Tissues pH Research Articles

Monitoring the Dilution of Buffer Solutions with Different pH Values above and below Physiological pH in Very Small Volumes.

The accurate determination of the post-dilution concentration of biological buffers is essential for retaining the necessary properties and effectiveness of the buffer to maintain stable cellular environments and optimal conditions for biochemical reactions. In this work, we introduce a silicon-based impedance chip, which offers a rapid and reagent-free approach for monitoring the buffer concentrations after dilution with deionized (DI) water. The impedance of the impedance chip is measured, and the impedance data are modeled using a multiparameter equivalent circuit model. We investigated six aqueous biological buffers with pH values above and below the physiological pH for most tissues (pH ~ 7.2-7.4) following dilution with DI water by factors of 2.0, 10.0, 20.0, 100.0, and 200.0. The impedance measurement is then performed for the frequency spectrum of 40 Hz to 1 MHz. From the interpretation of the impedance measurement using the multiparameter equivalent circuit model, we report a buffer-sensitive equivalent circuit parameter RAu/Si of the silicon-based impedance chip showing a linear trend on a logarithmic scale with the buffer concentration change after dilution. The parameter RAu/Si is independent of the buffer pH and the added volume. The results demonstrate the efficacy of the silicon-based impedance chip as a versatile tool for precise post-dilution concentration determination of diverse biologically relevant buffers. The presented impedance chip offers rapid, accurate, and reliable monitoring, making it highly suitable for integration into automated liquid-handling systems to enhance the efficiency and precision of biological and chemical processes.

Counterion-induced antibiotic-based small-molecular micelles for methicillin-resistant Staphylococcus aureus infections.

A new counterion-induced small-molecule micelle (SM) with surface charge-switchable activities for methicillin-resistant Staphylococcus aureus (MRSA) infections is proposed. The amphiphilic molecule formed by zwitterionic compound and the antibiotic ciprofloxacin (CIP), via a "mild salifying reaction" of the amino and benzoic acid groups, can spontaneously assemble into counterion-induced SMs in water. Through vinyl groups designed on zwitterionic compound, the counterion-induced SMs could be readily cross-linked using mercapto-3, 6-dioxoheptane by click reaction, to create pH-sensitive cross-linked micelles (CSMs). Mercaptosuccinic acid was also decorated on the CSMs (DCSMs) by the same click reaction to afford charge-switchable activities, resulting in CSMs that were biocompatible with red blood cells and mammalian cells in normal tissues (pH 7.4), while having strong retention to negatively charged bacterial surfaces at infection sites, based on electrostatic interaction (pH 5.5). As a result, the DCSMs could penetrate deep into bacterial biofilms and then release drugs in response to the bacterial microenvironment, effectively killing the bacteria in the deeper biofilm. The new DCSMs have several advantages such as robust stability, a high drug loading content (∼ 30%), easy fabrication, and good structural control. Overall, the concept holds promise for the development of new products for clinical application. STATEMENT OF SIGNIFICANCE: We fabricated a new counterion-induced small-molecule micelle with surface charge-switchable activities (DCSMs) for methicillin-resistant Staphylococcus aureus (MRSA) infections. Compared with reported covalent systems, the DCSMs not only have improved stability, high drug loading content (∼ 30%), and good biosafety, but also have the environmental stimuli response, and antibacterial activity of the original drugs. As a result, the DCSMs exhibited enhanced antibacterial activities against MRSA both in vitro and in vivo. Overall, the concept holds promise for the development of new products for clinical application.

Charge-Convertible and Reduction-Sensitive Cholesterol-Containing Amphiphilic Copolymers for Improved Doxorubicin Delivery.

For achieving successful chemotherapy against cancer, designing biocompatible drug delivery systems (DDSs) with long circulation times, high cellular endocytosis efficiency, and targeted drug release is of upmost importance. Herein, a well-defined PEG-b-P(MASSChol-co-MANBoc) block copolymer bearing redox-sensitive cholesteryl-side group was prepared via reversible addition-fragmentation chain transfer (RAFT) polymerization (with non-redox PEG-b-P(MACCChol-co-MAN-DCA) as the reference), and 1,2-dicarboxylic-cyclohexene acid (DCA) was then grafted onto the hydrophobic block to endow it with charge-convertible characteristics under a tumor microenvironment. The amphiphilic copolymer could be assembled into polymeric spherical micelles (SSMCs) with polyethylene glycol (PEG) as the corona/shell, and anti-cancer drug doxorubicin (DOX) was successfully encapsulated into the micellar core via strong hydrophobic and electrostatic interactions. This nanocarrier showed high stability in the physiological environment and demonstrated “smart” surface charge conversion from negative to positive in the slightly acidic environment of tumor tissues (pH 6.5~6.8), as determined by dynamic light scattering (DLS). Moreover, the cleavage of a disulfide bond linking the cholesterol grafts under an intracellular redox environment (10 mM GSH) resulted in micellar dissociation and accelerated drug release, with the non-redox-responsive micelles (CCMCs) as the control. Additionally, a cellular endocytosis and tumor proliferation inhibition study against MCF-7 tumor cells demonstrated the enhanced endocytosis and tumor cell inhibitory efficiency of dual-responsive SSMCs/DOX nanomedicines, revealing potentials as multifunctional nanoplatforms for effective oncology treatment.

Antibacterial Vancomycin@ZIF-8 Loaded PVA Nanofiber Membrane for Infected Bone Repair.

Bone substitutes with strong antibacterial properties and bone regeneration effects have an inherent potential in the treatment of severe bone tissue infections, such as osteomyelitis. In this study, vancomycin (Van) was loaded into zeolitic imidazolate framework-8 (ZIF-8) to prepare composite particles, which is abbreviated as V@Z. As a pH-responsive particle, ZIF-8 can be cleaved in the weak acid environment caused by bacterial infection to realize the effective release of drugs. Then, V@Z was loaded into polyvinyl alcohol (PVA) fiber by electrospinning to prepare PVA/V@Z composite bone filler. The drug-loading rate of V@Z was about 6.735%. The membranes exhibited super hydrophilicity, water absorption and pH-controlled Van release behavior. The properties of anti E. coli and S. aureus were studied under the pH conditions of normal physiological tissues and infected tissues (pH 7.4 and pH 6.5, respectively). It was found that the material had good surface antibacterial adhesion and antibacterial property. The PVA/V@Z membrane had the more prominent bacteria-killing effect compared with the same amount of single antibacterial agent containing membrane such as ZIF-8 or Van loaded PVA, and the antibacterial rate was up to 99%. The electrospun membrane had good biocompatibility and can promote MC3T3-E1 cell spreading on it.

A Magnetocatalytic Propelled Cobalt–Platinum@Graphene Navigator for Enhanced Tumor Penetration and Theranostics

A Magnetocatalytic Propelled Cobalt–Platinum@Graphene Navigator for Enhanced Tumor Penetration and Theranostics

A high stable pH-temperature dual-sensitive liposome for tuning anticancer drug release

In order to improve the targeting and availability of liposomes to cancer cells, the temperature sensitivity of 1, 2-Dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and the pH sensitivity of PASP in PASP-g-C8 are incorporated in a drug delivery system. A composite pH-temperature dual-sensitive liposomes (CPTLPs) was obtained as an efficient drug delivery system. The bionic bilayer is self-assembled by cholesterol/cationic temperature-sensitive lipids as base layer and pH-sensitive octylamine grafted poly aspartic acid (PASP-g-C8) as anchors coated outside. Cytarabine (CYT) was chosen as a model drug. SEM and DLS were used to observe the morphology characteristics of CPTLPs in different micro environment. The results demonstrated that the CPTLPs remained active in both normal (pH7.4 and 37 °C) and tumor tissues (pH 5.0 and 42 °C). As a stable colloidal system, the zeta potential of CPTSLs was −41.6 mV. In vitro drug-release experiments, the CTY encapsulated dual-sensitive liposomes, CPTSLs(+), not only have significant pH-temperature sensitivity but have more prolonged release in vitro than control groups. MTT tests results indicated that the cell apoptotic effects induced by CPTSLs(+) were nearly 30% higher than the naked drug CTY in HepG2 cells, and 20% lower apoptotic in vero cells. The CPTSLs(+) sustained a stable emulsion form, less toxic effects on normal cells, and exhibited a good pH-temperature sensitivity, thus expected to be a promising tumor targeting drug delivery.

Bioinspired Membrane-Disruptive Macromolecules as Drug-Free Therapeutics.

Membrane-disruptive, drug-free macromolecular therapeutics may help overcome cancer drug-resistance. Their inability to distinguish cancerous from normal cells, however, results in significant off-target toxicity. Note that the tumor has a slightly acidic microenvironment (pH 6.5-6.8) in contrast to the alkaline microenvironment in normal tissues (pH 7.4) and that host-defense peptides (HDPs) and their synthetic mimetics need to be net cationic to be membrane-disruptive. We herein endow polymer mimetics of HDPs with acid-triggered cationicity, to make them membrane-disruptive at only tumor pH. For these polymer mimetics, there exists a maximal threshold of chain length that determines whether the micelle of a mimetic inherits its pH-sensitive activity. Using the most and least active micelles as representatives, we find that their distinct potency in disrupting membranes arises because of their striking tendency to dissociate upon exposure to tumor pH. As expected, these micelles exhibit in vitro cytotoxicity profiles that correlate with their membrane-disruptive activity profiles. When administered intravenously, these micelles-irrespective of their distinct activity profiles-unanimously exhibit long systemic circulation as do PEGylated micelle nanoparticles, despite of their lacking stealth materials, owing to the zwitterionic nature of their surfaces at blood pH. Nevertheless, the pH-sensitive micelle achieves significantly higher tumor uptake and strikingly better therapeutic efficacy than its completely inactive analogue. More important, the pH-sensitive micelle exhibits undetectable off-target toxicity, owing to its pH-sensitivity. Clearly, making HDPs and their mimetics sensitive to tumor-characteristic cues (e.g., acidic pH) is efficient in minimizing their off-target toxicity, thereby offering membrane-disruptive, drug-free macromolecular therapeutics for fighting against cancer drug-resistance.

A porous Cu(II)-based metal-organic framework carrier for pH-controlled anticancer drug delivery

A new metal-organic framework with suitable channel size and good stability in biological buffer solution was investigated to load 5-fluorouracil (5-FU) though a simple adsorption process. The successful loading of 5-Fu was confirmed by the gas sorption measurement and the loading capacity was characterized by UV–Vis spectroscopy, which reveal a drug loading of 37.22%. The drug delivery in the simulated cancerous tissues (pH = 5.8 and 6.8) exhibited a more progressive release in comparison with that in the normal tissues (pH = 7.4), demonstrating a physiological pH-responsive drug release. Furthermore, as demonstrated by the MTT assay, this drug/MOF composite shows low cytotoxicity, good biocompatibility, and anticancer activity against cell lines A549 and HeLa. The result shows that 1 could be taken as a potential drug carrier.

PH-sensitive loading/releasing of doxorubicin using single-walled carbon nanotube and multi-walled carbon nanotube: A molecular dynamics study

Background and objectiveDoxorubicin is one of the drugs used to treat cancer, and many studies have been conducted to control its release. In this study, carbon nanotubes have been proposed as a doxorubicin carrier, and the effect of carboxyl functional group on the controlled release of doxorubicin has been studied. MethodsThis study has been done by molecular dynamics simulation and was based on changing the pH as a mechanism controller. ResultsThis work is intended to test the efficacy of this drug carrier for the release of doxorubicin. A comparison was also made between single-walled and double-walled carbon nanotubes to answer the question of which one can be a better carrier for doxorubicin. The study of DOXORUBICIN adsorption and release showed that the DOXORUBICIN adsorption on single-walled carbon nanotube and multi-walled carbon nanotube in neutral pH was stronger than it was in acidic pH, which could be due to the electrostatic interactions between the carboxyl group of nanotubes and DOXORUBICIN. Based on this and according to the investigation of hydrogen bonds, diffusion coefficients, and other results it was clear that the drug release in acidic pH was appropriate for body conditions. Since cancer tissues pH is acidic, this shows the suitability of carbon nanotube in drug delivery and DOXORUBICIN release in cancer tissues. In addition, it was shown that the blood pH (pH = 7) is suitable for DOXORUBICIN loading on the carbon nanotube and carbon nanotube-DOXORUBICIN linkage remained stable at this pH; accordingly, the carbon nanotube could deliver DOXORUBICIN in blood quite well and release it in cancerous tissues. This suggests the carbon nanotubes as a promising drug carrier in the cancer therapy which can be also investigated in experiments. ConclusionIt was revealed that the bonds between multi-walled carbon nanotube and DOXORUBICIN was stronger and this complex had a slower release in the cancer tissues compared to the single-walled carbon nanotube; this can be regarded as an advantage over the single-walled carbon nanotube in the DOXORUBICIN delivery and release.

Preparation of Immunotherapy Liposomal-Loaded Thermal-Responsive Hydrogel Carrier in the Local Treatment of Breast Cancer.

To reduce the side effects of immune drugs and the sustainable release of immune drugs on local parts, we have designed an injectable thermal-sensitive hydrogel containing an imiquimod-loaded liposome system. In the extracellular environment of tumor tissues (pH 6.4), 50% of the drug was released from the carrier, which could be a result of the morphological changes of the liposomal microstructure in the acidic environment. According to the results in animals, the drug-containing liposomes combined with hydrogel can be effectively applied in breast cancer therapy to delay the growth of tumors as well as to dramatically reduce the death rate of mice.

Electrolyzed acid water: A clean technology active on fungal vascular pathogens in grapevine nurseries

Phaeomoniella chlamydospora (Pc) and Phaeoacremonium minimum (Pm) are among the main grapevine trunk disease pathogens affecting vines in the nursery. These pathogens can cause infections of the propagation material often appearing as dark wood streaking, and are associated with decline occurrence in young vineyards. The infection may occur during the grafting process, particularly during hydration. Promising preliminary results were obtained in the nursery using electrolyzed acid water (EAW) for the hydration of cuttings; EAW is characterized by low values of pH (2.5), high oxidation reduction potential (ORP>1000) and a certain amount of free chlorine. No differences in absorption kinetics were recorded between EAW and tap water, nor among 1103P, K5BB and SO4 rootstocks. In all combinations no significant additional absorption was observed after 7 h of immersion. In order to assess the characteristics of EAW after the contact with the inner plant tissues ORP and pH were measured from the liquid extracted from rootstocks after immersion in EAW. The values of the liquid, named “weakened” EAW (wEAW) (625–650 mV ORP and 3.1–3.3 pH), were significantly different from the values of both EAW and the liquid extracted after immersion in tap water. When the propagation material was hydrated for 7 h in EAW no significant effect on vegetating growth performance and percentage of certifiable plants was observed for SO4 or 1103P, whereas a reduction in plant vegetative growth was observed in K5BB hydrated vines at 12hr hydration. EAW and wEAW gave no significant reduction of in vitro mycelial growth, whereas a consistent decrease in conidial germination was observed in Pc and Pm. The three-year experiments carried out in the nursery on cuttings inoculated with Pc and hydrated in EAW showed a remarkable reduction of the infection level in the treated plants.

Silver nanoparticles with pH induced surface charge switchable properties for antibacterial and antibiofilm applications.

Silver nanoparticles (AgNPs) are widely used as antibacterial agents because of their significant antimicrobial activities and little sign of antimicrobial resistance. However, the relatively high toxicity to healthy cells and low penetration efficiency into bacterial biofilms prevent their further use in biomedical applications. In order to decrease the cytotoxicity of the AgNPs to mammalian cells while increasing their antibacterial and antibiofilm efficiency, a novel nanocomposite composed of AgNPs decorated with carboxyl betaine groups (AgNPs-LA-OB) was prepared. The zwitterion modified AgNPs showed a pH responsive transition from a negative charge to a positive charge, which enabled the AgNPs to be compatible with mammalian cells and red blood cells (RBCs) in healthy tissues (pH ∼ 7.4), while strongly adhering quickly to negatively charged bacterial surfaces at infectious sites (pH ∼ 5.5) based on electrostatic attraction. The AgNPs penetrated deeply into bacterial biofilms and killed the bacteria living in an acidic environment. The results indicated that the designed zwitterion NPs for antibacterial applications and eradication of bacterial biofilms, which also had particles that did not harm the healthy cells showed promise for future use in humans. The satisfactory selectivity for bacteria compared to RBCs, together with their potent eradication of bacterial biofilms make AgNPs-LA-OB a promising antibacterial nanomedicine in biomedical fields.

RETRACTED ARTICLE: A Low Cytotoxic Metal–Organic Framework Carrier: pH-Responsive 5-Fluorouracil Delivery and Anti-Cervical Cancer Activity Evaluation

A new porous metal–organic framework (MOF) [Zn2(ad)2(fmdb)(H2O)](DMF)3 (1, DMF = N,N-dimethylformamide) based on zinc(II) ions, biomolecular adenine (Had) and 4,4′-(fluoromethylene)dibenzoic acid (H2fmdb) has been successfully obtained via a one-pot solvothermal reaction. The structural analysis via the single crystal X-ray diffraction reveals that compound 1 locates in the monoclinic space group C2/c and demonstrates a three-dimensional channel-type neutral framework. The as-prepared complex 1 exhibits low toxicity by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium (MTT) assay, revealing its potential application in human health care. In light of its nano-sized channel space and good stability in biological buffers solution, the activated compound 1 (1a) has been applied as a carrier for loading the anticancer drug 5-Fu (5-Fluorouracil) though a simple adsorption process. The successful loading of 5-Fu was confirmed by the gas sorption measurement and the loading capacity was determined by UV–Vis spectroscopy, which reveals a drug loading capacity of 44.6 wt%. The drug delivery in the simulated cancerous tissues (pH = 5.0) exhibited a more complete release in comparison with that in the normal tissues (pH = 7.4), demonstrating the compound 1a could be potentially used as a pH-controlled drug delivery carrier. In connection to these, in vitro anticancer activity of 5-Fu loaded 1a was also evaluated using MTT assays against two human cervical cancer cells HeLa and SiHa.

A low cytotoxic porous zinc-adeninate metal-organic framework carrier: pH-triggered drug release and anti-breast cancer study

In this study, a new zinc-based porous metal-organic framework (MOF) [Zn2(ad)2(hmdb)(H2O)](DMF)2(H2O) based on zinc(II) ions, biomolecular adenine (Had) and 4,4′-(hydroxymethylene)dibenzoic acid (H2hmdb) has been successfully prepared under solvothermal conditions. The X-ray study reveals that compound 1 belongs to the monoclinic space group C2/c and reveals a three-dimensional channel-type neutral framework. This MOF exhibits low toxicity by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium (MTT) assay. Due to its suitable channel size and good stability in biological buffer solution, the activated 1 has been used as a carrier for loading the anticancer drug 5-Fu (5-fluorouracil) though a simple adsorption process. The successful loading of 5-Fu was confirmed by the gas sorption measurement and the loading capacity was characterized by UV–Vis spectroscopy, which reveal a drug loading of 32.2 wt%. The drug delivery in the simulated cancerous tissues (pH = 5.0) exhibited a more effective release in comparison with that in the normal tissues (pH = 7.4), demonstrating a physiological pH-responsive drug release. Furthermore, in vitro cytotoxicity of 1 and 5-Fu loaded 1a was also evaluated using MTT assays against HepG2 and MCF-7 cells. A new zinc-based porous metal-organic framework (MOF) has been successfully prepared under solvothermal conditions. Due to its suitable channel size and good stability in biological buffers solution, compound 1 has been used as a carrier for loading the anticancer drug 5-Fu (5-fluorouracil) though a simple adsorption process. The drug-loaded MOF demonstrates a physiological pH-responsive drug release.

Dual-pH-sensitive mesoporous silica nanoparticle-based drug delivery system for tumor-triggered intracellular drug release

Reducing the side effects and improving the drug utilization are important work in anti-cancer drug delivery. In this paper, a novel dual-pH-sensitive drug delivery system was reported. Mesoporous silica nanoparticle (MSN) was applied to load anti-cancer drug doxorubicin hydrochloride (DOX) and was covered by mono-6-deoxy-6-EDA-β-cyclodextrine (β-CD-NH2) to block the pores through pH-sensitive boronate ester bond. And the carriers were then coated with methoxy poly(ethylene glycol) (mPEG) through another pH-sensitive benzoic imine bond. mPEG leaving studies, in vitro cellular uptake studies and the flow cytometry analysis, proved that carriers was “stealthy” at pH 7.4, but could be “activated” for cytophagy by cancer cells in weakly acidic tumor tissues (pH 6.5) due to the departure of mPEG. β-CD-NH2 leaving studies, the in vitro drug release studies and the in vitro cytotoxicity studies proved that boronate ester bond linking MSN and β-CD-NH2 was stable at both pH 7.4 and 6.5, but could be hydrolyzed intracellular to release DOX for cellular apoptosis due to the lower pH (5.0). In summary, the novel dual-pH-sensitive drug delivery system fabricated with a dynamic protection strategy should have great application potential in anti-cancer drug delivery fields.

Acid-sensitive polymeric vector targeting to hepatocarcinoma cells via glycyrrhetinic acid receptor-mediated endocytosis

Liver cancer is one of the top death causing cancers, traditional treatments have not settled for the requirement of patients. In this work, a smart acid-responsive micelle based on glycyrrhetinic acid modified chitosan-polyethyleneimine-4-Hydrazinobenzoic acid-doxorubicin (GA-CS-PEI-HBA-DOX) was synthesized for targeted delivery of DOX to liver cancer. A dual pH-sensitive and receptor-mediated strategy has been exploited to enhance the delivery efficiency. The micelle possesses positive charges under pH 6.8 and can be turned into negative charges above pH 7.0, which help to be accumulated in tumor tissues (pH 6.0–7.0). In the intracellular environment (pH 4.5–6.5) of tumor cells, the pH-sensitive hydrazone bonds between DOX and GA-CS-PEI-HBA would break and release as much as 90.3% of the encapsulated payloads in 48 h. In addition, GA was modified to improve the targeting abilities. The micelles exhibited high lethality to HepG2 cells while showed much lower cytotoxicity to HUVEC cells. With high drug-loading capacity and the targeted release ability, the GA-CS-PEI-HBA-DOX micelle might be employed as a promising candidate for targeted cancer treatment.

Biodegradable Polymeric Micelle-Mediated Delivery of a pH-Activatable Prodrug of 7-Ethyl-10-Hydroxy-Camptothecin (SN-38) to Enhance Anti-Angiogenesis and Anti-Tumor Activity.

7-Ethyl-10-hydroxy-camptothecin (SN-38), an efficient topoisomerase inhibitor, is the biological metabolite of irinotecan used as the first-line chemotherapy drug for colon cancer. However, the hydrophobicity and instability of SN-38 limit its further clinical application. In this study, to improve water dispersity and the anti-tumor efficiency of SN-38, a prodrug, SN-38-BOC, that could efficiently transform to active SN-38 in the acidic tumor microenvironment was synthesized and encapsulated into MPEG-P(CL-ran-TMC) micelles (SN-38-BOC micelles). SN-38-BOC micelles could accumulate in tumors due to the EPR effect and exhibit a sustained release behavior, which was rapidly transformed to active SN-38 by the acidic environment of tumor tissues (pH 5.5-6.8), thus achieving efficient anti-tumor activity. Compared with the free SN-38-BOC group, enhanced cytotoxicity and apoptotic induction were obtained from the SN-38-BOC micelle-treated group in both HCT116 and CT26 cells. In addition, SN-38-BOC micelles showed more effective anti-angiogenesis than free SN-38-BOC in a transgenic zebrafish model. Furthermore, SN-38-BOC micelles exhibited stronger inhibition of tumor growth in both HCT116 and CT26 subcutaneous xenograft tumor models. Histological analysis revealed that SN-38-BOC micelles showed a more effective anti-tumor activity than the free drug by inducing more apoptosis, inhibiting angiogenesis, and suppressing proliferation. Thus, the pH-activatable SN-38-BOC micelle could serve as a promising candidate in colorectal tumor therapy.

Surface-Adaptive Gold Nanoparticles with Effective Adherence and Enhanced Photothermal Ablation of Methicillin-Resistant Staphylococcus aureus Biofilm.

Biofilms that contribute to the persistent bacterial infections pose serious threats to global public health, mainly due to their resistance to antibiotics penetration and escaping innate immune attacks by phagocytes. Here, we report a kind of surface-adaptive gold nanoparticles (AuNPs) exhibiting (1) a self-adaptive target to the acidic microenvironment of biofilm, (2) an enhanced photothermal ablation of methicillin-resistant Staphylococcus aureus (MRSA) biofilm under near-infrared (NIR) light irradiation, and (3) no damage to the healthy tissues around the biofilm. Originally, AuNPs were readily prepared by surface modification with pH-responsive mixed charged zwitterionic self-assembled monolayers consisting of weak electrolytic 11-mercaptoundecanoic acid (HS-C10-COOH) and strong electrolytic (10-mercaptodecyl)trimethylammonium bromide (HS-C10-N4). The mixed charged zwitterion-modified AuNPs showed fast pH-responsive transition from negative charge to positive charge, which enabled the AuNPs to disperse well in healthy tissues (pH ∼7.4), while quickly presenting strong adherence to negatively charged bacteria surfaces in MRSA biofilm (pH ∼5.5). Simultaneous AuNP aggregation within the MRSA biofilm enhanced the photothermal ablation of MRSA biofilm under NIR light irradiation. The surrounding healthy tissues showed no damage because the dispersed AuNPs had no photothermal effect under NIR light. In view of the above advantages as well as the straightforward preparation, AuNPs developed in this work may find potential applications as a useful antibacterial agent in the areas of healthcare.

PH-sensitive polymersomes: controlling swelling via copolymer structure and chemical composition

pH-sensitive vesicles used as drug delivery systems (DDSs) are generally composed of protonable copolymers. The disaggregation of these nanoparticles (NPs) during drug release implies the dispersion of positively charged cytotoxic polyelectrolytes in the human body. To alleviate such issue, we synthesised A(BC)n amphiphilic block copolymers with linear (n = 1) and branched (n = 2) architectures to obtain pH-sensitive vesicles capable of releasing drugs in acidic conditions via controlled swelling instead of disaggregation. We obtained this feature by fine-tuning the relative amount of pH-sensitive and hydrophobic monomers. We studied pH-driven swelling by measuring NPs size in neutral and acidic conditions, the latter typical of tumours or inflamed tissues (pH∼6) and lysosomes (pH∼4.5). Dynamic light scattering (DLS) and zeta potential data provided useful indications about the influence of architecture and chemical composition on NPs swelling, stability and polycation release. Results demonstrated that vesicles made of linear copolymers with ∼22–28% in mol of protonable monomers in the ‘BC’ block swelled more than other species following a pH change from pH 7.4 to pH 4.5. We finally evaluated the cytotoxicity of vesicles composed of linear species, and paclitaxel (PTX) release from the latter in both cancer and normal cells.

Charge-Reversible Multifunctional HPMA Copolymers for Mitochondrial Targeting

Mitochondrial-oriented delivery of anticancer drugs has been considered as a promising strategy to improve the antitumor efficiency of chemotherapeutics. However, the physiological and biological barriers from the injection site to the final mitochondrial action site remain great challenges. Herein, a novel mitochondrial-targeted multifunctional nanocomplex based on N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers (MPC) is designed to enhance drug accumulation in mitochondria. MPC possesses various functions such as extracellular pH response, superior cellular uptake, lysosomal escape, and mitochondrial targeting. In detail, MPC was formed by two oppositely charged HPMA copolymers, that is, positively charged mitochondrial-targeting guanidine group-modified copolymers and charge-reversible 2,3-dimethylmaleic anhydride (DMA)-modified copolymers (P-DMA). It was validated that MPC could remain stable in the blood circulation (pH 7.4) but could be cleaved to expose the positive charge of the guanidine group immediately in response to the mild acidity of tumor tissues (pH 6.5). The gradual exposure of positively charged guanidine will simultaneously facilitate endocytosis, endosomal/lysosomal escape, and mitochondrial targeting. The in vitro experiments showed that compared with copolymers without guanidine modification, the cellular uptake and mitochondrial-targeting ability of MPC in the simulated tumor environment (MPC@pH6.5) separately increased 4.3- and 23.8-fold, respectively. The in vivo experiments were processed on B16F10 tumor-bearing C57 mice, and MPC showed the highest accumulation in the tumor site and a peak tumor inhibition rate of 82.9%. In conclusion, multifunctional mitochondrial-targeting HPMA copolymers provide a novel and versatile approach for cancer therapy.