Strategies for the development of stimuli-responsive small molecule prodrugs for cancer treatment.

Approved anticancer drugs typically face challenges due to their narrow therapeutic window, primarily because of high systemic toxicity and limited selectivity for tumors. Prodrugs are initially inactive drug molecules designed to undergo specific chemical modifications. These modifications render the drugs inactive until they encounter specific conditions or biomarkers in vivo, at which point they are converted into active drug molecules. This thoughtful design significantly improves the efficacy of anticancer drug delivery by enhancing tumor specificity and minimizing off-target effects. Recent advancements in prodrug design have focused on integrating these strategies with delivery systems like liposomes, micelles, and polymerosomes to further improve targeting and reduce side effects. This review outlines strategies for designing stimuli-responsive small molecule prodrugs focused on cancer treatment, emphasizing their chemical structures and the mechanisms controlling drug release. By providing a comprehensive overview, we aim to highlight the potential of these innovative approaches to revolutionize cancer therapy.

Unlocking the potential of stimuli-responsive biomaterials for bone regeneration.

Bone defects caused by tumors, osteoarthritis, and osteoporosis attract great attention. Because of outstanding biocompatibility, osteogenesis promotion, and less secondary infection incidence ratio, stimuli-responsive biomaterials are increasingly used to manage this issue. These biomaterials respond to certain stimuli, changing their mechanical properties, shape, or drug release rate accordingly. Thereafter, the activated materials exert instructive or triggering effects on cells and tissues, match the properties of the original bone tissues, establish tight connection with ambient hard tissue, and provide suitable mechanical strength. In this review, basic definitions of different categories of stimuli-responsive biomaterials are presented. Moreover, possible mechanisms, advanced studies, and pros and cons of each classification are discussed and analyzed. This review aims to provide an outlook on the future developments in stimuli-responsive biomaterials.

Esterase-Responsive Fluorogenic Prodrugs of Aldose Reductase Inhibitor Epalrestat: An Innovative Strategy toward Enhanced Anticancer Activity.

In addition to the conventional chemotherapeutic drugs, potent inhibitors of key enzymes that are differentially overexpressed in cancer cells and associated with its progression are often considered as the drugs of choice for treating cancer. Aldose reductase (AR), which is primarily associated with complications of diabetes, is known to be closely related to the development of cancer and drug resistance. Epalrestat (EPA), an FDA-approved drug, is a potent inhibitor of AR and exhibits anticancer activity. However, its poor pharmacokinetic properties limit its bioavailability and therapeutic benefits. We report herein the first examples of esterase-responsive turn-on fluorogenic prodrugs for the sustained release of EPA to cancer cells with a turn-on fluorescence readout. Carboxylesterases are known to be overexpressed in several organ-specific cancer cells and help in selective uncaging of drug from the prodrugs. The prodrugs were synthesized using a multistep organic synthesis and successfully characterized. Absorption and emission spectroscopic studies indicated successful activation of the prodrugs in the presence of porcine liver esterase (PLE) under physiological condition. HPLC studies revealed a simultaneous release of both the drug and the fluorophore from the prodrugs over time with mechanistic insights. While the inhibitory potential of EPA released from the prodrugs toward the enzyme AR was validated in the aqueous medium, the anticancer activity of the prodrugs was studied in a representative cervical cancer cell line. Interestingly, our results revealed that the development of the prodrugs can significantly enhance the anticancer potential of EPA. Finally, the drug uncaging process from the prodrugs by the intracellular esterases was studied in the cellular medium by measuring the turn-on fluorescence using fluorescence microscopy. Therefore, the present study highlights the rational development of the fluorogenic prodrugs of EPA, which will help enhance its anticancer potential with better therapeutic potential.

Intertumoral and intratumoral barriers as approaches for drug delivery and theranostics to solid tumors using stimuli-responsive materials.

The solid tumors provide a series of biological barriers in cellular microenvironment for designing drug delivery methods based on advanced stimuli-responsive materials. These intertumoral and intratumoral barriers consist of perforated endotheliums, tumor cell crowding, vascularity, lymphatic drainage blocking effect, extracellular matrix (ECM) proteins, hypoxia, and acidosis. Triggering opportunities have been drawn for solid tumor therapies based on single and dual stimuli-responsive drug delivery systems (DDSs) that not only improved drug targeting in deeper sites of the tumor microenvironments, but also facilitated the antitumor drug release efficiency. Single and dual stimuli-responsive materials which are known for their lowest side effects can be categorized in 17 main groups which involve to internal and external stimuli anticancer drug carriers in proportion to microenvironments of targeted solid tumors. Development of such drug carriers can circumvent barriers in clinical trial studies based on their superior capabilities in penetrating into more inaccessible sites of the tumor tissues. In recent designs, key characteristics of these DDSs such as fast response to intracellular and extracellular factors, effective cytotoxicity with minimum side effect, efficient permeability, and rate and location of drug release have been discussed as core concerns of designing paradigms of these materials.

Stimuli-responsive linkers and their application in molecular imaging.

Molecular imaging is a non-invasive imaging method that is widely used for visualization and detection of biological events at cellular or molecular levels. Stimuli-responsive linkers that can be selectively cleaved by specific biomarkers at desired sites to release or activate imaging agents are appealing tools to improve the specificity, sensitivity, and efficacy of molecular imaging. This review summarizes the recent advances of stimuli-responsive linkers and their application in molecular imaging, highlighting the potential of these linkers in the design of activatable molecular imaging probes. It is hoped that this review could inspire more research interests in the development of responsive linkers and associated imaging applications.

Self-Assembly in Living Cells: Bottom-Up Syntheses in Natural Factory.

In situ self-assembly in living systems is referred to as the processes that regulate assembly by stimuli-responsive reactions at target sites under physiological conditions. Due to the advantages of precisely forming well-defined nanostructures at pathological lesions, in situ-formed assemblies with tailored bioactivity are promising for the development of next-generation biomedical agents. In this Perspective, we summarize the progress of in situ self-assembly of peptides in living cells with an emphasis on the state-of-the-art strategies regulating assembly processes, establishing complexity within assembly systems, and exploiting their applications in biomedicines. We also provide our forward conceiving perspectives on the challenges in the development of in situ assembly in living cells to demonstrate its great potential in creating biomaterials for healthcare in the future.

Stimuli-responsive materials in oral diseases: a review.

OBJECTIVES: Oral diseases, such as dental caries, periodontitis, and oral cancers, are highly prevalent worldwide. Many oral diseases are typically associated with bacterial infections or the proliferation of malignant cells, and they are usually located superficially. MATERIALS AND METHODS: Articles were retrieved from PubMed/Medline, Web of Science. All studies focusing on stimuli-responsive materials in oral diseases were included and carefully evaluated. RESULTS: Stimulus-responsive materials are innovative materials that selectively undergo structural changes and trigger drug release based on shifts at the molecular level, such as changes in pH, electric field, magnetic field, or light in the surrounding environment. These changes lead to alterations in the properties of the materials at the macro- or microscopic level. Consequently, stimuli-responsive materials are particularly suitable for treating superficial site diseases and have found extensive applications in antibacterial and anticancer therapies. These characteristics make them convenient and effective for addressing oral diseases. CONCLUSIONS: This review aimed to summarize the classification, mechanism of action, and application of stimuli-responsive materials in the treatment of oral diseases, point out the existing limitations, and speculate the prospects for clinical applications. CLINICAL RELEVANCE: Our findings may provide useful information of stimuli-responsive materials in oral diseases for dental clinicians.

Chitosan Nanoparticles for Targeted Cancer Therapy: A Review of Stimuli-Responsive, Passive, and Active Targeting Strategies.

Despite all major advancements in drug discovery and development in the pharmaceutical industry, cancer is still one of the most arduous challenges for the scientific community. The implications of nanotechnology have certainly resolved major issues related to conventional anticancer modalities; however, the undesired recognition of nanoparticles (NPs) by the mononuclear phagocyte system (MPS), their poor stability in biological fluids, premature release of payload, and low biocompatibility have restricted their clinical translation. In recent decades, chitosan (CS)-based nanodelivery systems (eg, polymeric NPs, micelles, liposomes, dendrimers, conjugates, solid lipid nanoparticles, etc.) have attained promising recognition from researchers for improving the pharmacokinetics and pharmacodynamics of chemotherapeutics. However, the specialty of this review is to mainly focus on and critically discuss the targeting potential of various CS-based NPs for treatment of different types of cancer. Based on their delivery mechanisms, we classified CS-based NPs into stimuli-responsive, passive, or active targeting nanosystems. Moreover, various functionalization strategies (eg, grafting with polyethylene glycol (PEG), hydrophobic substitution, tethering of stimuli-responsive linkers, and conjugation of targeting ligands) adapted to the architecture of CS-NPs for target-specific delivery of chemotherapeutics have also been considered. Nevertheless, CS-NPs based therapeutics hold great promise for improving therapeutic outcomes while mitigating the off-target effects of chemotherapeutics, a long-term safety profile and clinical testing in humans are warranted for their successful clinical translation.

Stimuli-Responsive Covalent Organic Frameworks for Cancer Therapy.

Chemotherapy as a common anticancer therapeutic modality is often challenged by various obstacles such as poor stability, low solubility, and severe side effects of chemotherapeutic agents as well as multidrug resistance of cancerous cells. Nanoparticles in the role of carriers for chemotherapeutic drugs and platforms for combining different therapeutic approaches have effectively participated in overcoming such drawbacks. In particular, nanoparticles able to induce their therapeutic effect in response to specific stimuli like tumor microenvironment characteristics (e.g., hypoxia, acidic pH, high levels of glutathione, and overexpressed hydrogen peroxide) or extrinsic stimulus of laser light bring about more precise and selective treatments. Among them, nanostructures of covalent organic frameworks (COFs) have drawn great interest in biomedical fields during recent years. Possessing large surface area, high porosity, structural stability, and customizable architecture, these biocompatible porous crystalline polymers properly translate to promising platforms for drug delivery and induction of combination therapies. With the focus on stimuli-responsive characteristics of nanoscale COFs, this study aims to propose an overview of their potentiality in cancer treatment on the basis of chemotherapy alone or in combination with sonodynamic, chemodynamic, photodynamic, and photothermal therapies.

Stimuli-Mediated Structural Interchange Between Pd6 and Pd12 Architectures: Selective Recognition of E-Stilbene by the Pd6 Architecture and its Photoprotection.

The dynamic behaviour of metal-ligand bonding cultivates stimuli-mediated structural transformations in self-assembled molecular architectures. The propensity of synthetically designed self-assembled systems to interchange between higher-order architectures is increased multi-fold when the building blocks have higher conformational degrees of freedom. Herein, we report a new ligand, (2,7-bis(di(pyridin-4-yl)amino)-9H-fluoren-9-one) (L), which, upon self-assembly with a cis-[(ethylene-1,2-diamine)Pd(NO3)2] acceptor (M), resulted in the formation of a M6L3 trifacial barrel (C1) in water. Interestingly, during crystallization, a rare M12L6 triangular orthobicupola architecture (C2) was generated along with C1. C2 could also be generated in solution via the application of several stimuli. C1 in aqueous medium could stabilize one trans-stilbene (tS) or cis-stilbene (cS) molecule in its cavity, with a selectivity for the former from their mixture. Moreover, C1 acted as an effective host to prevent the otherwise facile photoisomerization of tS to cS inside its hydrophobic cavity under UV irradiation. Conversely, the visible-light-induced reverse isomerization of encapsulated cS to encapsulated tS could be achieved readily due to the better stabilization of tS within the cavity of C1 and its transparency to visible light. A multi-functional system was therefore designed, which at the same time is stimuli-responsive, shows isomer selectivity, and photo-protects trans-stilbene.

Computer Simulations of Responsive Nanogels at Lipid Membrane.

The swelling and collapse of responsive nanogels on a planar lipid bilayer are studied by means of mesoscopic computer simulations. The effects of molecular weight, cross-linking density, and adhesion strength are examined. The conditions for collapse-mediated engulfing by the bilayer are found. In particular, the results show that at low hydrophobicity level the increase in the nanogel softness decreases the engulfing rate. On the contrary, for stronger hydrophobicity level the trend changes to the opposite one. At the same time, when the cross-linking density is too low or the adhesion strength is too high the nanogel deformation at the membrane suppresses the engulfing regardless of the network swelling ratio. Finally, for comparative reasons, the behavior of the nanogels is also studied at the solid surface. These results may be useful in the design of soft particles capable of tuning of their elasticity and porosity for successful intracellular drug delivery.

Polymer-drug and polymer-protein conjugated nanocarriers: Design, drug delivery, imaging, therapy, and clinical applications.

Polymer-drug conjugates and polymer-protein conjugates have been pivotal in the realm of drug delivery systems for over half a century. These polymeric drugs are characterized by the conjugation of therapeutic molecules or functional moieties to polymers, enabling a range of benefits including extended circulation times, targeted delivery, controlled release, and decreased immunogenicity. This review delves into recent advancements and challenges in the clinical translations and preclinical studies of polymer-drug conjugates and polymer-protein conjugates. The design principles and functionalization strategies crucial for the development of these polymeric drugs were explored followed by the review of structural properties and characteristics of various polymer carriers. This review also identifies significant obstacles in the clinical translation of polymer-drug conjugates and provides insights into the directions for their future development. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Designing intelligent bioorthogonal nanozymes: Recent advances of stimuli-responsive catalytic systems for biomedical applications.

Bioorthogonal nanozymes have emerged as a potent tool in biomedicine due to their unique ability to perform enzymatic reactions that do not interfere with native biochemical processes. The integration of stimuli-responsive mechanisms into these nanozymes has further expanded their potential, allowing for controlled activation and targeted delivery. As such, intelligent bioorthogonal nanozymes have received more and more attention in developing therapeutic approaches. This review provides a comprehensive overview of the recent advances in the development and application of stimuli-responsive bioorthogonal nanozymes. By summarizing the design outlines for anchoring bioorthogonal nanozymes with stimuli-responsive capability, this review seeks to offer valuable insights and guidance for the rational design of these remarkable materials. This review highlights the significant progress made in this exciting field with different types of stimuli and the various applications. Additionally, it also examines the current challenges and limitations in the design, synthesis, and application of these systems, and proposes potential solutions and research directions. This review aims to stimulate further research toward the development of more efficient and versatile stimuli-responsive bioorthogonal nanozymes for biomedical applications.

Vacancy Effect on the Luminescent and Water Responsive Properties of Vacancy-ordered Double Perovskite Derivatives.

Vacancy-ordered perovskites and derivatives represent an important subclass of hybrid metal halides with promise in applications including light emitting devices and photovoltaics. Understanding the vacancy-property relationship is crucial for designing related task-specific materials, yet research in this field remains sporadic. For the first time, we use the Connolly surface to quantitatively calculate the volume of vacancy (V□, □ = vacancy) in vacancy-ordered double perovskite derivatives (VDPDs). A relationship between void fraction and the structure, photoluminescent properties and humidity stability was established based on zero-dimensional (0-D) [N(alkyl)4]2Sb□Cl5□'-type VDPDs. Compared with the more commonly studied A2M(IV)X6□-type double perovskite (A = cation, M = metal ion, X = halide), [N(alkyl)4]2Sb□Cl5□' features double vacancy sites. Our results demonstrate an inverse relationship between the photoluminescent quantum yield and V□ in 0-D VDPDs. Additionally, structural transformation from A2SbCl5 to A3Sb2Cl9 was first reported, during which the novel 'gate-opening' gas adsorption phenomenon was observed in VDPDs for the first time, as evidenced by 'S'-shaped sorption isotherms for water vapor, indicating a cation-controlled water-vapor response behavior. A mixed-cation strategy was developed to modulate the humidity stability of VDPDs. Characterized by controllable water-responsive behavior and unique 'on-off-on' luminescent switching, A2M(III)□X5□'-type materials show great promise for multi-level information anti-counterfeiting applications.

Emerging Roles of Gossypol in Therapy: Innovations in Prodrug Design and Nanoformulation Frontiers.

Stimuli activatable systems have the potential to deliver drugs to targeted areas by releasing therapeutic agents in response to diseased specific microenvironments such as the acidic environment commonly found in diseased tissues. This review article focuses on gossypol, a bioactive compound with inherent toxicity due to its formyl groups. It highlights the potential of imine-linked gossypol-based prodrugs and nanoparticle formulations for targeted delivery and controlled release. The unique presence of polyphenolic cores on gossypol can be utilized to prepare nanoparticles. This review offers valuable insights into designing safer and more effective drug delivery systems by elucidating the masking effect and stimuli-responsive release mechanisms. Numerous examples demonstrate the conversion of formyl groups to imines, creating prodrugs that mask reactive functionalities and offer pH-responsive release. This insight can guide the design of combination therapeutics, where a second drug with an amine terminal group can form imine-linked prodrugs. Additionally, the second part discusses the use of polyphenolic moieties to create stable nanoparticles from infinite polymeric networks. Through a comprehensive examination of gossypol's properties and applications, this review emphasizes the broader implications of such a masking strategy for optimizing the therapeutic benefits of many similar bioactive compounds while minimizing adverse effects.

Multiple Stimuli-Responsive Color-Changing Polymer Materials for Reversible Writing and Anti-Counterfeiting.

Polymer materials with multiple stimuli-responsive properties have demonstrated many potential and practical applications. By covalently introducing spiropyran (SP1) and spirothiopyran (STP) into the polyurethane backbone, photochromic, mechanochromic, and thermally discolored polymer materials have been prepared. In this work, we report for the first time that white light (violet, blue, and green light) above a certain intensity can activate STP to green color. Based on the above discovery, the polyurethane with SP1 and STP can exhibit reversible three-color changes (brown, green, and purple) in response to four stimuli: ultraviolet irradiation, white light irradiation, mechanical stress, and heat. The color-changing polymer materials have high color contrast and excellent reversibility, and can be used for reversible writing, anticounterfeiting and information encryption, etc.

Photoactivated Cyclic Polyphthalaldehyde Microcapsules for Payload Delivery.

Microcapsules with a cyclic polyphthalaldehyde (cPPA) shell and oil core were fabricated by an emulsification process. The low ceiling temperature cPPA shell was made phototriggerable by incorporating a photoacid generator (PAG). Photoactivation of the PAG created a strong acid which catalyzed cPPA depolymerization, resulting in the release of the core payload, as quantified by 1H NMR. The high molecular weight cPPA (197 kDa) yielded uniform spherical microcapsules. The core diameter was 24.8 times greater than the cPPA shell thickness (2.4 to 21.6 µm). Nonionic bis(cyclohexylsulfonyl)diazomethane (BCSD) and N-hydroxynaphthalimide triflate (HNT) PAGs were used as the PAG in the microcapsule shells. BCSD required dual stimuli of UV radiation and post-exposure baking at 60 °C to activate cPPA depolymerization while room temperature irradiation of HNT resulted in instantaneous core release. A 300 s UV exposure (365 nm, 10.8 J/cm2) of the cPPA/HNT microcapsules resulted in 66.5 ± 9.4% core release. Faster core release was achieved by replacing cPPA with a phthalaldehyde/propanal copolymer. A 30 s UV exposure (365 nm, 1.08 J/cm2) resulted in 82 ± 13% core release for the 75 mol % phthalaldehyde/25 mol % propanal copolymer microcapsules. The photoresponsive shell provides a versatile polymer microcapsule technology for on-demand, controlled release of hydrophobic core payloads.

Highly Flexible and Reversible Stimuli-Responsive Photonic Crystal Film in Anti-Counterfeit, Detector, and Coating.

Various fascinating optical characteristics in organisms encourage scientists to develop biomimetic synthesis strategies and mimic their unique microstructure. Inspired by the Chameleon's skin with tunable color and superior flexibility, this work designs the evaporated-induced self-assembly technique to synthesize the chiral photonic crystal film. Ultrasonic-intensified and additive-assisted techniques synergistically optimize the film properties, on the aspects of optic and mechanic. The film shows considerable rigidity and superior flexibility, which can undergo multiple mechanical deformations. Without destroying the chiral nematic structure, the ultimate strain approaches 50%, which exceeds most cellulose-derived film materials. It also integrates excellent optical performance. The film color can cover the total visible region by tuning the photonic bandgap and has angle-dependent properties. It can make the response to humidity and solvents, and chromaticity variation reflects the degree of stimulation. Importantly, this structural-dependent color change is reversible. Lastly, the photonic crystal materials with excellent mechanics and unique optics have been applied in the security. The anti-counterfeiting material design contains photonic crystal ink, repeatable writing paper, information-hiding film, and color-changing labels, with the features of environmentally friendly, economical, non-destructive, and convenient for authentication.

Multi-Stimuli-Responsive Fluorescent Molecule with AIE and TICT Properties Based on 1,8-Naphthalimide.

A multi-stimuli responsive fluorophore, named NBDNI, was developed by constructing a 1,8-naphthalimide derivative in which a rotatable electron-donating N,N-dimethylaniline group attached to its 4-position. This molecular structure endowed NBDNI with aggregate-induced emission (AIE) and twisted intramolecular charge transfer (TICT) properties, enabling remarkable fluorescence changes in response to multiple external stimuli: (i) sensitivity to polarity in various solvent systems and polymer matrix; (ii) significant fluorescence response and excellent linearity towards temperature changes in solution; (iii) distinct switch of fluorescence color upon acid and base treatments; (iv) reversible mechanochromism behavior in the solid state. Moreover, the mechanisms underlying the aforementioned stimuli-responsive phenomena have been proposed based on comprehensive systematic measurements. Furthermore, preliminary applications such as fluorescence thermometry and acid/base test paper have been demonstrated. This research will bring about new opportunities for the development of novel stimuli-responsive luminescent materials.

Hydrogel-based therapeutic strategies for spinal cord injury repair: Recent advances and future prospects.

Spinal cord injury (SCI) is a debilitating condition that can result in significant functional impairment and loss of quality of life. There is a growing interest in developing new therapies for SCI, and hydrogel-based multimodal therapeutic strategies have emerged as a promising approach. They offer several advantages for SCI repair, including biocompatibility, tunable mechanical properties, low immunogenicity, and the ability to deliver therapeutic agents. This article provides an overview of the recent advances in hydrogel-based therapy strategies for SCI repair, particularly within the past three years. We summarize the SCI hydrogels with varied characteristics such as phase-change hydrogels, self-healing hydrogel, oriented fibers hydrogel, and self-assembled microspheres hydrogel, as well as different functional hydrogels such as conductive hydrogels, stimuli-responsive hydrogels, adhesive hydrogel, antioxidant hydrogel, sustained-release hydrogel, etc. The composition, preparation, and therapeutic effect of these hydrogels are briefly discussed and comprehensively evaluated. In the end, the future development of hydrogels in SCI repair is prospected to inspire more researchers to invest in this promising field.