Efficient Cisplatin Pro‐Drug Delivery Visualized with Sub‐100 nm Resolution: Interfacing Engineered Thermosensitive Magnetomicelles with a Living System

Temperature‐responsive magnetic nanomicelles can serve as thermal energy and cargo carriers with controlled drug release functionality. In view of their potential biomedical applications, understanding the modes of interaction between nanomaterials and living systems and evaluation of efficiency of cargo delivery is of the utmost importance. In this work, we investigate the interaction between the hybrid magnetic nanomicelles engineered for controlled platinum complex drug delivery and a biological system at three fundamental levels: subcellular compartments, a single cell and whole living animal. Nanomicelles with polymeric P(NIPAAm‐co‐AAm)‐b‐PCL core‐shell were loaded with a hydrophobic Pt(IV) complex and Fe₃O₄ nanoparticles though self‐assembly. The distribution of a platinum complex on subcellular level is visualized using hard X‐ray fluorescence microscopy with unprecedented level of detail at sub‐100 nm spatial resolution. We then study the cytotoxic effects of platinum complex‐loaded micelles in vitro on a head and neck cancer cell culture model SQ20B. Finally, by employing the magnetic functionality of the micelles and additionally loading them with a near infrared fluorescent dye, we magnetically target them to a tumor site in a live animal xenografted model which allows to visualize their biodistribution in vivo.     

Therapeutic‐Gas‐Responsive Hydrogel

Nitric oxide (NO) is a crucial signaling molecule with various functions in physiological systems. Due to its potent biological effect, the preparation of responsive biomaterials upon NO having temporally transient properties is a challenging task. This study represents the first therapeutic‐gas (i.e., NO)‐responsive hydrogel by incorporating a NO‐cleavable crosslinker. The hydrogel is rapidly swollen in response to NO, and not to other gases. Furthermore, the NO‐responsive gel is converted to enzyme‐responsive gels by cascade reactions from an enzyme to NO production for which the NO precursor is a substrate of the enzyme. The application of the hydrogel as a NO‐responsive drug‐delivery system is proved here by revealing effective protein drug release by NO infusion, and the hydrogel is also shown to be swollen by the NO secreted from the cultured cells. The NO‐responsive hydrogel may prove useful in many applications, for example drug‐delivery vehicles, inflammation modulators, and as a tissue scaffold.     

Photopolymerized Micelle‐Laden Hydrogels Can Simultaneously Form and Encapsulate Nanocrystals to Improve Drug Substance Solubility and Expedite Drug Product Design

Formulation technologies are critical for increasing the efficacy of drug products containing poorly soluble hydrophobic drugs, which compose roughly 70% of small molecules in commercial pipelines. Nanomedicines, such as nanocrystal formulations and amorphous solid suspensions, are effective approaches to increasing solubility. However, existing techniques require additional processing into a final dosage form, which strongly influences drug delivery and clinical performance. To enhance hydrophobic drug product efficacy and clinical throughput, a hydrogel material is developed as a sacrificial template to simultaneously form and encapsulate nanocrystals. These hydrogels contain micelles chemically bound to the hydrogel matrix, where the surfactant structure dictates the crystal size and drug loading. Therefore, nanocrystals can be produced in high yield (up to 90% drug loading, by weight) with precisely controlled sizes as small as 4 nm independently of hydrogel composition. Nanocrystals and surfactant are then released together to increase the solubility up to 70 times above bulk crystalline material. By integrating nanocrystals into a final dosage form, micelle‐laden hydrogels simplify hydrophobic drug product design.     

Drug delivery: Layer‐By‐Layer‐Assembled Capsules and Films for Therapeutic Delivery (Small 17/2010)

Polymeric materials formed via layer‐by‐layer (LbL) assembly have promise for use as drug delivery vehicles. These multilayered materials, both as capsules and thin films, can encapsulate a high payload of toxic or sensitive drugs, and can be readily engineered and functionalized with specific properties. This review highlights important and recent studies that advance the use of LbL‐assembled materials as therapeutic devices. It also seeks to identify areas that require additional investigation for future development of the field. A variety of drug‐loading methods and delivery routes are discussed. The biological barriers to successful delivery are identified, and possible solutions to these problems are discussed. Finally, state‐of‐the‐art degradation and cargo release mechanisms are also presented.     

Multifunctional Hybrid Nanoparticles for Traceable Drug Delivery and Intracellular Microenvironment‐Controlled Multistage Drug‐Release in Neurons

Innovative nanoparticles hold promising potential for disease therapy as drug delivery systems. For brain‐disease therapy, a drug delivery system that can sustainably control drug‐release and monitor fluorescence of the drug cargos is highly desirable. In this study, a light‐traceable and intracellular microenvironment‐responsive drug delivery system was developed based on the combination of glutathione‐responsive autoflurescent nanogel, dendrimer‐like mesoporous silica nanoparticles, and gold nanoparticles. The resulting hybrid nanoparticles represent a new class of delivery system that can efficiently load, transport, and control multistage‐release of sulfydryl‐containing drugs into neurons, with light‐traceable monitoring for future brain‐disease therapy.     

Near‐Infrared Light Responsive Multi‐Compartmental Hydrogel Particles Synthesized Through Droplets Assembly Induced by Superhydrophobic Surface

Light‐responsive hydrogel particles with multi‐compartmental structure are useful for applications in microreactors, drug delivery and tissue engineering because of their remotely‐triggerable releasing ability and combinational functionalities. The current methods of synthesizing multi‐compartmental hydrogel particles typically involve multi‐step interrupted gelation of polysaccharides or complicated microfluidic procedures with limited throughput. In this study, a two‐step sequential gelation process is developed to produce agarose/alginate double network multi‐compartmental hydrogel particles using droplets assemblies induced by superhydrophobic surface as templates. The agarose/alginate double network multi‐compartmental hydrogel particles can be formed with diverse hierarchical structures showing combinational functionalities. The synthesized hydrogel particles, when loaded with polypyrrole (PPy) nanoparticles that act as photothermal nanotransducers, are demonstrated to function as near‐infrared (NIR) light triggerable and deformation‐free hydrogel materials. Periodic NIR laser switching is applied to stimulate these hydrogel particles, and pulsatile release profiles are collected. Compared with massive reagents released from single‐compartmental hydrogel particles, more regulated release profiles of the multi‐compartmental hydrogel particles are observed.     

Poly(Methacrylic Acid) Polymer Hydrogel Capsules: Drug Carriers,Sub‐compartmentalized Microreactors,Artificial Organelles

Multilayered polymer capsules attract significant research attention and are proposed as candidate materials for diverse biomedical applications, from targeted drug delivery to microencapsulated catalysis and sensors. Despite tremendous efforts, the studies which extend beyond proof of concept and report on the use of polymer capsules in drug delivery are few, as are the developments in encapsulated catalysis with the use of these carriers. In this Concept article, the recent successes of poly(methacrylic acid) hydrogel capsules as carrier vessels for delivery of therapeutic cargo, creation of microreactors, and assembly of sub‐compartmentalized cell mimics are discussed. The developed technologies are outlined, successful applications of these capsules are highlighted, capsules properties which contribute to their performance in diverse applications are discussed, and further directions and plausible developments in the field are suggested.     

Smart Drug Delivery Nanocarriers with Self‐Assembled DNA Nanostructures

Self‐assembled DNA nanostructures have emerged as a type of nano‐biomaterials with precise structures, versatile functions and numerous applications. One particularly promising application of these DNA nanostructures is to develop universal nanocarriers for smart and targeted drug delivery. DNA is the genetic material in nature, and inherently biocompatible. Nevertheless, cell membranes are barely permeable to naked DNA molecules, either single‐ or double‐ stranded; transport across the cell membrane is only possible with the assistance of transfection agents. Interestingly, recent studies revealed that many DNA nanostructures could readily go into cells with high cell uptake efficiency. In this Progress Report, we will review recent advances on using various DNA nanostructures, e.g., DNA nanotubes, DNA tetrahedra, and DNA origami nanorobot, as drug delivery nanocarriers, and demonstrate several examples aiming at therapeutic applications with CpG‐based immunostimulatory and siRNA‐based gene silencing oligonucleotides.     

磁性水凝胶作为药物载体的应用研究进展

磁性水凝胶是一类同时具有磁性材料、高分子材料及水凝胶的性质特点的无机/有机复合材料。因具有优良的磁学性能及生物相容性,其作为新一代的药物载体可以实现磁响应、磁靶向及磁热疗等功能,在药物控制释放领域具有广阔的应用前景。对磁性水凝胶的制备方法及其在药物载体领域的研究情况进行了综述,详细介绍了磁性水凝胶作为药物载体的两种药物释放机理(ON/OFF模型及热敏释放原理),及其在磁靶向药物控释、磁热疗和磁共振成像方面的应用研究现状。     

Thread‐Like Radical‐Polymerization via Autonomously Propelled (TRAP) Bots

Micromotor‐mediated synthesis of thread‐like hydrogel microstructures in an aqueous environment is presented. The study utilizes a catalytic micromotor assembly (owing to the presence of a Pt layer), with an on‐board chemical reservoir (i.e., polymerization mixture), toward thread‐like radical‐polymerization via autonomously propelled bots (i.e., TRAP bots). Synergistic coupling of catalytically active Pt layer, together with radical initiators (H₂O₂ and FeCl₃ (III)), and PEGDA monomers preloaded into the TRAP bot, results in the polymerization of monomeric units into elongated thread‐like hydrogel polymers coupled with self‐propulsion. Interestingly, polymer generation via TRAP bots can also be triggered in the absence of hydrogen peroxide for cellular/biomedical application. The resulting polymeric hydrogel microstructures are able to entrap living cells (NIH 3T3 fibroblast cells), and are easily separable via a centrifugation or magnetic separation (owing to the presence of a Ni layer). The cellular biocompatibility of TRAP bots is established via a LIVE/DEAD assay and MTS cell proliferation assay (7 days observation). This is the first study demonstrating real‐time in situ hydrogel polymerization via an artificial microswimmer, capable of enmeshing biotic/abiotic microobjects in its reaction environment, and lays a strong foundation for advanced applications in cell/tissue engineering, drug delivery, and cleaner technologies.     

Combinatorial Drug Conjugation Enables Nanoparticle Dual‐Drug Delivery

A new approach to loading multiple drugs onto the same drug‐delivery nanocarrier in a precisely controllable manner, by covalently preconjugating multiple therapeutic agents through hydrolyzable linkers to form drug conjugates, is reported. In contrast to loading individual types of drugs separately, this drug‐conjugates strategy enables the loading of multiple drugs onto the same carrier with a predefined stoichiometric ratio. The cleavable linkers allow the therapeutic activity of the individual drugs to be resumed after the drug conjugates are delivered into the target cells and unloaded from the delivery vehicle. As a proof of concept, the synthesis and characterization of paclitaxel–gemcitabine conjugates are demonstrated. The time‐dependent hydrolysis kinetics and cytotoxicity of the combinatorial drug conjugates against human pancreatic cancer cells are examined. It is shown that the synthesized drug conjugates can be readily encapsulated into a lipid‐coated polymeric drug‐delivery nanoparticle, which significantly improves the cytotoxicity of the drug conjugates as compared to the free drug conjugates.     

Tough,Self‐Healing Hydrogels Capable of Ultrafast Shape Changing

Achieving multifunctional shape‐changing hydrogels with synergistic and engineered material properties is highly desirable for their expanding applications, yet remains an ongoing challenge. The synergistic design of multiple dynamic chemistries enables new directions for the development of such materials. Herein, a molecular design strategy is proposed based on a hydrogel combining acid–ether hydrogen bonding and imine bonds. This approach utilizes simple and scalable chemistries to produce a doubly dynamic hydrogel network, which features high water uptake, high strength and toughness, excellent fatigue resistance, fast and efficient self‐healing, and superfast, programmable shape changing. Furthermore, deformed shapes can be memorized due to the large thermal hysteresis. This new type of shape‐changing hydrogel is expected to be a key component in future biomedical, tissue, and soft robotic device applications.     

Protein‐Based Nanomedicine Platforms for Drug Delivery

Protein‐based nanomedicine platforms for drug delivery comprise naturally self‐assembled protein subunits of the same protein or a combination of proteins making up a complete system. They are ideal for drug‐delivery platforms due to their biocompatibility and biodegradability coupled with low toxicity. A variety of proteins have been used and characterized for drug‐delivery systems, including the ferritin/apoferritin protein cage, plant‐derived viral capsids, the small Heat shock protein (sHsp) cage, albumin, soy and whey protein, collagen, and gelatin. There are many different types and shapes that have been prepared to deliver drug molecules using protein‐based platforms, including various protein cages, microspheres, nanoparticles, hydrogels, films, minirods, and minipellets. The protein cage is the most newly developed biomaterial for drug delivery and therapeutic applications. The uniform size, multifunctionality, and biodegradability push it to the frontier of drug delivery. In this Review, the recent strategic development of drug delivery is discussed with emphasis on polymer‐based, especially protein‐based, nanomedicine platforms for drug delivery. The advantages and disadvantages are also discussed for each type of protein‐based drug‐delivery system.

     

Microfluidics‐Assisted Assembly of Injectable Photonic Hydrogels toward Reflective Cooling

Development of fast curing and easy modeling of colloidal photonic crystals is highly desirable for various applications. Here, a novel type of injectable photonic hydrogel (IPH) is proposed to achieve self‐healable structural color by integrating microfluidics‐derived photonic supraballs with supramolecular hydrogels. The supramolecular hydrogel is engineered via incorporating β‐cyclodextrin/poly(2‐hydroxypropyl acrylate‐co‐N‐vinylimidazole) (CD/poly(HPA‐co‐VI)) with methacrylated gelatin (GelMA), and serves as a scaffold for colloidal crystal arrays. The photonic supraballs derived from the microfluidics techniques, exhibit excellent compatibility with the hydrogel scaffolds, leading to enhanced assembly efficiency. By virtue of hydrogen bonds and host–guest interactions, a series of self‐healable photonic hydrogels (linear, planar, and spiral assemblies) can be facilely assembled. It is demonstrated that the spherical symmetry of the photonic supraballs endows them with identical optical responses independent of viewing angles. In addition, by taking the advantage of angle independent spectrum characteristics, the IPH presents beneficial effects in reflective cooling, which can achieve up to 17.4 °C in passive solar reflective cooling. The strategy represents an easy‐to‐perform platform for the construction of IPH, providing novel insights into macroscopic self‐assembly toward thermal management applications.     

TPGS‐Functionalized Polydopamine‐Modified Mesoporous Silica as Drug Nanocarriers for Enhanced Lung Cancer Chemotherapy against Multidrug Resistance

A nanocarrier system of d ‐a‐tocopheryl polyethylene glycol 1000 succinate (TPGS)‐functionalized polydopamine‐coated mesoporous silica nanoparticles (NPs) is developed for sustainable and pH‐responsive delivery of doxorubicin (DOX) as a model drug for the treatment of drug‐resistant nonsmall cell lung cancer. Such nanoparticles are of desired particle size, drug loading, and drug release profile. The surface morphology, surface charge, and surface chemical properties are also successfully characterized by a series of techniques such as transmission electron microscopy (TEM), X‐ray photoelectron spectroscopy (XPS), Brunauer‐Emmett‐Teller (BET) method, thermal gravimetric analysis (TGA), dynamic light scattering (DLS), and Fourier transform infrared spectroscopy (FTIR). The normal A549 cells and drug‐resistant A549 cells are employed to access the cytotoxicity and cellular uptake of the NPs. The therapeutic effects of TPGS‐conjugated nanoparticles are evaluated in vitro and in vivo. Compared with free DOX and DOX‐loaded NPs without TPGS ligand modification, MSNs‐DOX@PDA‐TPGS exhibits outstanding capacity to overcome multidrug resistance and shows better in vivo therapeutic efficacy. This splendid drug delivery platform can also be sued to deliver other hydrophilic and hydrophobic drugs.     

Rapid and Superior Bacteria Killing of Carbon Quantum Dots/ZnO Decorated Injectable Folic Acid‐Conjugated PDA Hydrogel through Dual‐Light Triggered ROS and Membrane Permeability

One of the most difficult challenges in the biomedical field is bacterial infection, which causes tremendous harm to human health. In this work, an injectable hydrogel is synthesized through rapid assembly of dopamine (DA) and folic acid (FA) cross‐linked by transition metal ions (TMIs, i.e., Zn²⁺), which was named as DFT‐hydrogel. Both the two carboxyl groups in the FA molecule and catechol in polydopamine (PDA) easily chelates Zn²⁺ to form metal–ligand coordination, thereby allowing this injectable hydrogel to match the shapes of wounds. In addition, PDA in the hydrogel coated around carbon quantum dot‐decorated ZnO (C/ZnO) nanoparticles (NPs) to rapidly generate reactive oxygen species (ROS) and heat under illumination with 660 and 808 nm light, endows this hybrid hydrogel with great antibacterial efficacy against Staphylococcus aureus (S. aureus, typical Gram‐positive bacteria) and Escherichia coli (E. coli, typical Gram‐negative bacteria). The antibacterial efficacy of the prepared DFT‐C/ZnO‐hydrogel against S. aureus and E. coli under dual‐light irradiation is 99.9%. Importantly, the hydrogels release zinc ions over 12 days, resulting in a sustained antimicrobial effect and promoted fibroblast growth. Thus, this hybrid hydrogel exhibits great potential for the reconstruction of bacteria‐infected tissues, especially exposed wounds.     

Synergistic Chemotherapy and Photodynamic Therapy of Endophthalmitis Mediated by Zeolitic Imidazolate Framework‐Based Drug Delivery Systems

Endophthalmitis, derived from the infections of pathogens, is a common complication during the use of ophthalmology‐related biomaterials and after ophthalmic surgery. Herein, aiming at efficient photodynamic therapy (PDT) of bacterial infections and biofilm eradication of endophthalmitis, a pH‐responsive zeolitic imidazolate framework‐8‐polyacrylic acid (ZIF‐8‐PAA) material is constructed for bacterial infection–targeted delivery of ammonium methylbenzene blue (MB), a broad‐spectrum photosensitizer antibacterial agent. Polyacrylic acid (PAA) is incorporated into the system to achieve higher pH responsiveness and better drug loading capacity. MB‐loaded ZIF‐8‐PAA nanoparticles are modified with AgNO₃/dopamine for in situ reduction of AgNO₃ to silver nanoparticles (AgNPs), followed by a secondary modification with vancomycin/NH₂‐polyethylene glycol (Van/NH₂‐PEG), leading to the formation of a composite nanomaterial, ZIF‐8‐PAA‐MB@AgNPs@Van‐PEG. Dynamic light scattering, transmission electron microscopy, and UV–vis spectral analysis are used to explore the nanoparticles synthesis, drug loading and release, and related material properties. In terms of biological performance, in vitro antibacterial studies against three kinds of bacteria, i.e., Escherichia coli, Staphylococcus aureus, and methicillin‐resistant S. aureus, suggest an obvious superiority of PDT/AgNPs to any single strategy. Both in vitro retinal pigment epithelium cellular biocompatibility experiments and in vivo mice endophthalmitis models verify the biocompatibility and antibacterial function of the composite nanomaterials.     

Reversible Ion‐Conducting Switch in a Novel Single‐Ion Supramolecular Hydrogel Enabled by Photoresponsive Host–Guest Molecular Recognition

A novel ion‐conducting supramolecular hydrogel with reversible photoconductive properties in which the azobenzene motif, α‐cyclodextrin (α‐CD), and ionic liquid are grafted onto the gel matrix is reported. Host–guest interactions with different association constants between α‐CD and azobenzene or the anionic part of the ionic liquid can be readily tuned by photoinduced trans–cis isomerization of the azobenzene unit. When irradiated by 365 nm light, α‐CD prefers to form a complex with the anionic part of the ionic liquid, resulting in decreased ionic mobility and thus high resistance of the hydrogel. However, under 420 nm light irradiation, a more stable complex is again formed between α‐CD and trans‐azobenzene, thereby releasing the bound anions to regenerate the low‐resistive hydrogel. As such, remote control of the ionic conductivity of the hydrogel is realized by simple host–guest chemistry. With the incorporation of a logic gate, this hydrogel is able to reversibly switch an electric circuit on and off by light irradiation with certain wavelengths. The concept of photoswitchable ionic conductivity of a hydrogel mediated by competitive molecular recognition is potentially promising toward the fabrication of optoelectronic devices and applications in bioelectronic technology.     

A Eutectic Mixture of Natural Fatty Acids Can Serve as the Gating Material for Near‐Infrared‐Triggered Drug Release

A smart release system responsive to near‐infrared (NIR) light is developed for intracellular drug delivery. The concept is demonstrated by coencapsulating doxorubicin (DOX) (an anticancer drug) and IR780 iodide (IR780) (an NIR‐absorbing dye) into nanoparticles made of a eutectic mixture of naturally occurring fatty acids. The eutectic mixture has a well‐defined melting point at 39 °C, and can be used as a biocompatible phase‐change material for NIR‐triggered drug release. The resultant nanoparticles exhibit prominent photothermal effect and quick drug release in response to NIR irradiation. Fluorescence microscopy analysis indicates that the DOX trapped in the nanoparticles can be efficiently released into the cytosol under NIR irradiation, resulting in enhanced anticancer activity. A new platform is thus offered for designing effective intracellular drug‐release systems, holding great promise for future cancer therapy.     

Immune Cell‐Mediated Biodegradable Theranostic Nanoparticles for Melanoma Targeting and Drug Delivery

Although tremendous efforts have been made on targeted drug delivery systems, current therapy outcomes still suffer from low circulating time and limited targeting efficiency. The integration of cell‐mediated drug delivery and theranostic nanomedicine can potentially improve cancer management in both therapeutic and diagnostic applications. By taking advantage of innate immune cell's ability to target tumor cells, the authors develop a novel drug delivery system by using macrophages as both nanoparticle (NP) carriers and navigators to achieve cancer‐specific drug delivery. Theranostic NPs are fabricated from a unique polymer, biodegradable photoluminescent poly (lactic acid) (BPLP‐PLA), which possesses strong fluorescence, biodegradability, and cytocompatibility. In order to minimize the toxicity of cancer drugs to immune cells and other healthy cells, an anti‐BRAF V600E mutant melanoma specific drug (PLX4032) is loaded into BPLP‐PLA nanoparticles. Muramyl tripeptide is also conjugated onto the nanoparticles to improve the nanoparticle loading efficiency. The resulting nanoparticles are internalized within macrophages, which are tracked via the intrinsic fluorescence of BPLP‐PLA. Macrophages carrying nanoparticles deliver drugs to melanoma cells via cell–cell binding. Pharmacological studies also indicate that the PLX4032 loaded nanoparticles effectively kill melanoma cells. The “self‐powered” immune cell‐mediated drug delivery system demonstrates a potentially significant advancement in targeted theranostic cancer nanotechnologies.