Smart Stimuli-Responsive Drug Delivery Systems for Advanced Diabetes Management.

Stimuli-responsive drug delivery systems for inflammatory skin conditions

Platinum-based anticancer drugs play a crucial role in the clinical treatment of various cancers. However, the application of platinum-based drugs is heavily restricted by their severe toxicity and drug resistance/cross resistance. Various drug delivery systems have been developed to overcome these limitations of platinum-based chemotherapy. Stimuli-responsive nanocarrier drug delivery systems as one of the most promising strategies attract more attention. And huge progress in stimuli-responsive nanocarrier delivery systems of platinum-based drugs has been made. In these systems, a variety of triggers including endogenous and extracorporeal stimuli have been employed. Endogenous stimuli mainly include pH-, thermo-, enzyme- and redox-responsive nanocarriers. Extracorporeal stimuli include light-, magnetic field- and ultrasound responsive nanocarriers. In this review, we present the recent advances in stimuli-responsive drug delivery systems with different nanocarriers for improving the efficacy and reducing the side effects of platinum-based anticancer drugs.

Simple SummaryCancer is one of the leading causes of death globally. Several studies, efforts and treatment strategies have been put forth for the treatment of different types of cancers. Several chemotherapeutic agents have been discovered and utilized for the treatment of various types of cancers and tumors, which play an important role in improving the quality of life of patients. The key problems associated with the abovementioned chemotherapeutic agents are the limited target ability and non-selective toxicity. The current review focuses on the achievement of improved targeting of anticancer agents at the tumor microenvironment without affecting normal tissues. The fulfilment of the mentioned objectives by stimuli-responsive drug delivery systems, as physical stimuli-responsive drug delivery systems and chemical stimuli-responsive drug delivery systems through active and passive targeting have extensively been discussed in the current review. The current review will help the wide community of researchers conducting research in targeted drug delivery systems and anticancer treatment strategies.The tumor-specific targeting of chemotherapeutic agents for specific necrosis of cancer cells without affecting the normal cells poses a great challenge for researchers and scientists. Though extensive research has been carried out to investigate chemotherapy-based targeted drug delivery, the identification of the most promising strategy capable of bypassing non-specific cytotoxicity is still a major concern. Recent advancements in the arena of onco-targeted therapies have enabled safe and effective tumor-specific localization through stimuli-responsive drug delivery systems. Owing to their promising characteristic features, stimuli-responsive drug delivery platforms have revolutionized the chemotherapy-based treatments with added benefits of enhanced bioavailability and selective cytotoxicity of cancer cells compared to the conventional modalities. The insensitivity of stimuli-responsive drug delivery platforms when exposed to normal cells prevents the release of cytotoxic drugs into the normal cells and therefore alleviates the off-target events associated with chemotherapy. Contrastingly, they showed amplified sensitivity and triggered release of chemotherapeutic payload when internalized into the tumor microenvironment causing maximum cytotoxic responses and the induction of cancer cell necrosis. This review focuses on the physical stimuli-responsive drug delivery systems and chemical stimuli-responsive drug delivery systems for triggered cancer chemotherapy through active and/or passive targeting. Moreover, the review also provided a brief insight into the molecular dynamic simulations associated with stimuli-based tumor targeting.

Currently, with the rapid development of nanotechnology, novel drug delivery systems (DDSs) have made rapid progress, in which nanocarriers play an important role in the tumour treatment. In view of the conventional chemotherapeutic drugs with many restrictions such as nonspecific systemic toxicity, short half-life and low concentration in the tumour sites, stimuli-responsive DDSs can deliver anti-tumour drugs targeting to the specific sites of tumours. Owing to precise stimuli response, stimuli-responsive DDSs can control drug release, so as to improve the curative effects, reduce the damage of normal tissues and organs, and decrease the side effects of traditional anticancer drugs. At present, according to the physicochemical properties and structures of nanomaterials, they can be divided into three categories: (1) endogenous stimuli-responsive materials, including pH, enzyme and redox responsive materials; (2) exogenous stimuli-responsive materials, such as temperature, light, ultrasound and magnetic field responsive materials; (3) multi-stimuli responsive materials. This review mainly focuses on the researches and developments of these novel stimuli-responsive DDSs based on above-mentioned nanomaterials and their clinical applications.

Stimuli-responsive drug-delivery systems (DDSs) have emerged as a potential tool for applications in healthcare, mainly in the treatment of cancer where versatile nanocarriers are co-triggered by endogenous and exogenous stimuli. Two-dimensional (2D) cell cultures are the most important in vitro model used to evaluate the anticancer activity of these stimuli-responsive DDSs due to their easy manipulation and versatility. However, some limitations suggest that these in vitro models poorly predict the outcome of in vivo studies. One of the main drawbacks of 2D cell cultures is their inadequate representation of the 3D environment’s physiological complexity, which sees cells interact with each other and the extracellular matrix (ECM) according to their specific cellular organization. In this regard, 3D cancer models are a promising approach that can overcome the main shortcomings of 2D cancer cell cultures, as these in vitro models possess many peculiarities by which they mimic in vivo tumors, including physiologically relevant cell–cell and cell–ECM interactions. This is, in our opinion, even more relevant when a stimuli-responsive DDS is being investigated. In this review, we therefore report and discuss endogenous and exogenous stimuli-responsive DDSs whose effectiveness has been tested using 3D cancer cell cultures.

Chapter 7 - Stimuli-responsive drug delivery systems for cancer immunotherapy

Intellective and stimuli-responsive drug delivery systems in eyes

This comprehensive review delineates the latest advancements in stimuli-responsive drug delivery systems engineered for the targeted treatment of breast carcinoma. The manuscript commences by introducing mammary carcinoma and the current therapeutic methodologies, underscoring the urgency for innovative therapeutic strategies. Subsequently, it elucidates the logic behind the employment of stimuli-responsive drug delivery systems, which promise targeted drug administration and the minimization of adverse reactions. The review proffers an in-depth analysis of diverse types of stimuli-responsive systems, including thermoresponsive, pH-responsive, and enzyme-responsive nanocarriers. The paramount importance of material choice, biocompatibility, and drug loading strategies in the design of these systems is accentuated. The review explores characterization methodologies for stimuli-responsive nanocarriers and probes preclinical evaluations of their efficacy, toxicity, pharmacokinetics, and biodistribution in mammary carcinoma models. Clinical applications of stimuli-responsive systems, ongoing clinical trials, the potential of combination therapies, and the utility of multifunctional nanocarriers for the co-delivery of assorted drugs and therapies are also discussed. The manuscript addresses the persistent challenge of drug resistance in mammary carcinoma and the potential of stimuli-responsive systems in surmounting it. Regulatory and safety considerations, including FDA guidelines and biocompatibility assessments, are outlined. The review concludes by spotlighting future trajectories and emergent technologies in stimuli-responsive drug delivery, focusing on pioneering approaches, advancements in nanotechnology, and personalized medicine considerations. This review aims to serve as a valuable compendium for researchers and clinicians interested in the development of efficacious and safe stimuli-responsive drug delivery systems for the treatment of breast carcinoma.

Stimuli-responsive natural gums-based drug delivery systems for cancer treatment

There has been an ever increasing interest in developing stimuli-responsive mesoporous silica drug delivery systems to improve therapeutic efficacy and minimize the adverse effects of drugs. This paper reports the works of our research group on valved and gated mesoporous silica drug delivery systems. Biocompatible mesoporous silica nanoparticles (MSNs), as drug carriers, were modified with active group-terminated silanes via self-assembly followed by diverse functionalization, a variety of macrocyclic hosts, proteins, DNA, and quantum dots were bound to the MSN surfaces to develop nanovalves and nanogates, through multiple noncovalent interactions, dynamic covalent bonds, and even strong covalent bonds, for the encapsulation of drugs within MSN pores, thus smart valved and gated MSN drug delivery systems were constructed. Under the stimuli of pH, redox, competitive binding, enzymes, and near infrared lights, controlled release of the encapsulated drugs was realized, because of the destruction of multiple noncovalent interactions, the cleavage of dynamic covalent bonds, and the disassociation of gatekeeping scaffolds. The carboxylate-substituted pillar [6] arene (CPA [6] )-valved dimethylbenzimidazolium or bipyridinium-functionalized MSN drug delivery systems were constructed for acidic pH, competitive binding, and metal chelating-responsive controlled release. The γ -CD-gated MSN delivery system functionalized with disulfide-linked carbamoylphenylboronic acid moieties and amines via dual dynamic covalent bonds with dual drug loading was constructed for simultaneous and cascade release of two drugs. It is a smart strategy to take advantage of the specific structures and properties of cyclodextrins (CDs) for use in the MSN drug delivery systems not only as gatekeepers but also as drug carriers. The γ -CD-gated MSN delivery system provided a smart platform for combination drug therapy, in addition to resistance to serum and normal blood glucose levels. The concanavalin A (Con A)-gated mannose-functionalized MSN drug delivery system via multivalent carbohydrate - protein interactions was constructed for the controlled release of drugs either by acidic pH or by competitive binding of glucose at high concentrations. The long and flexible spacers linked with the mannose ligands played an important role in adjusting the local spatial arrangement of the ligands to favor multivalent protein binding, as did the surface density of the ligands. The MSN drug delivery systems functionalized with N -(3-trimethoxysilylpropyl)ethylenediamine triacetate ligands, in the presence of metal ions with and without myoglobin containing surface-accessible histidine residues, were constructed for pH-responsive controlled release. Both the metal-latching ligands and the metal-chelating proteins played a synergetic role in gating MSNs for high-loading drug delivery and stimuli-responsive controlled release. The DNA-gated MSN drug delivery system functionalized with disulfide-linked acridinamine intercalators was constructed for multi-responsive controlled release under different stimuli, including disulfide reducing agents, elevated temperature, and deoxyribonuclease I. The DNA-gated MSN drug delivery system integrated multiple responses and AND logic gate operations into a single smart nanodevice not only for codelivery of drugs and DNA/genes but also for cascade release of two drugs in combination of dual stimuli. The DNA-gated gold nanorod-embedded MSN delivery system functionalized with titanium(IV)-chelating phosphonates with dual drug loading was constructed for simultaneous and cascade release of two drugs. Coordination chemistry is the first strategy for DNA cappings through multivalent chelating interactions in drug delivery systems not only as gatekeepers but also as drug carriers. The two drugs were simultaneously released upon triggering of endonuclease degradation or photothermal dehybridization and were successively released upon first triggering of basic pH and subsequent triggering of photothermal heating. The combination of NIR light-based thermotherapy and triggered chemotherapy (thermo-chemotherapy) could maximize therapeutic efficacy. In addition, the ZnO quantum dot (QD)-gated hollow mesoporous silica drug delivery system was constructed for pH and redox- responsive controlled release, and the ZnO QD-gated mesoporous carbon nanoparticle (MCN) drug delivery system was for pH-responsive controlled release. These constructed stimuli-responsive MSN drug delivery systems have promising applications in targeted tumor therapy.

The aim of this study was to evaluate glycemic levels in diabetic patients before, during, and after extractions using 2% lidocaine with 1:100,000 epinephrine (Lido/Epi) and 3% prilocaine with 0.03 IU/mL felypressin (Prilo/Fely). A double-blind, randomized clinical trial was conducted to evaluate changes in body parameters and glycemic levels in diabetic patients undergoing two anesthetic protocols during dental extractions. During surgery, we evaluated blood pressure (BP), heart rate (HR), saturation (SpO2), and capillary glycemic levels (Gly). These parameters were measured at the following surgical moments: basal, 30 min after medication, incision, tooth removal, suture, and 30 and 60 min after anesthesia. Data analysis showed no differences between the groups considering age, weight, and time spent in surgery. Increased systolic BP and decreased diastolic BP were observed in the lido/epi group. No difference was observed in the prilo/fely group among the surgical moments or between the groups regarding BP. No difference was observed in HR and SpO2 between the groups at any surgical moment. However, differences were found when compared the differences in glycemic and basal levels in both groups with greater decreases in blood glucose values for the lido/epi group. In anxiety level evaluation, there was no difference between the different surgical moments. Thus, both lido/epi and prilo/fely (maximum 3.6 mL) can be safely used in controlled diabetic patients CLINICAL RELEVANCE: The use of lidocaine associated with epinephrine did not increase glycemic levels but leads to decrease over time when associated with an anxiety reduction protocol, offering some advantage over prilocaine plus felypressin for diabetic patients.

Head and neck cancer (HNC) is among the most common malignancy that has a profound impact on human health and life quality. The treatment for HNC, especially for the advanced cancer is stage-dependent and in need of combined therapies. Various forms of adjuvant treatments such as chemotherapy, phototherapy, hyperthermia, gene therapy have been included in the HNC therapy. However, there are still restrictions with traditional administration such as limited in situ therapeutic effect, systemic toxicity, drug resistance, etc. In recent years, stimuli-responsive drug delivery systems (DDSs) have attracted the great attention in HNC therapy. These intelligent DDSs could respond to unique tumor microenvironment, external triggers or dual/multi stimulus with more specific drug delivery and release, leading to enhanced treatment efficiency and less reduced side effects. In this article, recent studies on stimuli-responsive DDSs for HNC therapy were summarized, which could respond to endogenous and exogenous triggers including pH, matrix metalloproteinases (MMPs), reactive oxygen species (ROS), redox condition, light, magnetic field and multi stimuli. Their therapeutic remarks, current limits and future prospect for these intelligent DDSs were discussed. Furthermore, multifunctional stimuli-responsive DDSs have also been reviewed. With the modification of drug carriers or co-loading with therapeutic agents. Those intelligent DDSs showed more biofunctions such as combined therapeutic effects or integration of diagnosis and treatment for HNC. It is believed that stimuli-responsive drug delivery systems showed great potential for future clinic translation and application for the treatment of HNC.

The purpose of this Research Topic, Microenvironmental stimuli-responsive nanomedicine for biomedical application, is to bring together the latest developments from researchers working on smart nanomaterials for biosensing and therapy applications. The guest editorial team would like to thank all colleagues who submitted their reviews and research articles for the Research Topic. The releasing of a microenvironment-responsive drug in the morbid site is one of the most effective therapeutic approaches, especially nanoparticles, for enhanced therapeutic outcomes for tumor therapy. That is because the compromised potency of nanomedicines has been attributed to its limited delivery efficiency into tumors, with less than ~1% of the nanoparticle dose reaching the solid tumors. Shen et al. analyzed the clinical value of magnetic resonance-guided microwave ablation in lung cancer. It showed that MRI-guided percutaneous ablation had significant prospects for the treatment of lung tumors and provided a satisfactory outcome. This suggested that local drug delivery could achieve favorable therapeutic efficacy. As it could not only significantly increase the local drug concentration but also decreased the number of drug administrations, it improved compliance and minimized side effects. Stimuli-responsive drug delivery systems are promising for the control of drug release in vivo. Various responsive systems triggered by microenvironment stimuli have been widely reported in the literature for controlled drug release studies. Among all types of stimuliresponsive drug delivery systems, pH-sensitive releasing has received increasing attention. Unlike the direct response to pH, Yang et al. developed an indirect pH-responsive insulin release system, which regulated insulin release behavior for diabetes therapy. In this work, glucose oxidase was employed as the microenvironment-responsive switch and converted a change in the hyperglycemic environment to a pH-stimulus to control the insulin releasing behavior. Furthermore, the regulation of the local microenvironment by ultrasound altered the release behavior of the insulin, because ultrasound can generate reactive oxygen species (ROS) and regulate the pharmacological effects in a timely manner. Inspired by this, Chen et al. showed a remote ultrasound-induced lidocaine delivery system for postoperative pain management. Under remote stimulation, drugs were released into the bloodstream because

Due to the great progress of nanotechnology in clinical application, numerous types of small drug delivery systems have been developed and utilized to improve the efficacy of anti-cancer drugs. Due to their excellent physiological properties, stimuli-responsive systems or “smart” systems that are able to release the drug at the desire site within the human body have received much interest in biomedical and cancer drug delivery. Herein, the recent advances and progress in the design and development of various stimuli-responsive drug delivery systems and their mechanisms of action are discussed in details.

The effects of aspartame (L-aspartyl-L-phenylalanine methyl ester) on plasma glucose and insulin levels were investigated in diabetic rats and patients with non-insulin-dependent diabetes mellitus. The oral administration of 0.45 mg aspartame per 100g body weight, which is equivalent to 150 mg of glucose in sweetness, to streptozotocin-induced diabetic rats had no effect on the plasma glucose or insulin levels. Also, 225 mg oral aspartame loading, which is equivalent to 75 g of glucose in sweetness, to patients with non-insulin-dependent diabetes mellitus did not increase plasma glucose or insulin levels, although 75 g of oral glucose loading increased plasma glucose and insulin levels in diabetic patients as expected. Aspartame ingestion for three days at a dose of 24-48 mg per day and the intake of snacks flavored with 240 mg of aspartame also did not increase fasting plasma glucose levels. These results suggest that acute administration of aspartame has no influence on plasma glucose or insulin levels in diabetic rats and patients with non-insulin-dependent diabetes mellitus.