Stimuli-responsive Systems Research Articles

Stimuli-Responsive Codelivery System Self-Assembled from in Situ Dynamic Covalent Reaction of Macrocyclic Disulfides for Cancer Magnetic Resonance Imaging and Chemotherapy.

Supramolecular self-assembly has gained increasing attention to construct multicomponent drug delivery systems for cancer diagnosis and therapy. Despite that these self-assembled nanosystems present surprising properties beyond that of each subcomponent, the spontaneous nature of co-self-assembly causes significant difficulties in control of the synthesis process and consequently leads to unsatisfactory influences in downstream applications. Hence, we utlized an in situ dynamic covalent reaction based on thiol-disulfide exchange to slowly produce disulfide macrocycles, which subsequently triggered the co-self-assembly of an anticancer drug (doxorubicin, DOX) and a magnetic resonance imaging (MRI) contrast agent of ultrasmall iron oxide nanoparticles (IO NPs). It showed concentration regulation of macrocyclic disulfides, DOX, and IO NPs by a dynamic covalent self-assembly (DCS) strategy, resulting in a stable codelivery nanosystem with high drug loading efficiency of 37.36%. More importantly, disulfide macrocycles in the codelivery system could be reduced and broken by glutathione (GSH) in tumor cells, thus leading to disassembly of nanostructures and intellgent release of drugs. These stimuli-responsive performances have been investigated via morphologies and molecular structures, revealing greatly enhanced dual-modal MRI abilities and smart drug release under the trigger of GSH. Moreover, the codelivery system conjugated with a targeting molecule of cyclic Arg-Gly-Asp (cRGD) exhibited significant biocompatibility, MR imaging, and chemotherapeutic anticancer effect in vitro and in vivo. These results indicated that in situ dynamic covalent chemistry enhanced the control over co-self-assembly and paved the way to develop more potential drug delivery systems.

Drug-Loaded Lipid Magnetic Nanoparticles for Combined Local Hyperthermia and Chemotherapy against Glioblastoma Multiforme.

Glioblastoma multiforme (GBM) is a devastating tumor of the central nervous system, currently missing an effective treatment. The therapeutic gold standard consists of surgical resection followed by chemotherapy (usually with temozolomide, TMZ) and/or radiotherapy. TMZ does not, however, provide significant survival benefit after completion of treatment because of development of chemoresistance and of heavy side effects of systemic administration. Improvement of conventional treatments and complementary therapies are urgently needed to increase patient survival and quality of life. Stimuli-responsive lipid-based drug delivery systems offer promising prospects to overcome the limitations of the current treatments. In this work, multifunctional lipid-based magnetic nanovectors functionalized with the peptide angiopep-2 and loaded with TMZ (Ang-TMZ-LMNVs) were tested to enhance specific GBM therapy on an in vivo model. Exposure to alternating magnetic fields (AMFs) enabled magnetic hyperthermia to be performed, that works in synergy with the chemotherapeutic agent. Studies on orthotopic human U-87 MG-Luc2 tumors in nude mice have shown that Ang-TMZ-LMNVs can accumulate and remain in the tumor after local administration without crossing over into healthy tissue, effectively suppressing tumor invasion and proliferation and significantly prolonging the median survival time when combined with the AMF stimulation. This powerful synergistic approach has proven to be a robust and versatile nanoplatform for an effective GBM treatment.

Fabrication of stimuli-responsive nanoparticles for high-efficiency chlorantraniliprole delivery and smart control of Spodoptera frugiperda

A novel stimuli-responsive delivery system consisting of silicon-based material and environmental-friendly carboxymethyl chitosan (CMCS) coating was designed to enhance the distribution of chlorantraniliprole (Cap) in maize plants (Zea mays L.) against fall armyworm (Spodoptera frugiperda). Herein, Cap was loaded into mesoporous silica nanoparticles and coated with CMCS as a delivery system. The synthesized Cap-loaded nanoparticles had a particle size of about 35 nm with good Cap loading efficiency and sustained-release properties. On the other hand, the delivery system could expand the distribution and duration of Cap in maize. Due to the difference in pH sensitivity of the nanocarrier, it improved the insecticidal activity of Cap against S. frugiperda and showed good biocompatibility for zebrafish (Danio rerio). Briefly, this new strategy for protecting maize plants not only meets the needs of the pest management markets, but also facilitates the utilization of agrochemical.

Switching it Up: The Promise of Stimuli-Responsive Polymer Systems in Biomedical Science.

Responsive polymer systems have the ability to change properties or behavior in response to external stimuli. The properties of responsive polymer systems can be fine-tuned by adjusting the stimuli, enabling tailored responses for specific applications. These systems have applications in drug delivery, biosensors, tissue engineering, and more, as their ability to adapt and respond to dynamic environments leads to improved performance. However, challenges such as synthesis complexity, sensitivity limitations, and manufacturing issues need to be addressed for successful implementation. In our review, we provide a comprehensive summary on stimuli-responsive polymer systems, delving into the intricacies of their mechanisms and actions. Future developments should focus on precision medicine, multifunctionality, reversibility, bioinspired designs, and integration with advanced technologies, driving the dynamic growth of sensitive polymer systems in biomedical applications.

Thermoresponsive cholesteric liquid–crystal systems doped with terpenoids as drug delivery systems for skin applications

Stimuli-responsive and tunable soft-matter systems are an advanced class of materials applicable for drug delivery. Liquid crystals (LCs) are promising candidates as multifunctional materials that can respond to temperature, light or magnetic field. Particularly, ordering and physical properties of thermoresponsive LCs depend predominantly on temperature as external trigger. The current work addresses an elegant strategy to implement the anisotropic properties of thermoresponsive LCs with a view to extending their application for drug delivery. We firstly fabricated novel compositions with a thermotropic core based on natural products – cholesteryl esters and mono-/bicyclic terpenoids. The distinctive feature of aforementioned systems is their temperature-induced switchability of drug release by transition to the LC state, depending on the skin temperature. Their mesomorphic and optical behavior was characterized via differential scanning calorimetry and polarizing optical microscopy. Furthermore, we describe the dependence of helical pitch on LC formulation for various ternary cholesteric systems doped with terpenoids, suggesting that these stimuli-responsive chiral dopants are nominally untwisting. Data from fluorescence probe technique indicate that cholesteryl esters and terpenoids as essential components of those LC systems jointly disrupt the tight structure of phospholipid bilayer packing enabling the facilitated penetration of drugs. The potential of LC formulations was explored for several model drugs with diverse physicochemical properties by in vitro and ex vivo penetration tests using artificial membranes and full human skin. Our findings confirm the potential of LC systems for various applications in skin drug delivery.

A Dual Protective Drug Delivery System Based on Lipid Coated Core-Shell Mesoporous Silica for Efficient Delivery of Cabazitaxel to Prostate Cancer Cells

Abstract Many advancements are happening in drug delivery to develop an excellent nanocarrier to deliver drugs to target sites bypassing clinical barriers, thereby improving cellular uptake. Lipid coating on mesoporous silica nanoparticles (MSNs) has significantly reduced the drawbacks of many MSNs and increased their compatibility. This study reports a dual protective acid stimuli-responsive lipid-coated core-shell mesoporous silica nanoparticle (CSMS) conjugated with cabazitaxel showing better drug release, cell uptake, and cytotoxicity, and suitability in the prostate cancer (PC-3) cell line. Initially, monodispersed CSMS were conjugated with cabazitaxel (CBZ) through a hydrazone linker (CBZ@Hy-CSMS), proving its appropriate use in designing a stimuli-responsive system. In the second part, CBZ-conjugated CSMS was coated with a lipid layer (L-CBZ@Hy-CSMS) by the liposome fusion method. The presented dual protective CSMS system showed a significant increase in drug delivery at pH 5.4 compared to 7.4, with a drastic decrease in premature drug release when exposed to pH 7.4. The lipid-coated CSMS showed excellent biocompatibility and better cellular uptake with enhanced cell cytotoxicity in PC-3 cancer cells as compared to the uncoated CSMS. CSMS with a lipid coating combined with a stimuli-responsive system could improve the therapeutic delivery and treatment difficulties in many other cell lines and diseases.

Stimuli-Responsive Systems Based on Polymer-like Wormlike Micelles of Ionic Surfactants and Their Modern Applications

Solutions based on polymer-like micelles of ionic surfactants attract the attention of scientists as stimuli-responsive systems that can transform from a low-viscosity Newtonian fluid to a viscoelastic solution having a viscosity of up to 10 kPa s and an elastic response. The shape of micelles and their length are determined by the balance of hydrophobic and electrostatic interactions; therefore, the use of various low molecular weight substances or functional nanoparticles as additives can significantly change the rheological properties of such solutions and impart new stimuli-responsive properties to them. This review presents the most commonly used methods for controlling the properties of multicomponent solutions of wormlike surfactant micelles, including nanocomposite systems. Modern areas of practical application of such systems and prospects for their development are described.

Stimuli-Responsive Systems Based on Polymer-like Wormlike Micelles of Ionic Surfactants and Their Modern Applications

Stimuli-Responsive Systems Based on Polymer-like Wormlike Micelles of Ionic Surfactants and Their Modern Applications

Stimuli-Responsive Drug Delivery Systems Based on Bilayer Lipid Vesicles: New Trends

The development of new efficient methods for combating serious diseases, among which, oncological and infectious diseases hold a special place, remains to be an urgent challenge of biomedicine and biotechnology. Currently, the efforts of scientists are focused on the search for drug systems that provide high efficiency of treatment with minimal impacts on a human body. The development of this field has led to the creation of stimuli-responsive liposomes that can release an encapsulated drug under a specific stimulus, such as temperature, pH, electromagnetic field, light, etc. Being stimulated, lipid bilayer vesicles change their structure, size, surface charge, or phase state, thus leading to a controlled release of the drug in a specific place of the body, thereby resulting in a more accurate and efficient delivery. This review discusses the current trends in the development of liposome-based stimuli-responsive systems for the controlled delivery of biologically active substances.

(Invited) Smart Molecular/2D Heterostructures

Graphene and other 2D materials are almost exclusively based on inorganic lattices. Except for the chemical functionalization of the surface of the 2D material, molecules have been scarcely considered in this area. Here I propose to create hybrid heterostructures by interfacing stimuli-responsive molecular systems with graphene and semiconducting transition metal dichalcogenides (MoS2 and WSe2). The aim is that of tuning the properties of the “all surface” 2D material via an active control of the hybrid interface. This concept will provide an entire new class of smart molecular/2D heterostructures, which may be at the origin of a novel generation of hybrid materials and devices of direct application in highly topical fields like electronics, spintronics and energy storage. As smart-molecular systems I will choose magnetic spin-crossover materials able to switch between two spin states upon the application of an external stimulus (temperature, light or pressure) [2]. This spin transition is always accompanied by a significant change of volume in the material (by ca. 10%), so it can generate strain in its surroundings. I will show that in these heterostructures the electronic properties of graphene and the optical photoluminescence of monolayers of semiconducting metal dichalcogenides can be switched by light or by varying the temperature due to the strain concomitant to the spin transition [3, 4].

Innovations in the Design and Application of Stimuli-Responsive Restorative Dental Polymers.

The field of dental materials is undergoing rapid advancements in the pursuit of an innovative generation of dental polymeric restorative materials. There is a growing interest in the development of a distinct category of dental polymers that transcend the conventional role of inertly filling prepared cavities. Instead, these materials possess the capacity to actively detect and respond to alterations within the host environment by undergoing dynamic and controlled molecular changes. Despite the well-established status of stimuli-responsive polymeric systems in other fields, their implementation in dentistry is still in its nascent stages, presenting a multitude of promising opportunities for advancement. These systems revolve around the fundamental concept of harnessing distinctive stimuli inherent in the oral environment to trigger precise, targeted, predictable, and demand-driven responses through molecular modifications within the polymeric network. This review aims to provide a comprehensive overview of the diverse categories of stimuli-responsive polymers, accentuating the critical aspects that must be considered during their design and development phases. Furthermore, it evaluates their current application in the dental field while exploring potential alternatives for future advancements.

Electrochemical Assembly Strategies of Polymer and Hybrid Thin Films for (Bio)sensors, Charge Storage, and Triggered Release.

In the context of functional and hierarchical materials, electrode reactions coupled with one or more chemical reactions constitute the most powerful bottom-up process for the electrosynthesis of film components and their electrodeposition, enabling the localized functionalization of conductive surfaces using an electrical stimulus. In analogy with developmental biological processes, our group introduced the concept of morphogen-driven film buildup. In this approach, the gradient of a diffusing reactive molecule or ion (called a morphogen) is controlled by an electrical stimulus to locally induce a chemical process (solubility change, hydrolysis, complexation, and covalent reaction) that induces a film assembly. One of the prominent advantages of this technique is the conformal nature of the deposits toward the electrode. This Feature Article presents the contributions made by our group and other researchers to develop strategies for the assembly of different polymer and nanoparticle/polymer hybrid films by using electrochemically generated reagents and/or catalysts. The main electrochemical-chemical approaches for conformal films are described in the case where (i) the products are noncovalent aggregates that spontaneously precipitate on the electrode (film electrodeposition) or (ii) new chemical compounds are generated, which do not necessarily spontaneously precipitate and enable the formation of covalent or noncovalent films (film electrosynthesis). The applications of those electrogenerated films will be described with a focus on charge storage/transport, (bio)sensing, and stimuli-responsive cargo delivery systems.

Photo- and Redox-Regulated Transmembrane Ion Transporters.

Synthetic supramolecular ion transporters find applications as potential therapeutics and as tools for engineering functional membranes. Stimuli-responsive systems enable external control over transport, which is necessary for targeted activation. The Minireview provides an overview of current approaches to developing stimuli-responsive ion transport systems, including channels and mobile carriers, that can be controlled using photo or redox inputs.

Enhanced Insecticidal Activity of Chlorfenapyr against Spodoptera frugiperda by Reshaping the Intestinal Microbial Community and Interfering with the Metabolism of Iron-Based Metal-Organic Frameworks.

Spodoptera frugiperda (S. frugiperda) is an invasive pest that threatens global crop production and food security and poses a serious threat to maize production worldwide. Metal-organic framework (MOF) nanocarriers have great potential for agricultural pest control applications. The present study successfully prepared the chemical cross-linking of iron-based metal-organic framework nanoparticles (MIL-101(Fe)-NH2 NPs) with sodium lignosulfonate (SL) as a pH/laccase double stimuli-responsive pesticide release system. The average particle size of the prepared chlorfenapyr (CF)-loaded nanoparticles (CF@MIL-101-SL NPs) was 161.54 nm, and the loading efficiency was 44.52%. Bioactivity assays showed that CF@MIL-101-SL NPs increased the toxicity of CF to S. frugiperda and caused the rupture of the peritrophic membrane and enlargement of the midgut. Data from 16S rRNA gene sequencing showed that CF@MIL-101-SL treatment reduced the resistance of S. frugiperda to pesticides and pathogens and affected nutrient and energy availability by remodeling the intestinal microbiota of S. frugiperda. The dysregulated microbial community interacted with the broken peritrophic membrane, which exacerbated damage to the host. Nontargeted metabolomic results showed that ABC transporters may be a potential mechanism for the enhanced toxicity of CF@MIL-101-SL to S. frugiperda. In summary, the present study provides effective strategies for toxicological studies of nanopesticides against insects.

Advances in the stimuli-responsive mesoporous silica nanoparticles as drug delivery system nanotechnology for controlled release and cancer therapy.

Mesoporous silica nanoparticles (MSN) have attracted widespread attention in the field of drug delivery and biomedicine due to their unique structure and physicochemical properties. However, MSN still have shortcomings, such as premature drug release, poorly controlled release ability and poor targeting. Therefore, in order to reduce the damage of anti-cancer drugs to normal cells, improve their utilization rate and realize their selective release in tumor cells, "gated" stimuli-responsive mesoporous silicon nanomaterials as antitumor drug delivery carriers have attracted widespread interest among researchers. The "gated" stimuli-responsive nanovalves drug delivery system can only be removed under certain specific stimuli, which makes the drug maintain "zero release" before reaching the lesion site and achieve drug accumulation in tumor cells, effectively reducing the toxic and side effects on normal cells or tissues, and greatly exerting the efficacy of anti-cancer drugs. Therefore, the construction of stimuli-responsive nano-drug delivery systems have great application potential and significance in cancer treatment and controlled release of anti-cancer drugs. This review article emphasizes the research progress of the "gated" stimuli-responsive MSN (e.g. pH, redox potential, enzyme, temperature and light) or controlled drug release and cancer treatment since 2019.

A click chemistry-based, free radical-initiated delivery system for the capture and release of payloads

Click chemistries are efficient and selective reactions that have been leveraged for multi-stage drug delivery. A multi-stage system allows independent delivery of targeting molecules and drug payloads, but targeting first-phase materials specifically to disease sites remains a challenge. Stimuli-responsive systems are an emerging strategy where common pathophysiological triggers are used to target payloads. Oxidative stress is widely implicated in disease, and we have previously demonstrated that reactive oxygen species (ROS) can crosslink and immobilize polyethylene glycol diacrylate (PEGDA) in tissue mimics. To build on these promising results, we present a two-step, catch-and-release system using azide-DBCO click chemistry and demonstrate the capture and eventual release of a fluorescent payload at defined times after the formation of a PEGDA capturing net. The azide component is included with radical-sensitive PEGDA, and the payload is conjugated to the DBCO group. In cell-free and cell-based tissue mimic models, azides were incorporated at 0–30% in the first-phase polymer net, and DBCO was delivered at 2.5–10 µM in the second phase to control payload delivery. The payload could be captured at multiple timepoints after initial net formation, yielding a flexible and versatile targeting system. Matrix metalloproteinase (MMP)-degradable peptides were incorporated into the polymer backbone to engineer fluorescent payload release by MMPs, which are broadly upregulated in diseases, through degradation of the capture net and directly from the DBCO. Taken together, this research demonstrates proof-of-principle for a responsive and clickable biomaterial to serve as a multi-potent agent for the treatment of diseases compounded by high free radicals.

Stimuli-responsive nanodelivery systems for amplifying immunogenic cell death in cancer immunotherapy.

Immunogenic cell death (ICD) is a special pattern of tumor cell death, enabling to elicit tumor-specific immune response via the release of damage-associated molecular patterns and tumor-associated antigens in the tumor microenvironment. ICD-induced immunotherapy holds the promise for completely eliminating tumors and long-term protective antitumor immune response. Increasing ICD inducers have been discovered for boosting antitumor immunity via evoking ICD. Nonetheless, the utilization of ICD inducers remains insufficient owing to serious toxic reactions, low localization efficiency within the tumor microenvironmental niche, etc. For overcoming such limitations, stimuli-responsive multifunctional nanoparticles or nanocomposites with ICD inducers have been developed for improving immunotherapeutic efficiency via lowering toxicity, which represent a prospective scheme for fostering the utilization of ICD inducers in immunotherapy. This review outlines the advances in near-infrared (NIR)-, pH-, redox-, pH- and redox-, or NIR- and tumor microenvironment-responsive nanodelivery systems for ICD induction. Furthermore, we discuss their clinical translational potential. The progress of stimuli-responsive nanoparticles in clinical settings depends upon the development of biologically safer drugs tailored to patient needs. Moreover, an in-depth comprehending of ICD biomarkers, immunosuppressive microenvironment, and ICD inducers may accelerate the advance in smarter multifunctional nanodelivery systems to further amplify ICD.

Synthetic molecular motor activates drug delivery from polymersomes.

The design of stimuli-responsive systems in nanomedicine arises from the challenges associated with the unsolved needs of current molecular drug delivery. Here, we present a delivery system with high spatiotemporal control and tunable release profiles. The design is based on the combination of an hydrophobic synthetic molecular rotary motor and a PDMS-b-PMOXA diblock copolymer to create a responsive self-assembled system. The successful incorporation and selective activation by low-power visible light (λ = 430 nm, 6.9 mW) allowed to trigger the delivery of a fluorescent dye with high efficiencies (up to 75%). Moreover, we proved the ability to turn on and off the responsive behavior on demand over sequential cycles. Low concentrations of photoresponsive units (down to 1 mol% of molecular motor) are shown to effectively promote release. Our system was also tested under relevant physiological conditions using a lung cancer cell line and the encapsulation of an Food and Drug Administration (FDA)-approved drug. Similar levels of cell viability are observed compared to the free given drug showing the potential of our platform to deliver functional drugs on request with high efficiency. This work provides an important step for the application of synthetic molecular machines in the next generation of smart delivery systems.

Carboxymethyl β-cyclodextrin grafted hollow copper sulfide@mesoporous silica carriers for stimuli-responsive pesticide delivery

Stimuli-responsive controlled release systems have received extensive attention to improve the pesticide bioavailability and minimize environmental pollution. Herein, a multiple stimuli-responsive IMI@HCuS@mSiO2 @ -ss-CβCD delivery system was constructed using modified carboxymethyl β-cyclodextrin (CβCD-ss-COOH) as sealing materials, hollow copper sulfide nanoparticles with amino-functionalized mesoporous silica shell (HCuS@mSiO2-NH2) as carriers and imidacloprid (IMI) as the model drug. The cavity structure of HCuS@mSiO2-NH2 would provide a large space for pesticide loading. The results revealed that HCuS@mSiO2-ss-CβCD was approximately 230 nm in size and the loading efficiency for IMI was 25.7%, and exhibited better biosafety on bacteria and seed. HCuS carriers were also served as photothermal agent and possessed high photothermal conversion effect (η = 38.4%). IMI@HCuS@mSiO2 @ -ss-CβCD displayed excellent foliage adhesion and multiple stimuli-responsive release properties to pH, α-amylase, GSH, and NIR. The photostability of IMI embedded in CuS@mSiO2 @ -ss-CβCD was approximately 10 times that of IMI solution. This work provides an efficient nanoplatform for realizing pesticide delivery.

K-Carrageenan based magnetic@polyelectrolyte complex composite hydrogel for pH and temperature-responsive curcumin delivery

The dual stimuli-responsive drug delivery system has attracted a lot of interest in controlled drug delivery to specific sites. The magnetic iron oxide nanoparticles integrated polyelectrolyte complex-based hydrogel (MPEC HG) system was developed in this work. First, magnetic nanoparticles were produced in situ in the synthetic polymer polyhexamethylene guanidine (PHMG). Furthermore, the natural biopolymer k-carrageenan (kCG) was employed to form the polyelectrolyte complex (PEC) through charge-balancing interaction between positively charged guanidine units and negatively charged sulfonate groups. Various characterization approaches were used to characterize the developed magnetic polyelectrolyte complex hydrogel (MPEC HG) system. Curcumin (Cur) was employed as a model bioactive agent to examine the drug loading and stimuli-responsive drug release efficiency of the MPEC HG system. Under the combined pH and temperature stimuli conditions (pH 5.0/42 °C), the developed hydrogel system demonstrated great drug loading efficiency (∼ 68 %) and enhanced drug release. Furthermore, the MPEC HG system's in vitro cytotoxicity behavior was investigated on a human liver cancer (HepG2) cell line, and the results revealed that the MPEC HG system is biocompatible. As a result, the MPEC HG system might be used for dual pH and temperature stimuli-responsive drug delivery applications in cancer therapy.