Bilirubin Nanoparticles as a Nanomedicine for Anti‐inflammation Therapy

Despite the high potency of bilirubin as an endogenous anti‐inflammatory compound, its clinical translation has been hampered because of its insolubility in water. Bilirubin‐based nanoparticles that may overcome this critical issue are presented. A polyethylene glycol compound (PEG) was covalently attached to bilirubin, yielding PEGylated bilirubin (PEG‐BR). The PEG‐BR self‐assembled into nanoscale particles with a size of approximately 110 nm, termed bilirubin nanoparticles (BRNPs). BRNPs are highly efficient hydrogen peroxide scavengers, thereby protecting cells from H₂O₂‐induced cytotoxicity. In a murine model of ulcerative colitis, intravenous injection of BRNPs showed preferential accumulation of nanoparticles at the sites of inflammation and significantly inhibited the progression of acute inflammation in the colon. Taken together, BRNPs show potential for use as a therapeutic nanomedicine in various inflammatory diseases.     

Disassembly‐Driven Fluorescence Turn‐on of Polymerized Micelles by Reductive Stimuli in Living Cells

Stimuli‐response nanoparticles have emerged as powerful tools for imaging and therapeutic applications. Ideally, they should be assembled from biodegradable materials featuring small size and cooperative response to biological stimuli that trigger particle disassembly and release of an active molecule that could be readily monitored in situ. A concept is developed that consists of organic nanoparticles, assembled from fluorescent amphiphiles and polymerized with a redox‐cleavable cross‐linker. We obtained 20 nm nanoparticles bearing self‐quenched Nile Red dye residues, which can disassemble in living cells into highly fluorescent molecular units owing to an external or internal reductive stimulus. The obtained results pave the way to new stimuli‐responsive nanomaterials for applications in background‐free imaging as well as in drug delivery, as the concept can be further extended to other active molecules including drugs and to cross‐linkers cleavable by other biological stimuli.     

Continuous Detection of pH‐responsive Drug Delivery System in Cells in situ by Confocal Laser Scanning Microscopy

Mesoporous silica nanoparticles (MSN) were coated by pH‐responsive polymer chitosan‐poly (methacrylic acid) (CS‐PMAA). This nano drug delivery system showed good application prospects and the polymer‐coated microspheres were promising site‐specific anticancer drug delivery carriers in biomedical field. A continuous detection of pH‐responsive drug delivery system in cells in situ, utilizing MSN/CS‐PMAA composite microspheres, was proposed. Two kinds of different cell lines, tumor cell line (Hela) and normal somatic cells (293T), were used to investigate the behaviours of the drug loaded system in the cells. Conclusions could be drawn from the fluorescent images obtained by confocal laser scanning microscopy (CLSM), modified drug‐loaded microspheres (MSN/CS‐PMAA) were ingested into cells more easily, the uptake of DOX@FITC‐MSN/CS‐PMAA by HeLa/293T cells were performed at pH 7.4/pH 6.8, DOX was released during the ingestion process, fluorescence intensity decreased with time because of efflux transport and photo‐bleaching. Fluoresence detection by flow cytometry was performed as comparison. The continuous fluorescent observation in situ could be widely used in the pH‐responsive releasing process of drug delivery system in the cells.     

Enhancing Tumor Cell Response to Chemotherapy through the Targeted Delivery of Platinum Drugs Mediated by Highly Stable,Multifunctional Carboxymethylcellulose‐Coated Magnetic Nanoparticles

The fabrication of nanoparticles using different formulations, and which can be used for the delivery of chemotherapeutics, has recently attracted considerable attention. We describe herein an innovative approach that may ultimately allow for the selective delivery of anticancer drugs to tumor cells by using an external magnet. A conventional antitumor drug, cisplatin, has been incorporated into new carboxymethylcellulose‐stabilized magnetite nanoparticles conjugated with the fluorescent marker Alexa Fluor 488 or folic acid as targeting agent. The magnetic nanocarriers possess exceptionally high biocompatibility and colloidal stability. These cisplatin‐loaded nanoparticles overcome the resistance mechanisms typical of free cisplatin. Moreover, experiments aimed at the localization of the nanoparticles driven by an external magnet in a medium that mimics physiological conditions confirmed that this localization can inhibit tumor cell growth site‐specifically.     

pH‐sensitive carbon quantum dots−doxorubicin nanoparticles for tumor cellular targeted drug delivery

A kind of pH‐responsive carbon quantum dots?doxorubicin nanoparticles drug delivery platform (D‐Biotin/DOX‐loaded mPEG‐OAL/N‐CQDs) was designed and synthesized. The system consists of fluorescent carbon dots as cross‐linkers, and D‐Biotin worked as targeting groups, which made the system have a pH correspondence, doxorubicin hydrochloride (DOX) as the target drug, oxidized sodium alginate (OAL) as carrier materials. Ultraviolet (UV)‐Vis spectrum showed that the drug‐loading rate of DOX is 10.5%, and the drug release in vitro suggested that the system had a pH response and tumor cellular targeted, the drug release rate is 65.6% at the value of pH is 5.0, which is much higher than that at the value of pH is 7.4. The cytotoxicity test and laser confocal fluorescence imaging showed that the synthesized drug delivery system has high cytotoxicity to cancer cells, and the drug‐loaded nanoparticles could enter the cells through endocytosis.     

Drug Delivery Nanocarriers from a Fully Degradable PEG‐Conjugated Polyester with a Reduction‐Responsive Backbone

The remarkably high intracellular concentration of reducing agents is an excellent endogenous stimulus for designing nanocarriers programmed for intracellular delivery of therapeutic agents. However, despite their excellent biodegradability profiles, aliphatic polyesters that are fully degradable in response to the intracellular reducing environment are rare. Herein, a reduction‐responsive drug delivery nanocarrier derived from a linear polyester bearing disulfide bonds is reported. The reduction‐responsive polyester is synthesized via a convenient polycondensation process. After conjugation of terminal carboxylic acid groups of polyester to polyethylene glycol (PEG), the resulting polymer self‐assembles into nanoparticles that are capable of encapsulating dye and anticancer drug molecules. The reduction‐responsive nanoparticles display a fast payload release rate in response to the intracellular reducing environment, which translates into superior anticancer activity towards PC‐3 cells.     

Tuning the In Vivo Transport of Anticancer Drugs Using Renal‐Clearable Gold Nanoparticles

Precise control of in vivo transport of anticancer drugs in normal and cancerous tissues with engineered nanoparticles is key to the future success of cancer nanomedicines in clinics. This requires a fundamental understanding of how engineered nanoparticles impact the targeting‐clearance and permeation‐retention paradoxes in the anticancer‐drug delivery. Herein, we systematically investigated how renal‐clearable gold nanoparticles (AuNPs) affect the permeation, distribution, and retention of the anticancer drug doxorubicin in both cancerous and normal tissues. Renal‐clearable AuNPs retain the advantages of the free drug, including rapid tumor targeting and high tumor vascular permeability. The renal‐clearable AuNPs also accelerated body clearance of off‐target drug via renal elimination. These results clearly indicate that diverse in vivo transport behaviors of engineered nanoparticles can be used to reconcile long‐standing paradoxes in the anticancer drug delivery.     

Stimuli‐Responsive Water‐Soluble Fullerene (C60) Polymeric Systems

This review documents the advances in stimuli‐responsive water‐soluble fullerene (C₆₀) polymeric systems. Stimuli‐responsive polymers, when grafted onto C₆₀ impart “smart” and “responsive” characteristics, and these novel materials adopt various morphologies when subjected to external stimuli, such as pH, temperature, and salt. Various synthetic approaches for producing C₆₀‐polymers are outlined and discussed. The responsive behavior, water solubility, and self‐assembly characteristics of these C₆₀‐polymers make them attractive for applications such as drug delivery, temperature sensors, and personal care.     

Dual Thermo‐ and pH‐Responsive Zwitterionic Sulfobataine Copolymers for Oral Delivery System

A novel oral delivery system consisting of thermoresponsive zwitterionic poly(sulfobetaine methacrylate) (PSBMA) and pH‐responsive poly(2‐(diisopropylamino)ethyl methacrylate) (PDPA) is synthesized via free radical polymerization. This copolymer can self‐aggregate into nanoparticles via electrostatic attraction between ammonium cation and sulfo‐anion of PSBMA and successfully encapsulate anticancer drug, curcumin (CUR), with highest loading content of 2.6% in the P(SBMA‐co‐DPA) nanoparticles. The stimuli‐responsive phase transition behaviors of P(SBMA‐co‐DPA) copolymers at different pH buffer solution show pH‐dependent upper critical solution temperature (UCST) attributed to the influence of protonation/deprotonation of the pH‐responsive DPA segments. Through the delicate adjustment of the PSBMA/PDPA molar ratios, the stimuli‐responsive phase transition could be suitable for physiological environment. The kinetic drug release profiles demonstrate that P(SBMA‐co‐DPA) nanoparticles have the potential as oral delivery carriers due to their effective release of entrapped drugs in the stimulated intestinal fluid and preventing the deterioration of drug in stimulated gastric fluid.

     

Enzyme‐Responsive Multifunctional Magnetic Nanoparticles for Tumor Intracellular Drug Delivery and Imaging

Enzyme‐responsive, hybrid, magnetic silica nanoparticles have been employed for multifunctional applications in selective drug delivery and intracellular tumor imaging. In this study, doxorubicin (Dox)‐conjugated, enzyme‐cleavable peptide precursors were covalently tethered onto the surface of uniform silica‐coated magnetic nanoparticles through click chemistry. This enzyme‐responsive nanoparticle conjugate demonstrated highly efficient Dox release upon specific enzyme interactions in vitro. It also exhibits multiple functions in selective tumor intracellular drug delivery and imaging in the tumor cells with high cathepsin B expression, whereas it exhibited lower cytotoxicity towards other cells without enzyme expression.     

Dual‐Controlled Macroscopic Motions in a Supramolecular Hierarchical Assembly of Motor Amphiphiles

Three‐dimensional unidirectionally aligned and responsive supramolecular hierarchical assemblies have much potential in adaptive materials for biomedical and soft actuator applications. However, to achieve systematical control of the motion of stimuli‐responsive materials by orthogonal external stimuli and to complete a series of complicated tasks remains a grand challenge. Herein, we demonstrate a novel designed hybrid supramolecular assembly of molecular motor amphiphiles that also serves as a template for iron nanoparticles growth, and as a consequence this soft hybrid material is orthogonally controlled by dual light/magnetic stimuli. Macroscopic motor amphiphile strings, decorated with iron nanoparticles, provide fast response photoactuations and magnet induced movements that allows a precisely controlled cargo transport process.     

Emerging Supramolecular Therapeutic Carriers Based on Host–Guest Interactions

Recent advances in host–guest chemistry have significantly influenced the construction of supramolecular soft biomaterials. The highly selective and non‐covalent interactions provide vast possibilities of manipulating supramolecular self‐assemblies at the molecular level, allowing a rational design to control the sizes and morphologies of the resultant objects as carrier vehicles in a delivery system. In this Focus Review, the most recent developments of supramolecular self‐assemblies through host–guest inclusion, including nanoparticles, micelles, vesicles, hydrogels, and various stimuli‐responsive morphology transition materials are presented. These sophisticated materials with diverse functions, oriented towards therapeutic agent delivery, are further summarized into several active domains in the areas of drug delivery, gene delivery, co‐delivery and site‐specific targeting deliveries. Finally, the possible strategies for future design of multifunctional delivery carriers by combining host–guest chemistry with biological interface science are proposed.     

Delivery of ROS Generating Anthraquinones Using Reduction‐Responsive Peptide‐Based Nanoparticles

In order to limit the side effects associated with antitumor drugs such as doxorubicin, nanosized drug‐delivery systems capable of selectively delivering and releasing the drug in the diseased tissue are required. We describe nanoparticles (NPs), self‐assembled from a reduction responsive amphiphilic peptide, capable of entrapping high amounts of a redox active anticancer drug candidate and releasing it in presence of a reducing agent. This system shows a high entrapment efficiency with up to 15 mg drug per gram of peptide (5.8 mol‐%). Treatment of the NPs with reducing agent results in the disassembly of the NPs and release of the drug molecules. A reduction in cell viability is observed at drug concentrations above 250 nm in HEK293T and HeLa cell lines. This drug delivery system has potential for targeting tumor sites via the EPR effect while taking advantage of the increased reduction potential in tumor microenvironment.     

A pH‐Responsive Carrier System that Generates NO Bubbles to Trigger Drug Release and Reverse P‐Glycoprotein‐Mediated Multidrug Resistance

Multidrug resistance (MDR) resulting from the overexpression of drug transporters such as P‐glycoprotein (Pgp) increases the efflux of drugs and thereby limits the effectiveness of chemotherapy. To address this issue, this work develops an injectable hollow microsphere (HM) system that carries the anticancer agent irinotecan (CPT‐11) and a NO‐releasing donor (NONOate). Upon injection of this system into acidic tumor tissue, environmental protons infiltrate the shell of the HMs and react with their encapsulated NONOate to form NO bubbles that trigger localized drug release and serve as a Pgp‐mediated MDR reversal agent. The site‐specific drug release and the NO‐reduced Pgp‐mediated transport can cause the intracellular accumulation of the drug at a concentration that exceeds the cell‐killing threshold, eventually inducing its antitumor activity. These results reveal that this pH‐responsive HM carrier system provides a potentially effective method for treating cancers that develop MDR.     

Smart functionalized thin gel layers for electrochemical sensors,biosensors and devices

Combining hydrogels sensitive to external stimuli with conducting surfaces opens new possibilities in electrochemistry. Thin hydrogel layers as unique electrode-modifying materials provide highly permeable matrix for easy diffusion of analytes. In addition, larger individuals, for example, nanoparticles and enzymes, can be straightforwardly immobilized in the polymeric networks at electrode surfaces. Such properties are strongly desired for construction of sensors and biosensors. In addition, sensitivity to external stimuli allows to significantly enhance or weaken the electroanalytical signal. Recently, a significant number of articles concerning switchable sensors/biosensors, switchable electrochemical systems and signal–responsive interfaces have been published. This report is also focused on the construction of various devices based on electrode surfaces modified with smart hydrogel layers, for example, logic gates and electroresponsive hydrogel layers as potentially advanced drug delivery systems, artificial muscles and electrochemical valves.     

Effect of the Folate Ligand Density on the Targeting Property of Folated‐Conjugated Polymeric Nanoparticles

Targeted drug delivery systems have attracted increasing attention due to their ability for delivering anticancer drugs selectively to tumor cells. Folic acid (FA)‐conjugated targeted block copolymers, FA‐Pluronic‐polycaprolactone (FA‐Pluronic‐PCL) are synthesized in this study. The anticancer drug paclitaxel (PTX) is loaded in FA‐Pluronic‐PCL nanoparticles by nanoprecipitation method. The in vitro release of PTX from FA‐Pluronic‐PCL nanoparticles shows slow and sustained release behaviors. The effect of FA ligand density of FA‐Pluronic‐PCL nanoparticles on their targeting properties is examined by both cytotoxicity and fluorescence methods. It is shown that FA‐Pluronic‐PCL nanoparticles indicated better targeting ability than non‐targeted PCL‐Pluronic‐PCL nanoparticles. Furthermore, FA‐F127‐PCL nanoparticle with 10% FA molar content has more effective antitumor activity and higher cellular uptake than those with 50% and 91% FA molar content. These results prove that FA‐F127‐PCL nanoparticle with 10% FA molar content can be a better candidate as the drug carrier in targeted drug delivery systems.     

Stimuli‐Responsive Biomolecule‐Based Hydrogels and Their Applications

This Review presents polysaccharides, oligosaccharides, nucleic acids, peptides, and proteins as functional stimuli‐responsive polymer scaffolds that yield hydrogels with controlled stiffness. Different physical or chemical triggers can be used to structurally reconfigure the crosslinking units and control the stiffness of the hydrogels. The integration of stimuli‐responsive supramolecular complexes and stimuli‐responsive biomolecular units as crosslinkers leads to hybrid hydrogels undergoing reversible triggered transitions across different stiffness states. Different applications of stimuli‐responsive biomolecule‐based hydrogels are discussed. The assembly of stimuli‐responsive biomolecule‐based hydrogel films on surfaces and their applications are discussed. The coating of drug‐loaded nanoparticles with stimuli‐responsive hydrogels for controlled drug release is also presented.     

Prussian Blue Derived Nanoporous Iron Oxides as Anticancer Drug Carriers for Magnetic‐Guided Chemotherapy

New nanoporous iron oxide nanoparticles with superparamagnetic behavior were successfully synthesized from Prussian blue (PB) nanocubes through a thermal conversion method and applied to the intracellular drug‐delivery systems (DDS) of bladder cancer cells (i.e., T24) with controlled release and magnetic guiding properties. The results of the MTT assay and confocal laser scanning microscopy indicate that the synthesized iron oxide nanoparticles were successfully uptaken by T24 cells with excellent biocompatibility. An anticancer drug, that is, cisplatin, was used as a model drug, and its loading/release behavior was investigated. The intracellular drug delivery efficiency was greatly enhanced for the cisplatin‐loaded, PB‐derived, magnetic‐guided drug‐delivery system compared with the non‐drug case. The synthesized nanomaterials show great potential as drug vehicles with high biocompatibility, controlled release, and magnetic targeting features for future intracellular DDS.     

Stimuli‐responsive zein‐based nanoparticles as a potential carrier for ellipticine: Synthesis,release, and in vitro delivery

In the present research, we have investigated a drug delivery system based on the pH‐responsive behaviors of zein colloidal nanoparticles coated with sodium caseinate (SC) and poly ethylene imine (PEI). These systematically designed nanoparticles were used as nanocarriers for encapsulation of ellipticine (EPT), as an anticancer drug. SC and PEI coatings were applied through electrostatic adsorption, leading to the increased size and improved polydispersity index of nanoparticles as well as sustained release of drug. Physicochemical characteristics such as hydrodynamic diameter, size distribution, zeta potential and morphology of nanoparticles prepared using different formulations and conditions were also determined. Based on the results, EPT was encapsulated into the prepared nanoparticles with a high drug loading capacity (5.06%) and encapsulation efficiency (94.8%) under optimal conditions. in vitro experiments demonstrated that the release of EPT from zein‐based nanoparticles was pH sensitive. When the pH level decreased from 7.4 to 5.5, the rate of drug release was considerably enhanced. The mechanism of pH‐responsive complexation in the drug encapsulation and release processes was extensively investigated. The pH‐dependent electrostatic interactions and drug state were hypothesized to affect the release profiles. Compared to the EPT‐loaded zein/PEI nanoparticles, the EPT‐loaded zein/SC nanoparticles exhibited a better drug sustained‐release profile, with a smaller initial burst release and longer release period. According to the results of in vitro cytotoxicity experiments, drug‐free nanoparticles were associated with a negligible cytotoxicity, whereas the EPT‐loaded nanoparticles displayed a high toxicity for the cancer cell line, A549. Our findings indicate that these pH‐sensitive protein‐based nanoparticles can be used as novel nanotherapeutic tools and potential antineoplastic drug carriers for cancer chemotherapy with controlled release.     

Dual‐Targeted Selenium Nanoparticles for Synergistic Photothermal Therapy and Chemotherapy of Tumors

A combination of chemo‐ and photothermal therapy has emerged as a promising tactic for cancer therapy. However, the intricacy of accurate delivery and the ability to initiate drug release in specific tumor sites remains a challenging puzzle. Hence, to assure that the chemotherapeutic drug and photothermal agent are synchronously delivered to a tumor area for their synergistic effect, dual‐target (RC‐12 and PG‐6 peptides) functionalized selenium nanoparticles loaded with both doxorubicin (DOX) and indocyanine green (ICG) were designed and successfully synthesized. The as‐synthesized nanoparticles exhibited good monodispersity, size stability, and consistent spectral characteristics compared with those of ICG or DOX alone. The nanoparticles underwent self‐immolated cleavage under irradiation from a near‐IR laser and released the loaded drug owing to sufficient hyperthermia. Moreover, the internalized nanoparticles triggered the overproduction of intracellular reactive oxygen species to induce cell apoptosis. Taken together, this study provides a sequentially triggered nanosystem to achieve precise drug delivery by chemo‐photothermal combination.