reduced. In addition, the acidity-treated HUVECs remarkably facilitated the transmigration of pancreatic cancer cells. The expression of miRNA-548ac was significantly decreased in the acidity-treated HUVECs. Moreover, overexpression of miR-548ac inhibited the EndMT of HUVECs and consequently impeded the transmigration of pancreatic cancer cells. The miR-548ac inhibited the expression of YB-1 by binding to the 3’UTR of its mRNA, and YB-1 promoted the translation of Snail which was a critical regulator of EndMT. What’s more, Snail transcriptionally inhibited the expression of miR-548ac through binding to the promoter of its host gene.ConclusionsOur data implicated that the acidic microenvironment promoted the EndMT of HUVECs by the miR-548ac/YB-1/Snail axis, which could contribute to the metastasis of pancreatic cancer.

Carbon Dots with Absorption Red-Shifting for Two-Photon Fluorescence Imaging of Tumor Tissue pH and Synergistic Phototherapy.

Phototherapy exhibits significant potential as a novel tumor treatment method, and the development of highly active photosensitizers and photothermal agents has drawn considerable attention. In this work, S and N atom co-doped carbon dots (S,N-CDs) with an absorption redshift effect were prepared by hydrothermal synthesis with lysine, o-phenylenediamine, and sulfuric acid as raw materials. The near-infrared (NIR) absorption features of the S,N-CDs resulted in two-photon (TP) emission, which has been used in TP fluorescence imaging of lysosomes and tumor tissue pH and real-time monitoring of apoptosis during tumor phototherapy, respectively. The obtained heteroatom co-doped CDs can be used not only as an NIR imaging probe but also as an effective photodynamic therapy/photothermal therapy (PDT/PTT) therapeutic agent. The efficiencies of different heteroatom-doped CDs in tumor treatment were compared. It was found that the S,N-CDs showed higher therapeutic efficiency than N-doped CDs, the efficiency of producing 1O2 was 27%, and the photothermal conversion efficiency reached 34.4%. The study provides new insight into the synthesis of carbon-based nanodrugs for synergistic phototherapy and accurate diagnosis of tumors.

PH and redox dual-responsive polymeric micelles with charge conversion for paclitaxel delivery

Here we demonstrate a type of pH and redox dual-responsive micelles, which were self-assembled in aqueous solution by an amphiphilic polymer, methoxypoly(ethylene glycol)-cystamine-poly(L-glutamic acid)-imidazole (mPEG-SS-PGA-IM). Considering tumor cells or tissues exhibiting low pH values and high glutathione (GSH) concentration, mPEG-SS-PGA-IM micelles possessed the charge conversion at pH of tumor tissues, which can facilitate cellular uptake of tumor cells. Furthermore, mPEG-SS-PGA-IM micelles can escape from endo/lysosomes based on the proton sponge effect, following degraded by higher concentration of GSH in cytoplasm. CLSM images of HCT116 cells indicated that mPEG-SS-PGA-IM micelles can escape from endo/lysosomes and enter cytoplasm. MTT assay showed that (paclitaxel) PTX-loaded mPEG-SS-PGA-IM micelles had higher cytotoxicity against HCT116 cells compared with PTX-loaded mPEG-PBLG and mPEG-SS-PBLG micelles. These results indicated that these mPEG-SS-PGA-IM micelles, as novel and effective pH- and redox-responsive nanocarriers, have great potential to both improve drug targeting efficiency while also enhancing the antitumor efficacy of PTX.

Recognition Sites for Cancer-targeting Drug Delivery Systems.

Target-homing drug delivery systems are now gaining significant attention for use as novel therapeutic approaches in antitumor targeting for cancer therapy. Numerous targeted drug delivery systems have been designed to improve the targeting effects because these systems can display a range of favorable properties, thus, providing suitable characteristics for clinical applicability of anticancer drugs, such as increasing the solubility, and improving the drug distribution at target sites. The majority of these targeting systems are designed with respect to differences between cancerous and normal tissues, for instance, the low pH of tumor tissues or overexpressed receptors on tumor cell membranes. Due to the growing number of targeting possibilities, it is important to know the tumor-specific recognition strategies for designing novel, targeted, drug delivery systems. Herein, we identify and summarize literature pertaining to various recognition sites for optimizing the design of targeted drug delivery systems to augment current chemotherapeutic approaches. This review focuses on the identification of the recognition sites for developing targeted drug delivery systems for use in cancer therapeutics. We have reviewed and compiled cancer-specific recognition sites and their abnormal characteristics within tumor tissues (low pH, high glutathione, targetable receptors, etc.), tumor cells (receptor overexpression or tumor cell membrane changes) and tumor cell organelles (nuclear and endoplasmic reticular dysregulation) utilizing existing scientific literature. Moreover, we have highlighted the design of some targeted drug delivery systems that can be used as homing tools for these recognition sites. Targeted drug delivery systems are a promising therapeutic approach for tumor chemotherapy. Additional research focused on finding novel recognition sites, and subsequent development of targeting moieties for use with drug delivery systems will aid in the evaluation and clinical application of new and improved chemotherapeutics.

A G2/M-phase specific drug delivery system based on increased exposure of phosphatidylethanolamine on mitotic cancer cells and low pH in tumor tissues

It is a challenge to carry G2/M-phase specific antitumor drugs into G2/M phase of cancer cells. For this purpose, we set up a pH-sensitive mixed micellar system based on poly(ethylene glycol)-b-poly(l-histidine) (PEG-PHIS) and poly(ethylene glycol)-b-poly(D, l-lactide) (PEG-PDLLA), and we used duramycin, a highly specific phosphatidylethanolamine-binding peptide, as a G2/M-phase specific targeting ligand to modify PEG-PDLLA. The mixed micelles were characterized by dynamic light scattering, electron microscopy and the pyrene fluorescence probe method. The G2/M-phase specific anti-cancer drug paclitaxel was loaded with a size of 189 ± 5 nm. And the drug-loading content and encapsulation efficiency were 14.7 ± 0.3% and 89.1 ± 2.5%, respectively. In addition, cytotoxicity assay showed that paclitaxel-loaded mixed micelles had effective antitumor effects, and the blank mixed micelles were safe. Importantly, the micelles showed pH sensitivity and G2/M-phase specific uptake. What's more, pharmacokinetic and in vivo imaging study showed that the mixed micelles displayed a prolonged circulation time and improved targeted accumulation at tumor sites. All these results suggest that the mixed micelle was a promising G2/M-phase specific drug delivery system.

Enzyme/pH-sensitive dendritic polymer-DOX conjugate for cancer treatment

It is in a great demand to design a biodegradable, tumor microenvironment-sensitive drug delivery system to achieve safe and highly efficacious treatment of cancer. Herein, a novel pH/enzyme sensitive dendritic pdiHPMA-DOX conjugate was designed. diHPMA dendritic copolymer with GFLG segments in the branches which are sensitive to the intracellular enzyme of the tumor was prepared through RAFT polymerization. DOX was attached to dendritic diHPMA polymer through a pH-sensitive hydrazone bond. The dendritic pdiHPMA-DOX conjugate self-assembled into nanoparticles with an ideal spherical shape at a mean size of 103 nm. The DOX attached to the polymeric carrier was released in an acidic environment, and the GFLG linker for synthesizing the dendritic vehicle with a high molecular weight ( M W, 220 kDa ) was cleaved to release low M W segments ( 40 kDa ) in the presence of cathepsin B. The dendritic polymeric conjugate was internalized via an endocytic pathway, and then released the anticancer drug, which led to significant cytotoxicity for tumors. The blood circulation time was profoundly prolonged, resulting in high accumulation of DOX into tumors. In vivo anti-tumor experiments with 4T1 tumor bearing mice demonstrated that the conjugate had a better antitumor efficacy in comparison with free DOX. Additionally, body weight measurements and histological examinations indicated that the conjugate showed low toxicities to normal tissues. This dendritic polymeric drug carrier in a response to intracellular enzyme and acidic pH of tumor tissue or cells holds great promise in tumor-targeted therapy.

Two-photon probes for pH: Detection of human colon cancer using two-photon microscopy.

607 Background: In cancer cells, lysosomal pH decreases along with a concomitant increase in lysosomal volume and cathepsin expression levels. Lysosomes also play crucial roles in cancer progression following their release into the extracellular space. Since cancer cells invade a tissue by secreting degradative enzymes, the extracellular pH of tumor tissues becomes acidic. However, to date, there has been no report on the use of multi-photon microscopy (MPM) probes to image human colon cancer tissues. Methods: We have developed multi-photon (MP) pH-sensitive probes (BH-2 and BHEt-1) that exhibit absorption and emission maxima at 370 and 466 nm, and TP absorption cross-section values of 51 and 61 GM (1 GM = 10−50 cm4 s/photon), respectively, at 750 nm and pH 3.0 in a universal buffer (0.1 M citric acid, 0.1 M KH2PO4, 0.1 M Na2B4O7, 0.1 M Tris, 0.1 M KCl)/1,4-dioxane (7/ 3) solution. Results: The TPM images of CCD-18co (a normal colon cell line) and HCT116 cells (a colon cancer cell line) labeled with BH-2 were too dim to be distinguished. When the same cells were labeled with BHEt-1, however, the MPM image of the HCT116 cells was much brighter than that of CCD-18co cells, and the relative proportion of the acidic vesicles (Pacid) of the former was 5-fold larger than that of latter. BHEt-1 could also differentiate HepG2 cells (a human liver cancer cell line) from LX-2 cells (a human hepatic stellate cell line) with a 6-fold larger P acid value. Human colon cancer tissues labeled with BHEt-1 showed similar results, demonstrating much brighter MPM images and 6-fold larger Pacid values compared to normal tissue. Conclusions: These results suggest the potential utility of BHEt-1 for molecular image analysis of colon cancer tissues using MPM.

Smart tetrazole-based antibacterial nanoparticles as multifunctional drug carriers for cancer combination therapy

Due to multidrug resistance of cancer tissues and immune-suppression of cancerous patients during chemotherapy in one hand and the use of tetrazole derivatives in medicine because of its anticancer, antifungal, and antiviral properties, on the other, we were encouraged to design novel smart antibacterial nanocomposites-based polymer of tetrazole as dual anticancer drug delivery systems. The structures of nanocomposites characterized by FTIR, 1H NMR, FESEM-EDX, and TGA analyzes and antibacterial activity of smart carriers were evaluated by determination of minimum inhibitory concentration (MIC) values against some bacteria and fungi. Then, the pH-responsive manner of both nanocomposites was proved by checking their release profiles at pH of the physiological environment (pH 7.4) and pH of tumor tissues (mildly acidic). Finally, the potential antitumoral activity of these nanocomposite systems against MCF7 cell lines was evaluated by MTT assay and cell cycle studies. The results demonstrated that the novel developed nanocomposites not only meet our expectations about simultaneous release of two anticancer drugs according to the predicted profile but also showed antibacterial and anticancer properties in vitro experimental. Moreover, it was proved that these carriers have tremendous potential in multifunctional drug delivery in cancer therapy.

PH-responsive drug release from functionalized electrospun poly(caprolactone) scaffolds under simulated in vivo environment

The difference in the tumor environment from the normal healthy tissue can be therapeutically exploited to develop new strategies for controlled and site-specific drug delivery. In the present study, a continuous flow system is designed to represent the in vivo environment of a tumor tissue and drug release is studied at different pH that represents normal tissue pH, tumor tissue pH, and stomach pH. The results obtained from these experiments were translated to a human embryonic kidney cell culture system and the effect of drug released from these functionalized PCL scaffolds on cell viability was studied. A significant decrease in cell viability was observed with the doxorubicin hydrochloride concentration that would be released at acidic pH, either present as a result of tumor extracellular environment or could be achieved via fabrication of a composite scaffold with a polyvinyl alcohol hydrogel containing acid. In the end, a study using zebrafish as an animal model is also undertaken in order to study the drug release from the scaffolds in vivo.

Loading of Gemcitabine on chitosan magnetic nanoparticles increases the anti-cancer efficacy of the drug

Targeted delivery of anti-cancer drugs increase the efficacy, while decreasing adverse effects. Among various delivery systems, chitosan coated iron oxide nanoparticles (CsMNPs) gained attention with their biocompatibility, biodegradability, low toxicity and targetability under magnetic field. This study aimed to increase the cellular uptake and efficacy of Gemcitabine.CsMNPs were synthesized by in situ co-precipitation and Gemcitabine was loaded onto the nanoparticles. Nanoparticle characterization was performed by TEM, FTIR, XPS, and zeta potential. Gemcitabine release and stability was analyzed. The cellular uptake was shown. Cytotoxicity of free-Gemcitabine and Gem-CsMNPs were examined on SKBR and MCF-7 breast cancer cells by XTT assay.Gemcitabine loading was optimized as 30µM by spectrophotometric analyses. Drug release was highest (65%) at pH 4.2, while it was 8% at pH 7.2. This is a desired release characteristic since pH of tumor-tissue and endosomes are acidic, while the blood-stream and healthy-tissues are neutral. Peaks reflecting the presence of Gemcitabine were observed in FTIR and XPS. At neutral pH, zeta potential increased after Gemcitabine loading. TEM images displayed, Gem-CsMNPs were 4nm with uniform size-distribution and have spherical shape. The cellular uptake and targetability of CsMNPs was studied on MCF-7 breast cancer cell lines. IC50 value of Gem-CsMNPs was 1.4 fold and 2.6 fold lower than free-Gem on SKBR-3 and MCF-7 cell lines respectively, indicating the increased efficacy of Gemcitabine when loaded onto nanoparticles.Targetability by magnetic field, stability, size distribution, cellular uptake and toxicity characteristics of CsMNPs in this study provides a useful targeted delivery system for Gemcitabine in cancer therapy.

Respiration gating and Bloch fitting improve pH measurements with acidoCEST MRI in an ovarian orthotopic tumor model.

We have developed a MRI method that can measure extracellular pH in tumor tissues, known as acidoCEST MRI. This method relies on the detection of Chemical Exchange Saturation Transfer (CEST) of iopamidol, an FDA-approved CT contrast agent that has two CEST signals. A log10 ratio of the two CEST signals is linearly correlated with pH, but independent of agent concentration, endogenous T1 relaxation time, and B1 inhomogeneity. Therefore, detecting both CEST effects of iopamidol during in vivo studies can be used to accurately measure the extracellular pH in tumor tissues. Past in vivo studies using acidoCEST MRI have suffered from respiration artifacts in orthotopic and lung tumor models that have corrupted pH measurements. In addition, the non-linear fitting method used to analyze results is unreliable as it is subject to over-fitting especially with noisy CEST spectra. To improve the technique, we have recently developed a respiration gated CEST MRI pulse sequence that has greatly reduced motion artifacts, and we have included both a prescan and post scan to remove endogenous CEST effects. In addition, we fit the results by parameterizing the contrast of the exogenous agent with respect to pH via the Bloch equations modified for chemical exchange, which is less subject to over-fitting than the non-linear method. These advances in the acidoCEST MRI technique and analysis methods have made pH measurements more reliable, especially in areas of the body subject to respiratory motion.

Zwitterionic polymeric micelles that undergo a pH-triggered positive charge for enhanced cellular uptake

To achieve a good stealth property and to enhance the uptake by tumor cells, polymeric micelles containing a slightly negatively charged and zwitterionic corona at pH 7.4 (i.e., blood pH) and a positively charged surface at a slightly acidic pH (i.e., tumor extracellular pH) were prepared. The amphiphilic diblock copolymer which was used to prepare the polymeric micelles contains a hydrophilic block comprised of nonionic hydrophilic groups, negatively charged groups (carboxyl groups) and pH-triggered positive charge-generation groups (morpholino groups). The zeta potential of the micelles was found to increase as the pH decreased over the pH range covering the blood and tumor tissue pH ranges, and the corona of the micelles should contain zwitterionic groups. This could be due to that, in the pH range studied, more morpholino groups become protonated as the pH decreased, whereas the carboxyl groups were almost completely deprotonated to form carboxylate anions. Furthermore, by adjusting the molar ratio of morpholino to carboxyl groups, the zeta potential of the polymeric micelles was controlled to achieve a slightly negative value at pH 7.4. Thus, the combination of a slightly negatively charged surface and a zwitterionic corona suggests that these micelles would possess good stealth property. When the pH decreased from 7.4 to 6.8 or 6.5, the zeta potential value of the micelles became positive due to increased protonation of the morpholino groups. Correspondingly, the cellular uptake of the micelles by HeLa cells was enhanced.

A reduction and pH dual-sensitive polymeric vector for long-circulating and tumor-targeted siRNA delivery.

A novel reduction and pH dual-sensitive nonviral vector for long-circulating and tumor-targeted siRNA delivery is described. The nanomedicine is negatively charged at neutral pH of bloodstream whereas it is positively charged at lower pH of tumor tissue (ca. 6.8). Interlayer crosslinking with disulfide bonds stabilizes the nanomedicine during blood circulation and allows quick intracellular siRNA release after endocytosis.

Two step mechanisms of tumor selective delivery of N-(2-hydroxypropyl)methacrylamide copolymer conjugated with pirarubicin via an acid-cleavable linkage

N-(2-Hydroxypropyl)methacrylamide copolymer containing hydrazide groups (PHPMA) conjugated with pirarubicin (THP) via a hydrazone bond (PHPMA-hyd-THP) is a drug conjugate that releases THP in the acidic milieu of a tumor. PHPMA-hyd-THP has an apparent Mw of 40,000 and a hydrodynamic diameter of 8.2±1.7nm but no apparent plasma protein binding. PHPMA-hyd-THP possesses two mechanisms of selectivity toward solid tumors and has potent antitumor action. The first one is drug accumulation in tumors that depends on the enhanced permeability and retention (EPR) effect, which results in a 4–20 times higher concentration of drug in the tumor than in normal tissues such as the heart, lung, and intestine. This accumulation in tumor tissue is in great contrast to that of conventional low-Mw THP. The second one is pH-dependent release of drug from PHPMA-hyd-THP: this conjugate released free THP more efficiently at a lower pH, which exists in tumors, and exerts cytotoxic activity. Free THP is known for its much faster uptake into tumor cells compared with doxorubicin. Thus, in our in vitro study, PHPMA-hyd-THP showed a higher cytotoxicity at the lower pH of tumor tissue than at the neutral pH of normal tissue. Furthermore, much more THP was liberated from the conjugate in acidic tumor tissue than in normal tissue. The EPR effect-dependent accumulation of PHPMA-hyd-THP and tumor-selective THP release in the tumor tissues led to highly tumor-selective drug accumulation, which continued for more than 72h, whereas the lowest free drug concentration was detected in normal tissues at 24h and no longer at a later time. In conclusion, we determined in our study here that the acid-cleavable PHPMA-hyd-THP conjugate had an excellent antitumor effect without appreciable adverse effects.

Noncovalent Functionalization of Carbon Nanotubes by Fluorescent Polypeptides: Supramolecular Conjugates with pH-Dependent Absorbance and Fluorescence

Fluorescent cut single-walled carbon nanotube (CSWCNT) were prepared by simply mixing CSWCNT with water soluble rhodamine 6G (Rh6G) conjugated poly(3,4-dihydroxyphenylalanine) and poly(L-tyrosine) to form highly stable product with good dispersity in buffer solution. The optical absorbance and fluorescence spectra of the resulting fluorescent CSWCNT display interesting pH-dependent optical properties, emitting strong fluorescence only in acidic environment. Considering the extracellular pH of tumor tissue is acidic, the pH-sensitive conjugates have advantages to sense tumor cells selectively, enabling it to be utilized as a biosensor for detecting cancer cells. The protocol employed to functionalize the CSWCNT with Rh6G conjugated polypeptides in aqueous solution is proven to be direct, fast and easily scalable.

One-Pot Construction of Functional Mesoporous Silica Nanoparticles for the Tumor-Acidity-Activated Synergistic Chemotherapy of Glioblastoma

Mesoporous silica nanoparticles (MSNs) have proved to be an effective carrier for controlled drug release and can be functionalized easily for use as stimuli-responsive vehicles. Here, a novel intelligent drug-delivery system (DDS), camptothecin (CPT)-loaded and doxorubicin (DOX)-conjugated MSN (CPT@MSN-hyd-DOX), is reported via a facile one-pot preparation for use in synergistic chemotherapy of glioblastoma. DOX was conjugated to MSNs via acid-labile hydrazone bonds, and CPT was loaded in the pores of the MSNs. At pH 6.5 (analogous to the pH in tumor tissues), a fast DOX release was observed that was attributed to the hydrolysis of the hydrazone bonds. In addition, a further burst release of DOX was found at pH 5.0 (analogous to the pH in lyso/endosomes of tumor cells), leading to a strong synergistic effect. In all, CPT and DOX could be delivered simultaneously into tumor cells, and this intelligent DDS has great potential for tumor-trigged drug release for use in the synergistic chemotherapy of tumors.

Ultrasound and pH Dually Responsive Polymer Vesicles for Anticancer Drug Delivery

Recently, smart polymer vesicles have attracted increasing interest due to their endless potential applications such as tunable delivery vehicles for the treatment of degenerative diseases. However, the evolution of stimuli-responsive vesicles from bench to bedside still seems far away for the limitations of current stimuli forms such as temperature, light, redox, etc. Since ultrasound combined with chemotherapy has been widely used in tumor treatment and the pH in tumor tissues is relatively low, we designed herein a novel polymer vesicle that respond to both physical (ultrasound) and chemical (pH) stimuli based on a PEO-b-P(DEA-stat-TMA) block copolymer, where PEO is short for poly(ethylene oxide), DEA for 2-(diethylamino)ethyl methacrylate and TMA for (2-tetrahydrofuranyloxy)ethyl methacrylate. These dually responsive vesicles show noncytotoxicity below 250 μg/mL and can encapsulate anticancer drugs, exhibiting retarded release profile and controllable release rate when subjected to ultrasound radiation or varying pH in tris buffer at 37°C.