Dual-responsive Nanocarriers Research Articles

Triggering Pyroptosis by Doxorubicin-Loaded Multifunctional Nanoparticles in Combination with Decitabine for Breast Cancer Chemoimmunotherapy.

Pyroptosis, a form of programmed cell death, holds great promise for breast cancer treatment. However, the downregulation of gasdermin E (GSDME) limits the effectiveness of pyroptosis. To address this challenge, we developed a folic acid-modified and glutathione/reactive oxygen species dual-responsive nanocarrier (FPSD NPs) for the targeted delivery of doxorubicin (DOX). Through the combination with DNA methyltransferase inhibitor decitabine (DAC), the GSDME protein expression was significantly increased in 4T1 cells, resulting in cell swelling and ballooning, which are characteristic features of pyroptosis. In vivo experiments further demonstrated the antitumor efficacy of DAC + DOX@FPSD NPs, and the 4T1-bearing mice treated with DAC + DOX@FPSD NPs exhibited reduced tumor volumes, minimized tumor weights, decreased Ki67-positive cells, increased TUNEL apoptosis ratios, and pronounced lesions in H&E staining. Furthermore, DAC + DOX@FPSD NP treatment could promote pyroptosis-associated antitumor immunity, as evidenced by the increased presence of CD3+, CD4+, and CD8+ T cells, heightened secretion of tumor necrosis factor-α and interferon-γ, elevated high-mobility group box-1 levels, and enhanced calreticulin exposure. The FPSD nanocarrier developed in this study had favorable stability, active targeting ability, biocompatibility, and controlled release properties, and the DAC + DOX@FPSD NPs represented an approach to antitumor therapy by inducing pyroptosis, which offers a promising avenue for breast cancer treatment.

Dual-responsive drug carrier based on zeolitic imidazolate framework-8 incorporated into gold nanoparticles/chitosan/copper sulfide for controlled drug delivery

Currently, two major obstacles in effective treatment of breast cancer are development of resistance to chemotherapeutic drugs by cancer cells and the off-target cytotoxicity of these drugs. The main aim of this study was to synthesize a dual responsive nanocarrier by incorporating the zeolitic-imidazolate framework-8 into the gold nanoparticles/chitosan/copper sulfide for controlled release of doxorubicin. The prepared nanocarrier was characterized using various techniques, including Fourier transform infrared spectroscopy, scanning electron microscopy, thermogravimetric analysis, X-ray diffraction, and zeta potentials. The optimum experimental conditions, including adsorbent dosage (0.01–0.03 g), pH of solutions (5–9), contact time (5–15 min), and temperature (25–45 °C) at three levels were studied using the central composite design based on the response surface methodology. Our results indicated highest response (99 %) with 0.03 g of nanocarrier, at pH of 5, time of 10 min, and temperature of 35 °C. The obtained data were further studied with seven isotherm models. Based on the lower error sum of square values (0.059–0.514) and higher correlation coefficient values (0.9857–0.9972), Langmuir and Sips isotherm models were observed to be the best fitted. The in-vitro drug release study indicated 37.97 % of the drug being released in the simulated environment with physiological conditions, while 71.29 % of the drug was released in the simulated cancer cells condition at higher temperature. This data confirms the pH and temperature sensitivity of the nanocarrier. Enhanced drug release from the nanocarrier indicated low cell viability in the breast cancer cell line (MCF-7) under near-infrared laser irradiation. The IC50 values of nanocarrier and pure drug in MCF-7 cells were 243.95 and 4.442 μg L−1, respectively. Based on these data, we are concluding that our dual responsive nanocarrier has the potential to overcome the problems development of resistance of cancer cells and toxicity associated with current treatment of breast cancer.

Dual-responsive nanocarriers for efficient cytosolic protein delivery and CRISPR-Cas9 gene therapy of inflammatory skin disorders.

Developing protein drugs that can target intracellular sites remains a challenge due to their inadequate membrane permeability. Efficient carriers for cytosolic protein delivery are required for protein-based drugs, cancer vaccines, and CRISPR-Cas9 gene therapies. Here, we report a screening process to identify highly efficient materials for cytosolic protein delivery from a library of dual-functionalized polymers bearing both boronate and lipoic acid moieties. Both ligands were found to be crucial for protein binding, endosomal escape, and intracellular protein release. Polymers with higher grafting ratios exhibit remarkable efficacies in cytosolic protein delivery including enzymes, monoclonal antibodies, and Cas9 ribonucleoprotein while preserving their activity. Optimal polymer successfully delivered Cas9 ribonucleoprotein targeting NLRP3 to disrupt NLRP3 inflammasomes in vivo and ameliorate inflammation in a mouse model of psoriasis. Our study presents a promising option for the discovery of highly efficient materials tailored for cytosolic delivery of specific proteins and complexes such as Cas9 ribonucleoprotein.

Design and Development of Dual Responsive Nanocarrier Based on Tungsten Disulfide Nanosheets and Its Cytotoxic Effect on PC-3 Cells as an Efficient In Vitro Drug Delivery System for Flutamide

Design and Development of Dual Responsive Nanocarrier Based on Tungsten Disulfide Nanosheets and Its Cytotoxic Effect on PC-3 Cells as an Efficient In Vitro Drug Delivery System for Flutamide

Responsive nanosystems for targeted therapy of ulcerative colitis: Current practices and future perspectives

The pharmacological approach to treating gastrointestinal diseases is suffering from various challenges. Among such gastrointestinal diseases, ulcerative colitis manifests inflammation at the colon site specifically. Patients suffering from ulcerative colitis notably exhibit thin mucus layers that offer increased permeability for the attacking pathogens. In the majority of ulcerative colitis patients, the conventional treatment options fail in controlling the symptoms of the disease leading to distressing effects on the quality of life. Such a scenario is due to the failure of conventional therapies to target the loaded moiety into specific diseased sites in the colon. Targeted carriers are needed to address this issue and enhance the drug effects. Conventional nanocarriers are mostly readily cleared and have nonspecific targeting. To accumulate the desired concentration of the therapeutic candidates at the inflamed area of the colon, smart nanomaterials with responsive nature have been explored recently that include pH responsive, reactive oxygen species responsive (ROS), enzyme responsive and thermo – responsive smart nanocarrier systems. The formulation of such responsive smart nanocarriers from nanotechnology scaffolds has resulted in the selective release of therapeutic drugs, avoiding systemic absorption and limiting the undesired delivery of targeting drugs into healthy tissues. Recent advancements in the field of responsive nanocarrier systems have resulted in the fabrication of multi-responsive systems i.e. dual responsive nanocarriers and derivitization that has increased the biological tissues and smart nanocarrier’s interaction. In addition, it has also led to efficient targeting and significant cellular uptake of the therapeutic moieties. Herein, we have highlighted the latest status of the responsive nanocarrier drug delivery system, its applications for on–demand delivery of drug candidates for ulcerative colitis, and the prospects are underpinned.

A multifunctional DNA repair enzyme and magnetic dual-triggered theranostic nanosystem for intelligent drug delivery

Due to the high specificity and efficiency of enzymes, enzyme-responsive drug delivery systems are important in cancer therapy and diagnosis. Human apurinic/apyrimidinic endonuclease (APE1) is a representative DNA repair enzyme overexpressed in various cancer cells, which is also proven to be a promising stimuli in our previous studies. In this work, to realize targeted chemotherapy, an APE1 and magnetic dual-responsive nanocarrier was designed. The carrier is composed of Fe3O4@SiO2 nanoparticles and specially designed AP-DNA strand that can be effectively hydrolyzed by APE1. The chemotherapeutic drug doxorubicin (DOX) was loaded onto the AP-DNA to form the theranostic nanosystem (FS@DNA-DOX). As the AP-DNA was parted under the hydrolysis of APE1 in cancer cells, DOX was released to inhibit tumor growth. In vitro experiment results indicated that the nanosystem possesses a high specificity to APE1 and effectively release DOX in MCF-7 cells. In vivo experiments demonstrated that the targeted delivery of the nanosystem to the tumor site was successfully achieved and that strong tumor suppressor effects were observed. Overall, the FS@DNA-DOX is a multifunctional and theranostic nanosystem for the chemotherapy of cancer by increasing the therapeutic effect as well as reducing the toxicity of drugs.

Construction of a pH/Temperature dual-responsive drug delivery platform based on exfoliated MoS2 nanosheets for effective delivery of doxorubicin: Parametric optimization via central composite design

The aim of the current work was to develop drug delivery system for encapsulation and release of doxorubicin using exfoliated molybdenum disulfide nanosheets modified N-isopropyl acrylamide/methyl methacrylate. Here, glutamine was conjugated to the surface of molybdenum disulfide nanosheets. Several techniques such as Fourier transform infrared spectroscopy, X-ray diffraction, thermal gravimetric analysis, field emission scanning electron microscopy, and Zeta potential were applied to characterize the nanoadsorbent. Three important parameters of pH, contact time, and temperature were optimized by the response surface methodology technique. According to the central composite design, the maximum adsorption efficiency of 95% is attained at the pH = 8, contact time of 15 min, and temperature of 30 °C. The non-linear isotherms and kinetics sorption of drug onto nanoadsorbent can be excellently simulated by the Freundlich isotherm model and pseudo-second-order kinetic models, respectively. The dual-responsive nanocarrier indicated a slow release profile in simulated blood fluid at pH = 7.4 (T = 37 °C), whereas 98% of drug was released when nanocarrier were dissolved in pH = 5.6 (T = 50 °C) after 6 h, showing a sustained pH and temperature dependent drug release. The biocompatibility of nanocarrier was evaluated by MTT assay on KB cell line as a breast cancer modal cell.

Synergy between pH- and hypoxia-responsiveness in antibiotic-loaded micelles for eradicating mature, infectious biofilms

Antibiotic-loaded PEG/PAE-based micelles are frequently considered for eradicating infectious biofilms. At physiological pH, PEG facilitates transport through blood. Near an acidic infection-site, PAE becomes protonated causing micellar targeting to a biofilm. However, micellar penetration and accumulation is confined to the surface region of a biofilm. Especially matured biofilms also possess hypoxic regions. We here designed dual-responsive PEG/PAE-b-P(Lys-NBCF) micelles, responding to both acidity and low oxygen-saturation level in matured biofilms. Dual, pH- and hypoxia-responsive micelles targeted and accumulated evenly over the depth of 7- to 14-days old biofilms. Delineation demonstrated that pH-responsiveness was responsible for targeting of the infection-site and accumulation of micelles in the surface region of the biofilm. Hypoxia-responsiveness caused deep penetration in the biofilm. Dual, pH- and hypoxia-responsive micelles loaded with ciprofloxacin yielded more effective, synergistic eradication of 10-days old, matured Staphylococcus aureus biofilms underneath an abdominal imaging-window in living mice than achieved by ciprofloxacin in solution or single, pH- or hypoxia responsive micelles loaded with ciprofloxacin. Also, wound-healing after removal of window and its frame proceeded fastest after tail-vein injection of ciprofloxacin-loaded, dual, pH- and hypoxia-responsive micelles. Concluding, pH- and hypoxia-responsiveness are both required for eradicating mature biofilms and advancing responsive antibiotic nanocarriers to clinical application. Statement of significancepH-responsive antibiotic nanocarriers have emerged as a possible new strategy to prevent antimicrobial-resistant bacterial infections from becoming the leading cause of death. In this paper, we show that commonly studied, pH-responsive micellar nanocarriers merely allow self-targeting to an infectious biofilm, but do not penetrate deeply into the biofilm. The dual-responsive (acidic pH- and hypoxia) antibiotic-loaded micelles designed here not only self-target to an infectious biofilm, but also penetrate deeply. The in vitro and in vivo advantages of dual-responsive nanocarriers are most obvious when studied in infectious biofilms grown for 10 viz a viz the 2 days, usually applied in the literature. Significantly, clinical treatment of bacterial infection usually starts more than 2 days after appearance of the first symptoms.

Fabrication and characterization of dual-responsive nanocarriers for effective drug delivery and synergistic chem-photothermal effects

Multifunctional drug delivery systems (DDS) with simultaneous multimodal therapeutic and stimuli-responsive capabilities are recently of considerable interest. Herein, a versatile DDS capable of glutathione (GSH)/pH responsivity was engineered for the effective drug delivery and chemo-photothermal synergistic effects. Polydopamine (PDA) and polyethylene glycol (PEG) were coated on the surface of degradable dendritic mesoporous silica nanoparticles (DDMSNs) to construct the dual-responsive and photothermal nanoplatform, coined as DDMSNs-DOX-PDA-PEG. The developed nanocarriers presented excellent GSH/pH responsivity due to PDA coating and tetrasulfide bonds imbedded in DDMSNs can be broken under in low pH and high GSH concentration environment, implementing the controlled drug release. Specifically, the DDS showed better stability, biocompatibility and photothermal properties owning to the modification of PDA and PEG, and the nanocarriers performed an efficient cell uptake and significant tumor permeability efficiency. Furthermore, upon near-infrared laser irradiation, the cyto-inhibition for 4T1 cells was enhanced evidently via a synergism of chemo-photothermal treatment. Therefore, the proposed DDMSNs-DOX-PDA-PEG has great potential as DDS for effective drug delivery and the synergistic treatment of chemo-photothermal therapy. As expected, the developed strategy provides a facile alternative for fabricating multifunctional DDS for tumor therapy.

Construction of a double-responsive modified guar gum nanoparticles and its application in oral insulin administration

The use of intelligent insulin delivery systems has become more important for treating diabetes. In this study, a dual-responsive oral insulin delivery nanocarrier that responds to glucose and pH has been developed. First, the oleic acid hydrophobic modified guar gum (GG) was synthesized by the esterification reaction, and the γ-polyglutamic acid (γ-PGA) was coupled with GG by the amidation reaction. The obtained pH-responsive copolymer (γ-PGA-GG) was cross-linked by concanavalin A to obtain pH/glucose dual-responsive nanocarriers, and insulin was effectively loaded into the dual-responsive nanocarriers. The insulin-loaded nanoparticles can achieve effective pH and glucose responses, releasing insulin on demand. In vitro and in vivo studies demonstrated the dual-responsive nanoparticles can protect insulin against the pH changes in the digestive tract and deliver insulin into the body to exert a hypoglycemic effect. Moreover, the dual-responsive nanoparticles have significant potential to be employed for oral insulin delivery.

Hybrid liposome/metal–organic framework as a promising dual-responsive nanocarriers for anticancer drug delivery

In this work, liposome-coated iron (III) benzene-1,3,5-tricarboxylate (Fe-BTC) metal–organic framework is examined as a promising pH/Ultrasound dual-responsive nanocarriers for doxorubicin (DOX) delivery. The successful coating of the MOF particles (Lip-Fe-BTC) with the phospholipid bilayer (PBL) was established by direct fusion into the synthesized liposomes. The liposome coating was verified using several techniques, including dynamic light scattering (DLS) and transmission electron microscopy (TEM). The DLS measurements showed an increase in the average particle diameter of liposomes from 150 nm to 163.1 nm for Lip-Fe-BTC particles. The Fe-BTC particles had the highest average particle diameter (287.3 nm). These results demonstrated that the PBL reduced the aggregation of the particles and improved their dispersity in the release medium. The TGA results demonstrated the MOF’s excellent thermal stability. Furthermore, the nanocarrier’s loading efficiency and capacity were determined to be ~90% and ~13.5 wt%, respectively. The in-vitro DOX release experiments demonstrated that the DOX-loaded Fe-BTC and liposome-coated Fe-BTC particles showed good pH and US dual-responsive capability, making them promising nanocarriers for drug delivery. The application of US enhanced DOX release from both Fe-BTC and liposome-coated Fe-BTC. In the case of Fe-BTC-DOX particles, the application of US enhanced the DOX release to around 38% and 67%, at pH levels of 7.4 and 5.3, respectively. Similarly, DOX release from the Lip-Fe-BTC-DOX particles reached ~35% and ~53%, at pH levels of 7.4 and 5.3, respectively. The MTT assay showed the biocompatibility and low cytotoxicity of these nanocarriers below 100 µg/ml.

Smart dual responsive nanocarriers with reactive oxygen species amplification assisted synergistic chemotherapy against prostate cancer

Conventional chemotherapy efficacy is impeded by poor water solubility, inferior tissue targeting, and severe systemic toxic effect. Synergistic chemotherapy has become prominent with the stimulus–response drug delivery system (DDS) to treat solid malignancies. The most popularly employed responsive stimulus is reactive oxygen species (ROS), which is proven to primarily sensitize chemotherapy and enhance antitumor impact. In this study, we have successfully developed smart dual responsive nanocarriers with ROS self-amplification, particularly responding to disassemble under the high levels of ROS and esterase in the tumor microenvironment (TME) and to release docetaxel (DTX) efficiently. Additionally, we utilized palmitoyl ascorbate (PA) as a stabilizer by taking advantage of its amphiphilic structure. PA is also an excellent ROS generator that produces a large amount of hydrogen peroxide (H2O2) in TME to achieve ROS self-amplification. Also, elevated levels of ROS could continue to activate ROS-sensitive thioketal and make the remaining nanocarriers disassemble for sustaining the release of chemotherapeutics, realizing a positive feedback loop for ROS generation and ROS amplification, as well as sensitizing chemotherapy efficacy. The smart dual responsive nanocarriers may serve as a promising and prospective strategy for treating prostate cancer and promoting synergistic cancer therapy.

Thermo/pH dual-responsive micelles based on the host\u2013guest interaction between benzimidazole-terminated graft copolymer and \u03b2-cyclodextrin-functionalized star block copolymer for smart drug delivery

Novel temperature and pH dual-sensitive amphiphilic micelles were fabricated exploiting the host–guest interaction between benzimidazole-terminated PHEMA-g-(PCL-BM) and β-CD-star-PMAA-b-PNIPAM. The fabricated graft copolymer had a brush-like structure with star side chains. The micelles were utilized as dual-responsive nanocarriers and showed the LCST between 40 and 41 °C. The acidic pH promoted the dissociation of the PHEMA-g-(PCL-BM: β-CD-star-PMAA-b-PNIPAM) micelles. DOX.HCl was loaded into the core of the micelles during self-assembly in an aqueous solution with a high encapsulation efficacy (97.3%). The average size of the amphiphilic micelles was about 80 nm, suitable size for the enhanced permeability and retention effect in tumor vasculature. In an aqueous environment, these micelles exhibited very good self-assembly ability, low CMC value, rapid pH- and thermo-responsiveness, optimal drug loading capacity, and effective release of the drug. The biocompatibility was confirmed by the viability assessment of human breast cancer cell line (MCF-7) through methyl tetrazolium assay. DOX-loaded micelles displayed excellent anti-cancer activity performance in comparison with free DOX.Graphical

Dual stimuli-responsive nanocarriers based on polyethylene glycol-mediated schiff base interactions for overcoming tumour chemoresistance

Multifunctional and stimulus-sensitive intelligent nanodrug delivery systems (NDDSs) can significantly optimize the effectiveness of theranostic agents for cancer treatment. In this study, redox and pH dual-responsive nanocarriers (CPNPs) were prepared through molecular assembly by utilizing the Schiff base interactions of cystamine (Cys), PEG-NH2 and formaldehyde (FA) under aqueous conditions with a one-pot, one-step technique. First, the degradation products of CPNPs exhibited good biocompatibility, and the high concentration of intact CPNPs (200 µg/mL) could inhibit the growth of cells. In addition, doxorubicin (DOX) was encapsulated in CPNPs simply by changing the pH (DOX@CPNPs), and pH/GSH-responsive release behaviour was confirmed. In vitro, CPNPs significantly increased the uptake of DOX and enhanced the cytotoxicity of DOX to tumour cells. More importantly, DOX@CPNPs strongly reversed drug resistance in three different types of cancer cells, exhibiting significant anticancer effects. Collectively, this study presents the easy preparation of nanomedicines that respond to multiple stimuli, which highlights the advantages of Schiff base-based nanomedicines for cancer therapy and reversing chemoresistance.

A Rapid Dual-Responsive Releasing Nano-Carrier by Decomposing the Copolymer and Reversing the Core Dissolution.

The accumulation of nanotechnology-based drugs has been realized in various ways. However, the concentration of drugs encapsulated by nanomaterials is not equal to the concentration of effective drugs; often, the drugs become effective only when they are released from the nanomaterials as free drugs. This means only when the drugs are rapidly released after the accumulated drug-encapsulating nanomaterials can they truly achieve the purpose of increasing the concentration of drugs in the tumor. Therefore, we herein report a dual-response nano-carrier of glutathione and acid to achieve the rapid release of encapsulated drug and increase the effective drug concentration in the tumor. The nano-carrier was constructed using a dual-responsive amphiphilic copolymer, composed of polyethylene glycol and hydrophobic acetylated dextran and connected by a disulfide bond. In the tumor microenvironment, disulfide bonds could be biodegraded by glutathione that is overexpressed in the tumor, exposing the core of nano-carrier composed of acetylated dextran. Then the acidic environment would induce the deacetylation of acetylated dextran into water-soluble dextran. In this way, the nano-carrier will degrade quickly, realizing the purpose of rapid drug release. The results showed that the drug release rate of dual-responsive nano-carrier was much higher than that of glutathione or acid-responsive nano-carrier alone. Furthermore, both in vitro and in vivo experiments confirmed that dual-responsive nano-carrier possessed more efficient anti-tumor effects. Therefore, we believe that dual-responsive nano-carriers have better clinical application prospects.

Oxygen-Abundant and pH/NIR Dual-Responsive Nanocarriers for Tumor Hypoxia Reduction Therapy

Oxygen-Abundant and pH/NIR Dual-Responsive Nanocarriers for Tumor Hypoxia Reduction Therapy

Multifunctional Size-Expandable Nanomedicines Enhance Tumor Accumulation and Penetration for Synergistic Chemo-Photothermal Therapy.

Size expansion can effectively improve tumor accumulation of nanocarriers where precise control is required. A dual-responsive nanocarrier stimulated by both endogenous pH and exogenous heat stimuli can change its size. Herein, a nanoparticle composed of poly(N,N-diethyl acrylamide) (PDEAA) and poly(2-(diisopropylamino) ethyl methacrylate) (PDPA) is developed. The antitumor drug celastrol (CLT) and the photosensitizer indocyanine green (ICG) are then loaded in it to form CIPP. ICG generates heat under near-infrared (NIR) stimulation to kill tumor cells and enhance CIPP penetration. Meanwhile, CIPP expands in response to hyperthermia and acid tumor microenvironments, preventing itself from returning to the blood flow, thus accumulating in tumor sites. Ultimately, the acidic lysosomal environment in tumor cells disintegrates CIPP to release CLT, directly inducing immunogenic cell death and sensitizing tumor cells for hyperthermia by disrupting the interaction of heat shock protein 90 and P50cdc37. Most of the tumors in B16F10-bearing mice are eradicated after single laser irradiation. The dual-responsive CIPP with multiple functions and simple design displays a synergistic antitumor effect. This study provides a basis for developing size-expandable stimulus-responsive drug delivery systems against tumors.

Reactive oxygen species and glutathione dual responsive nanoparticles for enhanced prostate cancer therapy

Docetaxel (DTX)-based chemotherapy of prostate cancer is still confronted with significant challenges due to insufficient drug accumulation at the tumor sites and the systemic side effects on normal cells and organs. Tumor microenvironment-responsive nanosized drug delivery systems have shown enormous potential to improve the anticancer efficacy and minimize the systemic side effects of chemotherapeutics. However, most of the currently redox-responsive nanoparticles respond only to single stimuli, which compromise the treatment effect. Hence, inspired by the abundance of reactive oxygen species (ROS) and intracellular glutathione (GSH) in cancer cells, we proposed a unique ROS and GSH dual responsive nanocarrier (PCL-SS) for DTX delivery. The DTX-loaded PCL-SS nanoparticles (PCL-SS@DTX NPs) were not only stable in a normal physiological environment but also rapidly triggered DTX release in prostate cancer cells. In vitro experiments showed that PCL-SS@DTX NPs had robust prostate cancer cell cytotoxicity, induced cell apoptosis, inhibited cell migration and invasion and exhibited satisfactory biocompatibility. In mice bearing orthotopic prostate cancer, PCL-SS@DTX NPs could accumulate in orthotopic tumor sites and then significantly weaken tumor growth by inhibiting prostate cancer cell proliferation and inducing cell apoptosis, without obvious damages to major organs. Overall, this dual responsive nanosized drug delivery system may act as a promising therapeutic option for prostate cancer chemotherapy.

Synthesis, characterisation and functionalisation of BAB-type dual-responsive nanocarriers for targeted drug delivery: evolution of nanoparticles based on 2-vinylpyridine and diethyl vinylphosphonate.

The emerging field of nanomedicine gives new opportunities in the treatment of cancer. Aspects such as dosage, bioavailability or the application to the patient can be drastically improved. Previously our group reported an efficient route towards cross-linked nanospheres based on ABB′ block copolymers made from 2-vinylpyridine (2VP), diethyl vinylphosphonate (DEVP) and diallyl vinylphosphonate (DAlVP). Followed by thiol–ene click chemistry stable nanoparticles were formed. Herein, this promising concept was extended to copolymers with the analogous B′BABB′ architecture. In this context the new yttrium complex 5 was investigated in the rare-earth metal-mediated group transfer polymerisation (REM-GTP) and used for the generation of copolymers with different monomer feeds (2VP: 100–300 equiv.; DEVP: 200–300 equiv.; DAlVP: 6–20 equiv.) to explore the influence of the copolymer compositon on the nanoparticle properties. After successful cross-linking with various cross-linking agents, all nanoparticles were characterised via DLS and TEM. These size measurements revealed defined, almost spherical particles (dDLS = 17–52 nm; dTEM = 17–43 nm) and were mainly affected by the 2VP content and the cross-linking density. Zeta potential measurements resulted in values in the range from −6 mV to −22 mV and revealed an influence of the cross-linking agent on the surface charge. Studies on the release behaviour exhibited the fastest release at pH = 4.5. Temperature-wise best results were achieved at 42 °C. Furthermore, we aimed for the conjugation of folic acid as a model compound for a potential application in active drug targeting. The consecutive couplings of cysteamine and dithiol 6 enabled the formation of an amine-modified precursor which was reacted with a folic acid derivative. Zeta potential measurements and analysis by NMR spectroscopy corroborated a successful conjugation while DLS and TEM (dDLS = 44 nm; dTEM = 38 nm) indicated defined nanoparticles.

Progress in dual-responsive nanocarriers based on acid sensitivity for anticancer drug

In order to achieve better tumor treatment, researchers have designed dual and multiple responsive smart nanocarriers in the tumor microenvironment. Among them, the research based on acid-sensitive dual-responsive nanocarriers is the most extensive and common one. Intelligent nanocarriers have initially achieved long circulation in body, effective accumulation in tumor cells, and controlled drug release in tumor microenvironment, with increased anti-tumor effect of drug and reduced damage to normal tissues. However, there are still many problems to be solved in current research, such as high price, complicated nanocarriers structure, and unclear mechanisms of drug delivery in the body, all hampering nanocarriers from clinical applications. This article introduces the progress of nanocarriers in recent years from the dual responsive aspects including acid-temperature, acid-magnetism, acid-redox, acid-enzyme, acid-light and acid-ultrasound, to provide reference for further clinical application of nanomedicine.