Programmed surface platform orchestrates anti-bacterial ability and time-sequential bone healing for implant-associated infection.

Implant-associated infection (IAI) has become an intractable challenge in clinic. The healing of IAI is a complex physiological process involving a series of spatiotemporal connected events. However, existing titanium-based implants in clinic suffer from poor antibacterial effect and single function. Herein, a versatile surface platform based on the presentation of sequential function is developed. Fabrication of titania nanotubes and poly-γ-glutamic acid (γ-PGA) achieves the efficient incorporation of silver ions (Ag+) and the pH-sensitive release in response to acidic bone infection microenvironment. The optimized PGA/Ag platform exhibits satisfactory biocompatibility and converts macrophages from pro-inflammatory M1 to pro-healing M2 phenotype during the subsequent healing stage, which creates a beneficial osteoimmune microenvironment and promotes angio/osteogenesis. Furthermore, the PGA/Ag platform mediates osteoblast/osteoclast coupling through inhibiting CCL3/CCR1 signaling. These biological effects synergistically improve osseointegration under bacterial infection in vivo, matching the healing process of IAI. Overall, the novel integrated PGA/Ag surface platform proposed in this study fulfills function cascades under pathological state and shows great potential in IAI therapy.

A pH-responsive dual-emission composite for fast detection of BAs and visual monitoring seafood freshness with large luminescence color difference.

Sensing biogenic amine (BAs) content is very important for assessing food freshness. To address the limitations such as small color difference values (ΔE) and complex preparation of probes for visualizing the freshness of seafood, a pH-responsive ratiometric fluorescent probe (EnEB) was prepared by Eu(NO3)3, trimeric acid (BTC), and hydrochloric acid norepinephrine (Enr). EnEB emitted blue (446 nm) and red fluorescence (616 nm) originating from Enr and Eu3+, respectively, and exhibiting a fluorescence wavelength difference up to 170 nm. The ratiometric fluorescent signals of EnEB showed a linear correlation with pH in the range of 5.5-8.0. Thus, EnEB can rapidly and precisely detect BAs, such as histamine, tyramine, and spermine, with detection limits and response times of 1.14 µmol/L (3 s), 1.04 µmol/L (8 s), and 0.41 µmol/L (2 s), respectively. Furthermore, an EnEB aerogel was prepared by loading EnEB in a matrix formed by polyvinyl alcohol (PVA) and agarose (AG). EnEB aerogel exhibited excellent acid-base gas-sensing properties. The fluorescence color of EnEB aerogel can change significantly with the deterioration of seafood. When seafood changed from fresh to decayed, the ΔE value of EnEB aerogel was as high as 80.9. Importantly, the results of seafood freshness by naked eye using EnEB aerogel was consistent well with the TVB-N content and the freshness standard stipulated by national food standard, indicating EnEB aerogel can accurately visually and real-time monitor seafood freshness. Furthermore, the strategy for sensing food freshness based on EnEB aerogel also offered multiple color variations to indicate fine freshness levels of seafood. This work provided a convenient, efficient, and accurate approach to assessing the freshness of seafood. Additionally, EnEB also has promising applications in security and anti-counterfeiting.

Polymer vesicles for the delivery of inhibitors of cariogenic biofilm.

OBJECTIVES: The goal of this study is to develop a novel drug delivery platform for the pH-responsive delivery of biofilm inhibitors as a potential avenue to prevent and treat dental caries. METHODS: Biofilm and growth inhibition assays were performed in polystyrene microtiter 96-well plates. Docking analysis was performed using the reported GtfB + HA5 co-crystal structure (PDB code: 8fg8) in SeeSAR 13.0.1 software. Polymersome vesicles were assembled from poly(N-vinylpyrrolidone)8-block-poly(dimethylsiloxane)64-block-poly(N-vinylpyrrolidone)8 (PVPON8-PDMS64-PVPON8) triblock copolymer using a nanoprecipitation method. Microbiome analysis of biofilm inhibitors and the in vivo drug release and antivirulence activities of polymersome encapsulated inhibitors have been carried out in a S. mutans induced rat caries model. RESULTS: Biofilm inhibitors for HA5 and HA6 have shown species-specific selectivity towards S. mutans and the ability to preserve the oral microbiome in a S. mutans induced dental caries model. The inhibitors were encapsulated into pH-responsive block copolymer vesicles to generate polymersome-encapsulated biofilm inhibitors, and their biofilm and growth inhibitory activities against S. mutans and representative strains of oral commensal streptococci have been assessed. A 4-week treatment of S. mutans UA159 infected gnotobiotic rats with 100 µM of polymersome-encapsulated biofilm inhibitor, PEHA5 showed significant reductions in buccal, sulcal, and proximal caries scores compared to an untreated control group. SIGNIFICANCE: Taken together, our data suggests that the biofilm-selective therapy using the polymersome-encapsulated biofilm inhibitors is a viable approach for the prevention and treatment of dental caries while preserving the oral microbiome.

Sustainable Doped Carbon Dots as Antioxidant and Nanocarrier for Therapeutic Cargos.

Aside from their fluorescence sensing capabilities, carbon dots doped with heteroatoms show tremendous promise as nanocarriers for medicinal compounds and as antioxidants. We present a method for producing carbon dots from chitosan and lemon extract (CLCDs) using a one-step hydrothermal coupling synthesis. The as-synthesized CLCDs exhibited remarkable colloidal stability, antioxidant behavior, cytocompatibility, and nanocarrier for drug molecules. The nanoparticles was analyzed using advanced techniques such as Fourier transform infrared (FTIR), X-ray photoelectron spectroscopy (XPS), fluorescence spectroscopy, electron paramagnetic resonance (EPR) spectroscopy, and transmission electron microscopy (TEM) to determine the precise composition of their surface. In order to evaluate the drug transport properties of CLCDs, their surfaces were further modified with anticancer drug compounds. The drug release behavior was studied against physiologically simulated fluids and at different pH environments showing better delayed response in acidic condition. The plausible mechanistic pathways have been confirmed after fitting the results into Higuchi, Weibull and Korsmeyer-Peppas models. The goodness of fit was more than 95% for the Korsmeyer-Peppas model, with the release mechanism supported by anomalous transport. Moreover, the radical scavenging activity of CLCDs was also confirmed at low levels (1 mg/mL) which could be inferred > 85% efficacy against mostly employed testing agents (DPPH, ABTS, and hydroxyl radicals). Thus, the prepared CLCDs could be used as suitable nanovector in payload delivery with prominent antioxidant activity and low toxicity against living cell lines.

A pH-responsive novel delivery system utilizing carbon quantum dots loaded with PT2385 for targeted inhibition of HIF-2α in the treatment of osteoarthritis.

BACKGROUND: Osteoarthritis (OA) is a progressive joint disorder marked by the degradation of cartilage. Elevated concentrations of hypoxia-inducible factor-2α (HIF-2α) are intricately linked to the pathological development of OA. PT2385 has demonstrated effective inhibition of HIF-2α, thereby potentially impeding the initial advancement of OA. Nevertheless, challenges persist, including limited penetration into the deeper layers of cartilage, issues related to charge rejection, and a heightened rate of clearance from the joint. These constraints necessitate further consideration and exploration. METHODS: It has been demonstrated that PT2385 exhibits efficient inhibition of HIF-2α expression, thereby contributing to the delay in the progression of osteoarthritis. The pH-responsive attributes of carbon quantum dots, specifically those employing m-phenylenediamine (m-CQDs) coated with bovine serum albumin (BSA), have been systematically evaluated. In both in vitro settings involving cartilage explants and in vivo experiments, the efficacy of BSA-m-CQDs-PT2385 (BCP) has been confirmed in facilitating the transport of PT2385 to the middle and deep layers of cartilage. Furthermore, the BCP system demonstrates controlled drug release contingent upon alterations in environmental pH. RESULTS: While the use of PT2385 alone provides protective effects on chondrocytes within an inflamed environment, there exists an opportunity for further enhancement in its efficacy when administered via intra-articular injection. The BCP formulation, characterized by appropriate particle size and charge, facilitates seamless penetration into cartilage tissue. Additionally, BCP demonstrates the capability to release drugs in response to changes in environmental pH. In vitro experiments reveal that BCP effectively inhibits Hif-2α expression and catabolic factors in chondrocytes. Notably, cartilage explants and in vivo experiments indicate that BCP surpasses PT2385 alone in inhibiting the expression of HIF-2α and matrix metalloproteinase 13, particularly in the middle and deep layers. CONCLUSIONS: The BCP drug delivery system exhibits selective release of PT2385 in response to pH changes occurring during the progression of osteoarthritis (OA), thereby inhibiting HIF-2α expression deep within the cartilage. The use of BCP significantly augments the capacity of PT2385 to retard both cartilage degeneration and the progression of osteoarthritis. Consequently, BCP as an innovative approach utilizing m-CQDs to deliver PT2385 into articular cartilage, shows potential for treating osteoarthritis.This strategy opens new avenues for osteoarthritis treatment.

A dual-pathway pyroptosis inducer based on Au-Cu2-xSe@ZIF-8 enhances tumor immunotherapy by disrupting the zinc ion homeostasis.

The regulation of intracellular ionic homeostasis to trigger antigen-specific immune responses has attracted extensive interest in tumor therapy. In this study, we developed a dual-pathway nanoreactor, Au-Cu2-xSe@ZIF-8@P18 NPs (ACS-Z-P NPs), which targets danger-associated molecular patterns (DAMPs) and releases Zn2+ and reactive oxygen species (ROS) within the tumor microenvironment (TME). Zn2+ released from the metal-organic frameworks (MOFs) was deposited in the cytoplasm, leading to aberrant transcription levels of intracellular zinc-regulated proteins and DNA damage, thereby inducing pyroptosis and immunogenic cell death (ICD) dependent on caspase1/gasdermin D (GSDMD) pathway. Furthermore, upon laser irradiation, ACS-Z-P NPs could break through the limitations of inherent defects of immunosuppression in TME, enhance ROS generation through a Fenton-like reaction cascade, which subsequently triggered the activation of inflammatory vesicles and the release of damage-associated molecular patterns (DAMPs). This cascade effect led to the amplification of pyroptosis and immunogenic cell death (ICD), thereby remodeling the immunosuppressed TME. Consequently, this process improved dendritic cell (DC) antigen presentation and augmented anti-tumor T-cell responses, effectively initiating antigen-specific immune responses and further enhancing pyroptosis and ICD. This study explores the therapeutic properties of these mechanisms in detail. STATEMENT OF SIGNIFICANCE: The synthesized Au-Cu2-xSe@ZIF-8@P18 nanoparticles (ACS-Z-Ps) can effectively enhance the body's immune response by regulating zinc ion levels within cells. This regulation leads to abnormal levels of zinc-regulated protein transcription and DNA damage, which induces cellular pyroptosis. As a result, antigen presentation to dendritic cells (DCs) is improved, and anti-tumor T-cell responses are enhanced. The ACS-Z-P NPs overcome the limitations of ROS deficiency and immunosuppression in the tumor microenvironment by using H2O2 in the tumor microenvironment through a Fenton-like reaction. This leads to an increased production of ROS and O2, remodeling of the immunosuppressed tumor microenvironment, and enhanced induction of cell pyroptosis and immunogenic cell death. ACS-Z-P NPs targeted B16 cells using the photosensitizer P18 in combination with PDT treatment. This approach significantly inhibited the proliferation of B16 cells and effectively inhibited tumor growth.

A pH-Responsive Hydrogel for the Oral Delivery of Ursolic Acid: A Pentacyclic Triterpenoid Phytochemical.

In this study, poly(HEMA-PEGxMEM-IA) hydrogels were prepared by radical copolymerization of poly(ethylene glycol) methyl ether methacrylate (PEGxMEM), 2-hydroxyethyl methacrylate (HEMA), and itaconic acid (IA). The reaction was carried out in ethanolic solution using N,N'-methylenebisacrylamide (MBA) as a crosslinking agent and 1-hydroxycyclohexyl phenyl ketone (HCPK) as a photo-initiator. The poly(HEMA-PEGxMEM-IA) hydrogels (HGx) were evaluated as a delivery system for ursolic acid (UA), a phytochemical extracted from the plant Clinopodium revolutum, "flor de arena". The hydrogels were characterized by Fourier-transform infrared spectroscopy (FTIR-ATR), Raman spectroscopy, X-Ray diffraction (XRD), thermogravimetric analysis (TGA), and scanning electron microscopy (SEM). The swelling behavior was studied in buffer solutions from pH 2 to 10, specifically at pH 2.2 (gastric environment) and 7.4 (intestinal environment). It was found that the hydrogels studied showed sensitivity to pH. At pH 2.2, the degree of swelling for HG5 and HG9 hydrogels was 0.45 and 0.93 (g water/g hydrogel), respectively. At pH 7.4, the degree of swelling for HG5 and HG9 hydrogels was 1.97 and 2.64 (g water/g hydrogel), respectively. The SEM images show the variation in pore size as a function of pH, and the UA crystals in the pores of the hydrogels can also be observed. The in vitro UA release data best fit the Korsmeyer-Peppas kinetic model and the diffusion exponent indicates that the release mechanism is governed by Fickian diffusion.

Antimicrobial Peptide Hydrogel with pH-Responsive and Controllable Drug Release Properties for the Efficient Treatment of Helicobacter pylori Infection.

Helicobacter pylori is the primary cause of gastric adenocarcinoma, which afflicts more than half of the world's population and seriously affects human health. However, achieving efficient treatment of H. pylori infection by effective drug delivery and bioavailability after oral administration remains a challenge due to the harsh microenvironment, short drug retention time, and physiological barriers in the stomach. Moreover, H. pylori has shown resistance to many clinical antibiotics. Antimicrobial peptides (AMPs) exhibit substantial therapeutic efficacy against H. pylori, while they are not likely to induce drug resistance, suggesting their potential utility for the treatment of diseases related to H. pylori. In this paper, we report the design and synthesis of an AMP (GE33) hydrogel with pH-responsive and controlled peptide release properties, in which the minimal inhibitory concentration of the AMP against H. pylori is as low as 1 µg/mL. GE33 self-assembles into a stable peptide hydrogel under neutral pH conditions but decomposes into monomers or oligomers under acidic conditions. Upon oral administration of the hydrogel, the acidic gastric environment would facilitate rapid release of active AMP molecules from the hydrogel and immediate targeting of H. pylori in the stomach wall. Additionally, the remaining peptide is protected in the hydrogel, extending its retention time in the stomach, so that persistent drug release is achieved. The controlled and sustained release manner of the active molecule GE33, which enhances drug bioavailability, along with its excellent bactericidal efficacy opens a great potential for treating H. pylori infection.

Carboxymethyl chitosan-based nanoparticles of acid response for the synergistic anti-tumor effect of PDT and chemotherapy.

The combination of multiple anti-tumor methods has shown significant application potential in overcoming the limitations of monotherapy. Photodynamic therapy (PDT) and chemotherapy combination is a promising strategy for reducing drug resistance and side effects. Here, inspired by the acidic environment of tumors, carboxymethyl chitosan-based pH-responsive nanovesicles were developed to co-deliver the chemotherapeutic drug doxorubicin (DOX) and photosensitizer 5-aminolevulinic acid (5-ALA). The in vitro drug release studies revealed that drugs could be responsively released when nanoparticles were triggered by the acidic environment. The controlled-release behavior improved drug retention and reduced the administration time. Our nanoparticles could significantly enhance the killing effect of drugs on tumor cells and increase intracellular levels of reactive oxygen species (ROS) compared to monotherapy, effectively achieving the effects of combined chemotherapy and PDT. The loaded DOX could kill tumor cells and the loaded 5-ALA could enhance the content of protoporphyrin IX (PpIX), resulting in excess ROS production to improve the effects of PDT. In summary, our nanoparticles could co-deliver the drugs and exert synergistical anti-tumor of PDT and chemotherapy by suppressing tumor cell proliferation and facilitating cell apoptosis.

Novel pH-Responsive Structural Rearrangement of Myristic Acid-Conjugated Quetiapine Nanosuspension for Enhanced Long-Acting Delivery Performance.

Quetiapine myristate (QM), an ester-bonded lipophilic prodrug of quetiapine (QTP), is synthesized and converted into an amphiphilic structure in acidic pH to trigger a novel self-assembled QM nanosuspension (QMN). Following injection, this QMN rearranges within physiological pH to form nanoaggregates in structure, resulting in enhanced physicochemical properties and in vivo therapeutic performance without an initial burst release. The 200-nm-sized QMN exhibits less invasive injection, higher drug content, and better storage stability profile than conventional poly(lactide-co-glycolide) (PLGA) nanosuspensions containing QTP or QM. Following a single intramuscular injection to beagle dogs (35 mg kg-1 QTP), QMN undergoes pH-responsive nanoaggregation to form the lipophilic prodrug, providing esterase-oriented sustained release for five weeks compared with the two-week period of PLGA nanosuspensions. Notably, QMN exhibits improved in vivo pharmacokinetic performance with long-acting delivery while minimizing issues associated with polymeric PLGA formulations, including the initial massive burst release, cellular toxicity, and adverse side effects. These results support the further development of QMN as a novel long-acting injectable to improve patient compliance and dosing frequency.

Magnetic and pH-responsive magnetite/chitosan (core/shell) nanoparticles for dual-targeted methotrexate delivery in cancer therapy.

Methotrexate successful therapy encounters various challenges in chemotherapy, such as poor oral bioavailability, low specificity, side effects and the development of drug resistances. In this study, it is proposed a dual-targeted nanocarrier comprising magnetite/chitosan nanoparticles for an efficient Methotrexate delivery. The formation of the particles was confirmed through morphological analysis using electron microscopy and elemental mappings via energy dispersive X-ray spectroscopy. These nanoparticles exhibited a size of ≈ 270 nm, a zeta potential of ≈ 24 mV, and magnetic responsiveness, as demonstrated by hysteresis cycle analysis and visual observations under a magnetic field. In addition, these particles displayed high stability, as evidenced by size and surface electric charge measurements, during storage at both 4 ºC and 25 ºC for at least 30 days. Electrophoretic properties were examined in relation to pH and ionic strength, confirming these core/shell nanostructure. The nanoparticles demonstrated a pH-responsive drug release as observed by a sustained Methotrexate release over the next 90 h under pH ≈ 7.4, while complete release occurred within 3 h under acidic conditions (pH ≈ 5.5). In the biocompatibility assessment, the magnetite/chitosan particles showed excellent hemocompatibility ex vivo and no cytotoxic effects on normal MCF-10 A and cancer MCF-7 cells. Furthermore, the Methotrexate-loaded nanoparticles significantly enhanced the antitumor activity reducing the half-maximal inhibitory concentration by ≈ 2.7-fold less compared to the free chemotherapeutic.

X-ray triggered scintillator versatile nanocatalytic platform for synergistic photodynamic/chemodynamic therapy.

Nanocatalysts with photodynamic therapy (PDT) and chemodynamic therapy (CDT) are excellent for tumor therapy. However, it is still challenging to achieve complete tumor eradication due to the drawbacks of limited penetration depth of intratumoural tissues, hypoxia and complexity of the tumor microenvironment (TME). Herein, we fabricated an integrated multifunctional nanoreactor (LuAG:Tb/Ce-RB@ZIF-8-Au2Pt-HA, LRZAPH) combining scintillating nanoparticles (SCNPs, LuAG:Tb/Ce), a metal-organic framework (ZIF-8), and bimetallic Au2Pt for X-ray-triggered PDT and dual noble-metal nanozyme catalyzed CDT. Such a nanoreactor not only significantly enhanced the PDT effect under X-ray irradiation through full resonance energy transfer from LuAG:Tb/Ce scintillator to Ross Bengal (RB), but also facilitated the reactive oxygen species (ROS) and oxygen (O2) production through the excellent peroxidase-like (POD-like) and catalase-like (CAT-like) catalytic properties of Au2Pt nanozymes. O2 also alleviates hypoxia in intratumoural tissues during coordinated PDT. In addition, the dissociation behavior of ZIF-8 with pH-responsive and targeted of hyaluronic acid (HA) in acidic TME significantly enhanced the therapeutic efficacy of LRZAPH nanocatalysts. Significantly, the high tumor growth inhibition rate of 93 % was revealed due to radiotherapy (RT)/PDT/CDT synergetic therapy in vivo, which minimized the toxic and side effects of conventional clinical radiotherapy/chemotherapy on human. The synergistic effect of LRZAPH nanocatalysts on PDT and catalytically induced CDT is expected to provide new pathways for effective treatment of deep tumors.

A FRET biosensor constructed using pH sensitive G-quadruplex DNA for detecting mitochondrial autophagy.

Mitochondria are crucial powerhouses and central organelles for maintaining normal physiological activities in eukaryotic cells. The use of highly specific optical biosensors to monitor mitochondrial autophagy (mitophagy) is an important way for detecting mitochondrial abnormalities. Herein, we report a pH responsive G-quadruplex (G4) structure folded by the oligonucleotide named P24. P24 is composed of four GGCCTG repeating units, and the high guanine content allows it to form an antiparallel G4 topology at pH 4.5 (lysosomal pH). However, when pH increases to around 7.4 (mitochondrial pH), P24 further transforms into a double-stranded structure. Unlike most oligonucleotides that enter lysosomes, P24 highly targets mitochondria in live cells. These characteristics enable P24 to construct a pH responsive optical biosensor by linking a pair of fluorescence resonance energy transfer (FRET) fluorophores. The P24 based biosensor demonstrates reliable applications in detecting mitophagy in live cells.

cRGD-Peptide Modified Covalent Organic Frameworks for Precision Chemotherapy in Triple-Negative Breast Cancer.

This study presents the use of nanoscale covalent organic frameworks (nCOFs) conjugated with tumor-targeting peptides for the targeted therapy of triple-negative breast cancer (TNBC). While peptides have previously been used for targeted delivery, their conjugation with COFs represents an innovative approach in this field. In particular, we have developed alkyne-functionalized nCOFs chemically modified with cyclic RGD peptides (Alkyn-nCOF-cRGD). This configuration is designed to specifically target αvß3 integrins that are overexpressed in TNBC cells. These nCOFs exhibit excellent biocompatibility and are engineered to selectively disintegrate under acidic conditions, allowing for precise and localized drug release in tumor environment. Doxorubicin, a chemotherapeutic agent, has been encapsulated in these nCOFs with high loading efficiency. The therapeutic potential of Alkyn-nCOF-cRGD has been demonstrated in vitro and in vivo models. It shows significantly improved drug uptake and targeted cell death in TNBC, highlighting the efficacy of receptor-mediated endocytosis and pH-controlled drug release. This strategy leverages the unique properties of nCOFs with targeted drug delivery to achieve significant advances in personalized cancer therapy and set a new standard for precision chemotherapeutic delivery.

pH-Responsive supramolecular vesicles for imaging-guided drug delivery: Harnessing aggregation-induced emission.

The water-soluble tribenzotriquinacene-based hexacarboxylic acid ammonium salt, TBTQ-C 6 , acts as the host component (H) forming host-guest complexes with tetraphenylethylene (TPE)-functionalized monotopic and tetratopic quaternary ammonium derivatives, G1 and G2, to yield supra-amphiphiles. These supra-amphiphiles self-assemble to form pH-responsive fluorescent vesicles, which have allowed us to capitalize on the aggregation-induced emission (AIE) effect for imaging-guided drug delivery systems. These systems exhibit efficient drug loading and pH-responsive delivery capabilities. Upon encapsulation of the anticancer drug doxorubicin (DOX), both the TPE and DOX chromophores undergo dual-fluorescence deactivation due to the energy transfer relay (ETR) effect. Under acidic conditions, the release of DOX interrupts the ETR effect, resulting in the fluorescence recovery of TPE fluorogens and DOX, allowing for real-time visual monitoring of the drug release process. Cytotoxicity experiments confirmed the low toxicity of the unloaded vectors to normal cells, while the DOX-loaded vectors were found to significantly enhance the anticancer activity of DOX against cancer cells in vitro. The AIE-featured supramolecular vesicles presented in this research hold great potential for imaging-guided drug delivery systems.

CRISPR-Cas9 gene editing strengthens cuproptosis/chemodynamic/ferroptosis synergistic cancer therapy.

Copper-based nanomaterials demonstrate promising potential in cancer therapy. Cu+ efficiently triggers a Fenton-like reaction and further consumes the high level of glutathione, initiating chemical dynamic therapy (CDT) and ferroptosis. Cuproptosis, a newly identified cell death modality that represents a great prospect in cancer therapy, is activated. However, active homeostatic systems rigorously keep copper levels within cells exceptionally low, which hinders the application of cooper nanomaterials-based therapy. Herein, a novel strategy of CRISPR-Cas9 RNP nanocarrier to deliver cuprous ions and suppress the expression of copper transporter protein ATP7A for maintaining a high level of copper in cytoplasmic fluid is developed. The Cu2O and organosilica shell would degrade under the high level of glutathione and weak acidic environment, further releasing RNP and Cu+. The liberated Cu+ triggered a Fenton-like reaction for CDT and partially transformed to Cu2+, consuming intracellular GSH and initiating cuproptosis and ferroptosis efficiently. Meanwhile, the release of RNP effectively reduced the expression of copper transporter ATP7A, subsequently increasing the accumulation of cooper and enhancing the efficacy of CDT, cuproptosis, and ferroptosis. Such tumor microenvironment responsive multimodal nanoplatform opens an ingenious avenue for colorectal cancer therapy based on gene editing enhanced synergistic cuproptosis/CDT/ferroptosis.

Preparation of cellulose-based nanoparticles via electrostatic self-assembly for the pH-responsive delivery of astaxanthin.

Oral administration of astaxanthin (AST), a potent antioxidant, is limited owing to its low solubility, physicochemical stability, and bioavailability. This study developed pH-responsive nanocarriers by the electrostatic self-assembly of 2,2,6,6-tetramethylpiperidine-1-oxyradical (TEMPO)-oxidized cellulose nanofibers (TCNFs) and chitosan (CS) to enhance the intestinal delivery of AST. The TCNF/CS@AST nanoparticles were optimized through single-factor experiments and Box-Behnken design, subsequently overcoming the hydrophobicity of AST and demonstrating improved stability against environmental stressors and controlled release in the intestinal environment. Transmission electron microscopy confirmed the near-spherical shape of these nanoparticles, with an average hydrodynamic diameter of 64 nm. TCNF/CS@AST enhanced the antioxidant effectiveness of AST after digestion and in lipopolysaccharide-stimulated RAW 264.7 cells while demonstrating good cellular compatibility. These nanoparticles present a promising strategy for the oral delivery of hydrophobic bioactive compounds orally, with potential applications in precision nutrition.

pH-Responsive Block Copolymer Micelles of Temsirolimus: Preparation, Characterization and Antitumor Activity Evaluation.

Purpose: Renal cell carcinoma (RCC) is the most common and lethal type of urogenital cancer, with one-third of new cases presenting as metastatic RCC (mRCC), which, being the seventh most common cancer in men and the ninth in women, poses a significant challenge. For patients with poor prognosis, temsirolimus (TEM) has been approved for first-line therapy, possessing pharmacodynamic activities that block cancer cell growth and inhibit proliferation-associated proteins. However, TEM suffers from poor water solubility, low bioavailability, and systemic side effects. This study aims to develop a novel drug formulation for the treatment of RCC. Methods: In this study, amphiphilic block copolymer (poly(ethylene glycol) monomethyl ether-poly(beta-amino ester)) (mPEG-PBAE) was utilized as a drug delivery vehicle and TEM-loaded micelles were prepared by thin-film hydration method by loading TEM inside the nanoparticles. Then, the molecular weight of mPEG-PBAE was controlled to make it realize hydrophobic-hydrophilic transition in the corresponding pH range thereby constructing pH-responsive TEM-loaded micelles. Characterization of pH-responsive TEM-loaded nanomicelles particle size, potential and micromorphology while its determination of drug-loading properties, in vitro release properties. Finally, pharmacodynamics and hepatorenal toxicity were further evaluated. Results: TEM loading in mPEG-PBAE increased the solubility of TEM in water from 2.6 µg/mL to more than 5 mg/mL. The pH-responsive TEM-loaded nanomicelles were in the form of spheres or spheroidal shapes with an average particle size of 43.83 nm and a Zeta potential of 1.79 mV. The entrapment efficiency (EE) of pH-responsive TEM nanomicelles with 12.5% drug loading reached 95.27%. Under the environment of pH 6.7, the TEM was released rapidly within 12 h, and the release rate could reach 73.12% with significant pH-dependent characteristics. In vitro experiments showed that mPEG-PBAE preparation of TEM-loaded micelles had non-hemolytic properties and had significant inhibitory effects on cancer cells. In vivo experiments demonstrated that pH-responsive TEM-loaded micelles had excellent antitumor effects with significantly reduced liver and kidney toxicity. Conclusion: In conclusion, we successfully prepared pH-responsive TEM-loaded micelles. The results showed that pH-responsive TEM-loaded micelles can achieve passive tumor targeting of TEM, and take advantage of the acidic conditions in tumor tissues to achieve rapid drug release.

Preparation of Water-Soluble Polyion Complex (PIC) Micelles with pH-Responsive Carboxybetaine Block.

A dual zwitterionic diblock copolymer (M100C100) consisting of poly(2-(methacryloyloxy)ethyl phosphorylcholine) (PMPC, M) and poly(3-((2-(methacryloyloxy)ethyl) dimethylammonio) propionate) (PCBMA, C) is synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization. A double hydrophilic diblock copolymer (M100S100) consist of PMPC and anionic poly(3-sulfopropyl methacrylate potassium salt) (PMPS, S) is synthesized via RAFT. The degrees of polymerization of each block are 100. The charges of PMPC are neutralized intramolecularly. At neutral pH, the charges in PCBMA are also neutralized intramolecularly due to its carboxybetaine structure. Under acidic conditions, PCBMA exhibits polycation behavior as the pendant carboxy groups become protonated, forming cationic tertiary amine groups. PMPS shows permanent anionic nature independent of pH. Charge neutralized mixture of cationic M100C100 and anionic M100S100 in acidic aqueous solution forms water-soluble polyion complex (PIC) micelle owing to electrostatic attractive interactions. The core is composed of the cationic PCBMA and anionic PMPS blocks, with the PMPC blocks serving as shells that covered the core surface, forming spherical core-shell PIC micelles. Above pH 4 the pendant carboxy groups in PCBMA undergo deprotonation, transitioning to a zwitterionic state, thereby eliminating the cationic charge in PCBMA. Therefore, above pH 4 the PIC micelles are dissociated due to the disappearance of the charge interactions.

pH factors in chronic wound and pH-responsive polysaccharide-based hydrogel dressings.

Chronic wounds present a significant healthcare challenge marked by complexities such as persistent bleeding, inhibited cell proliferation, dysregulated inflammation, vulnerability to infection, and compromised tissue remodeling. Conventional wound dressings often prove inadequate in addressing the intricate requirements of chronic wound healing, leading to slow healing and heightened susceptibility to infections in patients with prolonged medical conditions. Bacterial biofilms in chronic wounds pose an additional challenge due to drug resistance. Advanced wound dressings have emerged as promising tools in expediting the healing process. Among these, pH-responsive polysaccharide-based hydrogels exhibit immense prospect by adapting their functions to dynamic wound conditions. Despite their potential, the current literature lacks a thorough review of these wound dressings. This review bridges this gap by meticulously examining factors related to chronic wounds, current strategies for healing, and the mechanisms and potential applications of pH-responsive hydrogel wound dressings as an emerging therapeutic solution. Special focus is given to their remarkable antibacterial properties and significant self-healing abilities. It further explores the pH-monitoring functions of these dressings, elucidating the associated pH indicators. This synthesis of knowledge aims to guide future research and development in the field of pH-responsive wound dressings, providing valuable insights into their potential applications in wound care.