Regioselective Ring‐Opening Polymerization of a Polyhydroxycarboxylic Acid for the Synthesis of a Nanoscale Carrier Material with pH‐Dependent Stability and Sustained Drug Release

Synthetic polyesters are usually composed of monohydroxycarboxylic acids to avoid the problem of regioselectivity during ring‐opening polymerization. In contrast, the linear polyester BICpoly contains four secondary OH groups and is nevertheless esterified regioselectively at only one of these positions. Neither the synthesis of the tricyclic monomers nor the ring‐opening polymerization requires protecting groups, making BICpoly an attractive novel and biocompatible polymer. BICpoly nanoparticles can be loaded with low‐molecular weight drugs or coated onto surfaces as thin films. The release of loaded compounds makes BICpoly an attractive depot for drug release, as shown herein by loading BICpoly with dyes or the cytostatic drug doxorubicin. BICpoly is distinguishable from other polymers by its characteristic pH‐dependent degradation.     

Metal–Organic‐Framework‐Templated Polyelectrolyte Nanocapsules for the Encapsulation and Delivery of Small‐Molecule–Polymer Conjugates

Herein, we report a strategy for exploiting nanoscale metal–organic frameworks (nano‐MOFs) as templates for the layer‐by‐layer (LbL) assembly of polyelectrolytes. Because small‐molecule drugs or imaging agents cannot be efficiently encapsulated by polyelectrolyte nanocapsules, we investigated two promising and biocompatible polymers (comb‐shaped polyethylene glycol (PEG) and hyperbranched polyglycerol‐based PEG) for the conjugation of model drugs and imaging agents, which were then encapsulated inside the nano‐MOF‐templated nanocapsules. Furthermore, we also systemically explored the release kinetics of the encapsulated conjugates, and examined how the encapsulation and/or release processes could be controlled by varying the composition and architecture of the polymers. We envision that our nano‐MOFs‐templated nanocapsules, through combining with small‐molecule–polymer conjugates, will represent a new type of delivery system that could open up new opportunities for biomedical applications.     

Hybrid cross‐linked hydrogels as a technology platform for in vitro release of cephradine

Hydrogel‐based drug delivery systems can leverage therapeutically favorable upshots of drug release and found clinical uses. Hydrogels offer temporal and spatial control over the release of different therapeutic agents. Because of their tailor made controllable degradability, physical properties, and ability to prevent the labile drugs from degradation, hydrogels provide platform on which diverse physicochemical interactions with entrapped drugs cause to control drug release. Herein, we report the fabrication of novel vinyltrimethoxy silane (VTMS) cross‐linked chitosan/polyvinyl pyrrolidone hydrogels. Swelling in distilled water in conjunction with different buffer and electrolyte solutions was performed to assess the swellability of hydrogels. Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), and X‐ray diffraction (XRD) analysis were further conducted to investigate the possible interactions between components, thermal stability, and crystallinity of as‐prepared hybrid hydrogels, respectively. In vitro time‐dependent biodegradability, antimicrobial study, and cytotoxicity were also carried out to evaluate their extensive biocompatibility and cytotoxic behavior. More interestingly, in vitro drug release study allowed for the controlled release of cephradine. Therefore, this facile strategy developed the novel biocompatible and biodegradable hybrid hydrogels, which could significantly expand the scope of these hydrogels in other biomedical applications like scaffolds, skin regeneration, tissue engineering, etc.     

Near‐Infrared‐Controlled,Targeted Hydrophobic Drug‐Delivery System for Synergistic Cancer Therapy

Hydrophobicity has been an obstacle that hinders the use of many anticancer drugs. A critical challenge for cancer therapy concerns the limited availability of effective biocompatible delivery systems for most hydrophobic therapeutic anticancer drugs. In this study, we have developed a targeted near‐infrared (NIR)‐regulated hydrophobic drug‐delivery platform based on gold nanorods incorporated within a mesoporous silica framework (AuMPs). Upon application of NIR light, the photothermal effect of the gold nanorods leads to a rapid rise in the local temperature, thus resulting in the release of the entrapped drug molecules. By integrating chemotherapy and photothermotherapy into one system, we have studied the therapeutic effects of camptothecin‐loaded AuMP‐polyethylene glycol‐folic acid nanocarrier. Results revealed a synergistic effect in vitro and in vivo, which would make it possible to enhance the therapeutic effect of hydrophobic drugs and decrease drug side effects. Studies have shown the feasibility of using this nanocarrier as a targeted and noninvasive remote‐controlled hydrophobic drug‐delivery system with high spatial/temperal resolution. Owing to these advantages, we envision that this NIR‐controlled, targeted drug‐delivery method would promote the development of high‐performance hydrophobic anticancer drug‐delivery system in future clinical applications.     

Tumor‐Microenvironment‐Induced Degradation of Ultrathin Gadolinium Oxide Nanoscrolls for Magnetic‐Resonance‐Imaging‐Monitored,Activatable Cancer Chemotherapy

The development of biodegradable inorganic nanoparticles with a tumor microenvironment‐activated therapeutic mode of action is urgently needed for precision cancer medicine. Herein, the synthesis of ultrathin lanthanide nanoscrolls (Gd₂O₃ NSs) is reported, which biodegrade upon encountering the tumor microenvironment. The Gd₂O₃ NSs showed highly controlled magnetic properties, which enabled their high‐resolution magnetic resonance imaging (MRI). Importantly, Gd₂O₃ NSs degrade in a pH‐responsive manner and selectively penetrate tumor tissue, enabling the targeted release of anti‐cancer drugs. Gd₂O₃ NSs can be efficiently loaded with an anti‐cancer drug (DOX, 80 %) and significantly inhibit tumor growth with negligible cellular and tissue toxicity both in vitro and in vivo. This study may provide a novel strategy to design tumor microenvironment‐responsive inorganic nanomaterials for biocompatible bioimaging and biodegradation‐enhanced cancer therapy.     

Tumor‐Microenvironment‐Induced Degradation of Ultrathin Gadolinium Oxide Nanoscrolls for Magnetic‐Resonance‐Imaging‐Monitored,Activatable Cancer Chemotherapy

The development of biodegradable inorganic nanoparticles with a tumor microenvironment‐activated therapeutic mode of action is urgently needed for precision cancer medicine. Herein, the synthesis of ultrathin lanthanide nanoscrolls (Gd₂O₃ NSs) is reported, which biodegrade upon encountering the tumor microenvironment. The Gd₂O₃ NSs showed highly controlled magnetic properties, which enabled their high‐resolution magnetic resonance imaging (MRI). Importantly, Gd₂O₃ NSs degrade in a pH‐responsive manner and selectively penetrate tumor tissue, enabling the targeted release of anti‐cancer drugs. Gd₂O₃ NSs can be efficiently loaded with an anti‐cancer drug (DOX, 80 %) and significantly inhibit tumor growth with negligible cellular and tissue toxicity both in vitro and in vivo. This study may provide a novel strategy to design tumor microenvironment‐responsive inorganic nanomaterials for biocompatible bioimaging and biodegradation‐enhanced cancer therapy.     

pH‐Responsive Drug‐Delivery Systems

In many biomedical applications, drugs need to be delivered in response to the pH value in the body. In fact, it is desirable if the drugs can be administered in a controlled manner that precisely matches physiological needs at targeted sites and at predetermined release rates for predefined periods of time. Different organs, tissues, and cellular compartments have different pH values, which makes the pH value a suitable stimulus for controlled drug release. pH‐Responsive drug‐delivery systems have attracted more and more interest as “smart” drug‐delivery systems for overcoming the shortcomings of conventional drug formulations because they are able to deliver drugs in a controlled manner at a specific site and time, which results in high therapeutic efficacy. This focus review is not intended to offer a comprehensive review on the research devoted to pH‐responsive drug‐delivery systems; instead, it presents some recent progress obtained for pH‐responsive drug‐delivery systems and future perspectives. There are a large number of publications available on this topic, but only a selection of examples will be discussed.     

A new access to polypyrrole‐based functionalized magnetic core‐shell nanoparticles

Magnetic nanoparticles (NP) have found various important applications in nanotechnology and nanomedicine, because they can be manipulated by external magnetic field and can be functionalized on their surface. Although a variety of magnetic core shell NP are known present research focuses on new NP with better properties (reduced toxicity, high colloidal and chemical stability, wide scope of application) and more straightforward and reproducible syntheses. In this work, we report the synthesis of azido‐functionalized polypyrrole (PPy)‐based superparamagnetic core shell NP by surface initiated polymerization wherein miniemulsion technique have been applied in this field for the first time. The new NP are attractive for biomedical applications because the PPy is biocompatible, the shell can easily be functionalized by Cu‐catalyzed click‐reaction as shown by the introduction of biotin and the material exhibits superparamagnetic behavior. The surface initiated polymerization is carried out at new magnetite NP, which are stabilized by pyrrol‐containing fatty acids. Although these starting NP lack a polymer shell, they show a remarkable stability and thus have the potential for further functionalization. The magnetic NP are characterized by various methods such as FTIR, X‐ray photoelectron spectroscopy, magnetic measurements, thermal gravimetric analysis, and dynamic light scattering. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Natural Triterpenoid‐ and Oligo(Ethylene Glycol)‐Pendant‐Containing Block and Random Copolymers: Aggregation and pH‐Controlled Release

In this research, a series of random and block amphiphilic copolymers of norbornene derivatives containing biocompatible natural triterpenoid and oligo(ethylene glycol) pendants were synthesized by ring‐opening metathesis polymerization. These copolymers were heat and pH responsive, and could self‐assemble into core–shell spherical micelles in aqueous solution. Their hydrodynamic diameters corresponded to pH values and monomer sequences. By evaluating the loading and release capacity of hydrophobic molecules, it was found that 1) the higher the content of the hydrophobic triterpenoid, the higher the loading capacity; 2) the release speed could be trigged by the pH because of the deprotonation of the carboxyl groups on the triterpenoid. Additionally, the copolymers exhibited low cytotoxicity toward L929 cells, which makes them potential nanocarrier candidates for controlled drug delivery.     

Supramolecular Proteoglycan Aggregate Mimics: Cyclodextrin‐Assisted Biodegradable Polymer Assemblies for Electrostatic‐Driven Drug Delivery

Self‐assembled, noncovalent polymeric biodegradable materials mimicking proteoglycan aggregates were synthesized from inclusion complexes of cationic surfactants with γ‐cyclodextrin and the natural anionic polymer hyaluronan. The amorphous structure of this ternary system was proven by X‐ray diffraction and thermal analysis. Light‐scattering measurements showed that there was a competition between hyaluronic acid and the surfactant for the cyclodextrin cavity. These self‐assembled supramolecular matrices were loaded with both hydrophilic and lipophilic drug substances for dissolution studies. The release of the entrapped drugs was found to be controlled by cations in the surrounding media and by biodegradation. Slow drug release in an ion‐free medium became faster in physiological salt solution in which the macroscopic polymer matrix was disassembled. In contrast, the enzymatic degradation of hyaluronan was hindered in the polymeric matrix. The supramolecular systems consisting of γ‐cyclodextrin as a macrocyclic host, a cationic surfactant guest, and hyaluronic acid as the anionic polymer electrostatically cross‐linked by the inclusion complex of the first two was found to be a novel drug‐delivery system for the controlled release of traditional drugs such as curcumin and ketotifen and proteins such as bovine serum albumin.     

Photo‐responsive amphiphilic poly(α‐hydroxy acids) with pendent o‐nitrobenzyl ester constructed via copper‐catalyzed azide‐alkyne cycloaddition reaction

Photo‐responsive block copolymer mPEG‐b‐poly(Tyr)‐g‐NB was prepared by introduction of o‐nitrobenzyl ester group into the side chain of amphiphilic poly(ethylene glycol)‐b‐poly(α‐hydroxy acids) (mPEG‐b‐poly(Tyr)) containing pendent alkynyl group via copper‐catalyzed azide‐alkyne cycloaddition reaction. The amphiphilic mPEG‐b‐poly(Tyr) was synthesized via the ring‐opening polymerization of O‐carboxyanhydrides, with monomethoxy poly(ethylene glycol) (mPEG) as macroinitiator. The molecular structure, self‐assembly, and photo‐controlled release of the obtained mPEG‐b‐poly(Tyr)‐g‐NB were thoroughly investigated. mPEG‐b‐poly(Tyr)‐g‐NB could self‐assemble into spherical micelles in water and showed disassembly under UV light irradiation, which was demonstrated by means of UV‐vis spectroscopy, scan electron microscopes, and dynamic light scattering measurement. Fluorescence emission measurements demonstrated that Nile red, encapsulated by micelles, can be released upon UV irradiation. This study provides a convenient way to construct smart poly(α‐hydroxy acids)‐based nanocarriers for controlled release of hydrophobic drugs. Copyright © 2015 John Wiley & Sons, Ltd.     

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.     

Preparation and characterization of poly(lactic‐co‐glycolic acid)/chitosan electrospun membrane containing amoxicillin‐loaded halloysite nanoclay

The main attitude of new wound dressings with biocompatible natural or synthetic polymers is improving and accelerating the healing process. In this study, halloysite nanotubes (HNTs) loaded with a model antibiotic drug, amoxicillin (AMX), were incorporated within poly(lactic‐co‐glycolic acid) (PLGA) solution that were electrospun with hydrophilic chitosan nanofibers simultaneously in two different syringes to make composite nanofibrous mat. The morphology, homogeneity, and fiber diameter of electrospun (PLGA/HNTs/AMX/chitosan) composite nanofibers were investigated by scanning electron microscopy and image J software. To evaluate the chemical structure, mechanical property, contact angle, and water absorption of samples, Fourier transform infrared spectroscopy, tensile testing, water contact angle, and immersion in phosphate buffer saline were utilized, respectively. Results indicated that incorporation of HNTs does not significantly alter nanofibers' morphology but rather increases their diameter, while the mechanical properties are improved because of its high modulus. Also, addition of natural hydrophilic polymer nanofibers (chitosan) enhanced the hydrophilicity property of samples. According to high‐performance liquid chromatography drug release analysis, HNTs as a good nanocarrier decreased initial burst release and showed controlled release behavior. MTT assay determined biocompatibility of PLGA/HNTs/AMX/chitosan. Copyright © 2016 John Wiley & Sons, Ltd.     

Effect of non‐rubber components on the mechanical properties of natural rubber

Effect of the nanomatrix structure on mechanical properties of natural rubber was investigated in relation to the strain‐induced crystallization. Structure of natural rubber was analyzed through Fourier transform infrared spectroscopy, wide‐angle X‐ray diffraction measurement and transmission electron microscopy. The nanomatrix of the non‐rubber components was found to be inevitably formed in natural rubber, in which natural rubber particles linking to fatty acids were dispersed in the nanomatrix of the proteins and phospholipids. The nanomatrix disappeared after deproteinization of natural rubber with urea. Tensile strength and modulus of natural rubber were reduced by removal of the fatty acids and the proteins, which resulted in disappearance of the nanomatrix structure. The effect of fatty acids on the crystallization of natural rubber in small particles as a dispersoid was proved by tensile test of blend of natural rubber and styrene butadiene rubber. Copyright © 2016 John Wiley & Sons, Ltd.     

An efficient approach to synthesize polysaccharides‐graft‐poly(p‐dioxanone) copolymers as potential drug carriers

Starch and poly(p‐dioxanone) (PPDO) are the natural and synthetic biodegradable and biocompatible polymers, respectively. Their copolymers can find extensive applications in biomedical materials. However, it is very difficult to synthesize starch‐graft‐PPDO copolymers in common organic solvents with very good solubility. In this article, well‐defined polysaccharides‐graft‐poly(p‐dioxanone) (SA_n‐PPDO) copolymers were successfully synthesized via the ring‐opening polymerization of p‐dioxanone (PDO) with an acetylated starch (SA) initiator and a Sn(Oct)₂ catalyst in bulk. The copolymers were characterized via Fourier transform infrared spectroscopy, ¹H NMR, gel permeation chromatography, thermogravimetric analysis (TG), differential scanning calorimetry, and wide angle x‐ray diffraction. The in vitro degradation results showed that the introduction of SA segments into the backbone chains of the copolymers led to an enhancement of the degradation rate, and the degradation rate of SA_n‐PPDO increased with the increase of SA wt %. Microspheres with an average volume diameter of 20 μm, which will have potential applications in controlled release of drugs, were successfully prepared by using these new copolymers. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 5344–5353, 2009     

Ring‐Opening Polymerization of Prodrugs: A Versatile Approach to Prepare Well‐Defined Drug‐Loaded Nanoparticles

The synthesis of polymer–drug conjugates from prodrug monomers consisting of a cyclic polymerizable group that is appended to a drug through a cleavable linker is achieved by organocatalyzed ring‐opening polymerization. The monomers polymerize into well‐defined polymer prodrugs that are designed to self‐assemble into nanoparticles and release the drug in response to a physiologically relevant stimulus. This method is compatible with structurally diverse drugs and allows different drugs to be copolymerized with quantitative conversion of the monomers. The drug loading can be controlled by adjusting the monomer(s)/initiator feed ratio and drug release can be encoded into the polymer by the choice of linker. Initiating these monomers from a poly(ethylene glycol) macroinitiator results in amphiphilic diblock copolymers that spontaneously self‐assemble into micelles with a long plasma circulation, which is useful for systemic therapy.     

Engineered Targeted Hyaluronic Acid–Glutathione‐Stabilized Gold Nanoclusters/Graphene Oxide–5‐Fluorouracil as a Smart Theranostic Platform for Stimulus‐Controlled Fluorescence Imaging‐Assisted Synergetic Chemo/Phototherapy

A theranostic platform with integrated diagnostic and therapeutic functions as well as specific targeted and controlled combination therapy to enhance treatment efficacy is of great importance for a wide range of biomedical applications. Here, we first attempted to develop biocompatible hyaluronic acid (HA)–glutathione (GSH) conjugate stabilized gold nanoclusters (GNCs) combined with graphene oxide (GO), accompanied by loading 5‐fluorouracil (5FU), as a novel theranostic platform (HG‐GNCs/GO‐5FU, HG refers to HA‐GSH). Multifunctional HG‐GNCs possessed excellent fluorescence, photosensitivity and specific targeting ability to the cancer cells while their fluorescence and singlet oxygen generation could be strongly inhibited by GO and then effectively restored by lysosomal hyaluronidase in tumor cells. The sustained and complete release of 5FU from HG‐GNCs/GO could also be stimulated successively by enzymatic degradation of HA and light‐induced heat effect of GO under laser irradiation so that turn‐on cell imaging‐assisted synergistic therapeutic strategies associated with triple enzyme/light‐controlled chemo/photothermal/photodynamic therapy could be achieved at the same time, reducing greatly the side effects of materials to normal cells. Our study presents a novel strategy to combine targeting and bioimaging with triple therapies to enhance the antitumor effect.     

Fuel‐Responsive Allosteric DNA‐Based Aptamers for the Transient Release of ATP and Cocaine

We show herein that allostery offers a key strategy for the design of out‐of‐equilibrium systems by engineering allosteric DNA‐based nanodevices for the transient loading and release of small organic molecules. To demonstrate the generality of our approach, we used two model DNA‐based aptamers that bind ATP and cocaine through a target‐induced conformational change. We re‐engineered these aptamers so that their affinity towards their specific target is controlled by a DNA sequence acting as an allosteric inhibitor. The use of an enzyme that specifically cleaves the inhibitor only when it is bound to the aptamer generates a transient allosteric control that leads to the release of ATP or cocaine from the aptamers. Our approach confirms that the programmability and predictability of nucleic acids make synthetic DNA/RNA the perfect candidate material to re‐engineer synthetic receptors that can undergo chemical fuel‐triggered release of small‐molecule cargoes and to rationally design non‐equilibrium systems.     

β‐cyclodextrin‐based polymeric nano‐receptor: the self‐assembly of cyclodextrin‐appended comb‐copolymer

Well‐defined β‐cyclodextrin (β‐CD)‐appended biocompatible comb‐copolymer ethyl cellulose‐graft‐poly (ε‐caprolactone) (EC‐g‐PCL) was synthesized via the combination of ring‐opening polymerization (ROP) and click chemistry. The resulting products were characterized by ¹H NMR, FT‐IR spectroscopy, and GPC. The synthesized comb‐copolymer could assemble to micelles, with the surface covered by β‐CD. The inclusion with ferrocene derivation was investigated by cyclic voltammetric (CV) experiments, which indicated the potential application of the micelles as nano‐receptors for molecule recognization and controlled drug release. Copyright © 2011 John Wiley & Sons, Ltd.     

Synthesis and Characterization of PEG‐Based Drug‐Responsive Biohybrid Hydrogels

Interactive materials being responsive to a biocompatible stimulus represent a promising approach for future therapeutic applications. In this study, we present a novel biohybrid material synthesized from biocompatible components being stimulus‐responsive to the pharmaceutically approved small‐molecule novobiocin. The hydrogel design is based on the gyrase B (GyrB) protein, which is covalently grafted to multi‐arm polyethylene glycol (PEG) using a Michael‐type addition reaction. Upon addition of the GyrB‐dimerizing substance coumermycin, stable hydrogels form which can be dissolved in a dose‐adjustable manner by the antibiotic novobiocin. The switchable properties of this PEG‐based hydrogel are favorable for future applications in tissue engineering and as externally controlled drug depot.