Stimuli-responsive Drug Delivery Systems Research Articles

Novel Stimuli-Responsive Pectin-PVP-Functionalized Clay Based Smart Hydrogels for Drug Delivery and Controlled Release Application

Stimuli-responsive drug delivery systems are urgently required for injectable site-specific delivery and release of drugs in a controlled manner. For this purpose, we developed novel pH-sensitive, biodegradable, and antimicrobial hydrogels from bio-macromolecule pectin, polyvinylpyrrolidone (PVP), 3-aminopropyl (diethoxy)methyl silane (3-APDEMS), and sepiolite clay via blending and solution casting technique. The purified sepiolite (40 um) was functionalized with 3-APDEMS crosslinker (ex-situ modification) followed by hydrogels fabrication. FTIR and SEM confirmed crosslinked structural integrity and rod-like morphology of hydrogels respectively. The swelling properties of hydrogels could be controlled by varying the concentration of modified clay in pectin/PVP blends. Moreover, the decrease in pH increased the swelling of hydrogels indicating the pH-responsiveness of hydrogels. All hydrogels were degraded after 21 days in phosphate buffer saline pH 7.4 (human blood pH). In-vitro cytotoxicity against 3T3 mouse fibroblast cell line analysis confirmed cytocompatibility of all hydrogels. Ceftriaxone sodium (CTX-S) was selected as a model drug. The release profile of the hydrogel showed 91.82% release in PBS for 2 h in a consistent and controlled manner. The chemical structure of the drug remained intact during and after release confirmed through UV-Visible spectroscopy. Overall, these hydrogels could be used as potential scaffolds for future biomedical applications.

Tumor-Selective Cascade-Amplified Dual-Prodrugs Activation for Synergistic Oxidation-Chemotherapy

Tumor-Selective Cascade-Amplified Dual-Prodrugs Activation for Synergistic Oxidation-Chemotherapy

Advanced application of stimuli-responsive drug delivery system for inflammatory arthritis treatment.

Inflammatory arthritis is a major cause of disability in the elderly. This condition causes joint pain, loss of function, and deterioration of quality of life, mainly due to osteoarthritis (OA) and rheumatoid arthritis (RA). Currently, available treatment options for inflammatory arthritis include anti-inflammatory medications administered via oral, topical, or intra-articular routes, surgery, and physical rehabilitation. Novel alternative approaches to managing inflammatory arthritis, so far, remain the grand challenge owing to catastrophic financial burden and insignificant therapeutic benefit. In the view of non-targeted systemic cytotoxicity and limited bioavailability of drug therapies, a major concern is to establish stimuli-responsive drug delivery systems using nanomaterials with on-off switching potential for biomedical applications. This review summarizes the advanced applications of triggerable nanomaterials dependent on various internal stimuli (including reduction-oxidation (redox), pH, and enzymes) and external stimuli (including temperature, ultrasound (US), magnetic, photo, voltage, and mechanical friction). The review also explores the progress and challenges with the use of stimuli-responsive nanomaterials to manage inflammatory arthritis based on pathological changes, including cartilage degeneration, synovitis, and subchondral bone destruction. Exposure to appropriate stimuli induced by such histopathological alterations can trigger the release of therapeutic medications, imperative in the joint-targeted treatment of inflammatory arthritis.

Microfluidic Synthesis of a Bioactive Metal-Organic Framework for Glucose-Responsive Insulin Delivery.

In the current study, we report the microfluidic synthesis of a metal-organic framework (MOF) for insulin delivery based on the stimulus response of glucose. Insulin- and gold nanoparticle (AuNP)-encapsulated zeolitic imidazolate framework-8 (ZIF-8) was synthesized using a continuous-flow, microfluidic mixing system via a single-step process. Glucose oxidase mimicking the activity of AuNPs was utilized for oxidizing glucose molecules that entered the porous ZIF-8. The AuNPs oxidized glucose into gluconic acid and hydrogen peroxide inside the MOF (Ins-AuNP-ZIF-8). The resulting acidic pH led to the disruption of ZIF-8 and released insulin. Thus, the presence of glucose molecules provided a stimulus for insulin release. The bioactive MOFs were characterized for the presence of functional groups, morphology, crystallinity, size, and elemental confirmation. The presence of fluorescein-5-isothiocyanate-labeled insulin in the composite was confirmed using confocal laser scanning microscopy. The loading of insulin per unit weight of the MOF, determined by size-exclusion-high-performance liquid chromatography, was 77 and 88% in the batch and microfluidic processes, respectively. Drug release studies confirmed the response of the MOFs to glucose, which triggered insulin release. The synthesis process did not affect the characteristics and application of ZIF-8 and Ins-AuNP-ZIF-8. This study involving the facile synthesis of bioactive MOFs offers a sustainable strategy to design stimulus-responsive drug delivery systems and could be exploited for biosensing applications.

Biocompatible, photo-responsive layer-by-layer polymer nanocapsules with an oil core: in vitro and in vivo study.

In cancer therapy, stimulus-responsive drug delivery systems are of particular interest for reducing side effects in healthy tissues and improving drug selectivity in the tumoral ones. Here, a strategy for the preparation of a photo-responsive cross-linked trilayer deposited onto an oil-in-water nanoemulsion via a layer-by-layer technique is reported. The system is made of completely biocompatible materials such as soybean oil, egg lecithin and glycol chitosan, with heparin as the polymeric shell. The oil core is pre-loaded with curcumin as a model lipophilic active molecule with anti-tumoral properties. The trilayer cross-linkage is performed via a photoinitiator-free thiol-ene 'click' reaction. In particular, the system is implemented with an o-nitrobenzyl group functionalized with a thiol moiety which can perform both the thiol-ene 'click' reaction and the cleavage meant for controlled drug release at two different wavelengths, respectively. So the preparation and characterization of a photo-responsive natural nanocarrier (PNC) that is stable under physiological conditions owing to the thiol-ene cross-linkage are reported. PNC performance has been assessed in vitro on melanoma cells as well as in vivo on xenograft tumour-induced mice.

PH- and H2O2-sensitive drug delivery system based on sodium xanthate: Dual-responsive supramolecular vesicles from one functional group

Nano-drug delivery systems with multiple stimulus-responsive capabilities have superior response performance and efficient drug release. Nevertheless, it is sophisticated to construct multiple stimulus-responsive systems where the two or more functional groups need to be introduced simultaneously. Xanthate, one functional group with pH and H2O2 stimulus responsiveness, has significant potential applications for building dual-responsive drug delivery system. Herein, we present a novel dual stimuli-responsive supramolecular drug delivery system by using sodium xanthate derivative (SXD) as guest molecule and quaternary ammonium capped pillar[5]arene (QAP5) as host molecule through host-guest interaction on the basis of electrostatic interaction. The amphiphile QAP5⊃SXD could self-assemble into vesicles to efficiently load the anti-cancer drug DOX. The experimental results showed that QAP5⊃SXD nanoparticles could achieve efficient drug delivery and controlled release in the tumor microenvironment. Cytotoxicity experiments proved that DOX@QAP5⊃SXD nanoparticles could significantly improve the anticancer efficiency of free DOX on cancer cells. The present study provides an efficient strategy to develop supramolecular nanocarriers with dual-responsiveness in one functional group for controlled drug release.

Hollow polydopamine spheres with removable manganese oxide nanoparticle caps for tumor microenvironment-responsive drug delivery

The development of stimuli-responsive drug delivery system has gained much attention for drug delivery. Recent studies have demonstrated that polydopamine (PDA)-based drug delivery system is capable of loading and delivering drugs, but its therapeutic efficacy has been dampened due to limited stimuli-responsiveness. In this study, a novel hybrid hollow PDA sphere was designed to deliver therapeutic agents by responding to tumor microenvironments. To overcome the limited stimuli-responsiveness in the PDA platform, manganese oxide (MnO2) nanoparticles were employed to cap the surface of PDA hollow spheres as they exhibited potent responsiveness to endogenous Glutathione (GSH) in tumor microenvironments. Meanwhile, the GSH-sensitive MnO2 caps can prevent drug leakage, resulting in the selective delivery of the as-loaded drug for improved antitumor effect. In addition, the outer surface of the hybrid PDA hollow sphere can be integrated with Polyethylene glycol (PEG), which facilitates the use of the novel hollow sphere for cancer therapy. Collectively, the hybrid PDA hollow sphere with removable MnO2 nanoparticle caps is a promising vehicle to reduce drug leakage and facilitate drug release through different surroundings, providing a simple and yet effective strategy for cancer therapy.

Stimuli-Responsive Drug Delivery Systems for the Diagnosis and Therapy of Lung Cancer.

Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer death worldwide. Numerous drugs have been developed to treat lung cancer patients in recent years, whereas most of these drugs have undesirable adverse effects due to nonspecific distribution in the body. To address this problem, stimuli-responsive drug delivery systems are imparted with unique characteristics and specifically deliver loaded drugs at lung cancer tissues on the basis of internal tumor microenvironment or external stimuli. This review summarized recent studies focusing on the smart carriers that could respond to light, ultrasound, pH, or enzyme, and provided a promising strategy for lung cancer therapy.

Bacterial Succinoglycans: Structure, Physical Properties, and Applications.

Succinoglycan is a type of bacterial anionic exopolysaccharide produced from Rhizobium, Agrobacterium, and other soil bacteria. The exact structure of succinoglycan depends in part on the type of bacterial strain, and the final production yield also depends on the medium composition, culture conditions, and genotype of each strain. Various bacterial polysaccharides, such as cellulose, xanthan, gellan, and pullulan, that can be mass-produced for biotechnology are being actively studied. However, in the case of succinoglycan, a bacterial polysaccharide, relatively few reports on production strains or chemical and structural characteristics have been published. Physical properties of succinoglycan, a non-Newtonian and shear thinning fluid, have been reported according to the ratio of substituents (pyruvyl, succinyl, acetyl group), molecular weight (Mw), and measurement conditions (concentration, temperature, pH, metal ion, etc.). Due to its unique rheological properties, succinoglycan has been mainly used as a thickener and emulsifier in the cosmetic and food industries. However, in recent reports, succinoglycan and its derivatives have been used as functional biomaterials, e.g., in stimuli-responsive drug delivery systems, therapeutics, and cell culture scaffolds. This suggests a new and expanded application of succinoglycan as promising biomaterials in biomedical fields, such as tissue engineering, regenerative medicine, and pharmaceuticals using drug delivery.

A bioinspired stimuli-responsive amino acid-based antibacterial drug delivery system in cancer therapy

Design of tyrosine based stimuli responsive antibacterial drug delivery system with potential application in cancer therapy.

Local detection of pH-induced disaggregation of biocompatible micelles by fluorescence switch ON.

Fluorogenic nanoparticles (NPs) able to sense different physiological environments and respond with disaggregation and fluorescence switching OFF/ON are powerful tools in nanomedicine as they can combine diagnostics with therapeutic action. pH-responsive NPs are particularly interesting as they can differentiate cancer tissues from healthy ones, they can drive selective intracellular drug release and they can act as pH biosensors. Controlled polymerization techniques are the basis of such materials as they provide solid routes towards the synthesis of pH-responsive block copolymers that are able to assemble/disassemble following protonation/deprotonation. Ring opening metathesis polymerization (ROMP), in particular, has been recently exploited for the development of experimental nanomedicines owing to the efficient direct polymerization of both natural and synthetic functionalities. Here, we capitalize on these features and provide synthetic routes for the design of pH-responsive fluorogenic micelles via the assembly of ROMP block-copolymers. While detailed photophysical characterization validates the pH response, a proof of concept experiment in a model cancer cell line confirmed the activity of the biocompatible micelles in relevant biological environments, therefore pointing out the potential of this approach in the development of novel nano-theranostic agents.

Cross-Linked Ionic Polysaccharides: Insights from the Structure to Stimuli-Sensitive Drug Delivery System Applications

The review provides an insight regarding the state of the art of cross-linked ionic polysaccharides, which are a part of common drug delivery systems, which are involved in the regulation of release of drug in specific required sites. The changes in pH, ion concentration, wavelength, redox potential, temperature, electric and magnetic field intensity are the stimuli sensitive functions, which play a major roles. Due to their high reproducibility and better characterization from natural resources, the polysaccharides remains as a point of interest for compiling many stimuli-responsive drug delivery systems. The hydrogel networks are formed from ready cross-linking of ionic polysaccharides, subject to control of internal and external variables. These hydrogel networks become operative for drug release on-off through complex mechanisms. The polysaccharide-based drug delivery systems are now responsive to different hybrids, composites and grafted polymers with a broad range of stimuli functions.

Microfluidic-Assisted Preparation of Targeted pH-Responsive Polymeric Micelles Improves Gemcitabine Effectiveness in PDAC: In Vitro Insights.

Simple SummaryThis research suggests a new potential therapeutic approach to pancreatic ductal adenocarcinoma to improve drug effectiveness and overcome drug resistance. A double actively targeted gemcitabine delivery system, consisting of polymeric micelles, was developed by microfluidic technique to ensure a narrow size distribution, a good colloidal stability, and drug-encapsulation efficiency for the selective and controlled release of the loaded drug, in response to the pH variations and uPAR expression in tumors. In vitro studies assessed that the release of the drug in the acidic environment was higher than in the neutral one, and that the pH-responsive and uPAR-targeted polymeric micelles enhanced the antitumor properties of gemcitabine in models resembling the pancreatic tumor microenvironment.Pancreatic ductal adenocarcinoma (PDAC) represents a great challenge to the successful delivery of the anticancer drugs. The intrinsic characteristics of the PDAC microenvironment and drugs resistance make it suitable for therapeutic approaches with stimulus-responsive drug delivery systems (DDSs), such as pH, within the tumor microenvironment (TME). Moreover, the high expression of uPAR in PDAC can be exploited for a drug receptor-mediated active targeting strategy. Here, a pH-responsive and uPAR-targeted Gemcitabine (Gem) DDS, consisting of polymeric micelles (Gem@TpHResMic), was formulated by microfluidic technique to obtain a preparation characterized by a narrow size distribution, good colloidal stability, and high drug-encapsulation efficiency (EE%). The Gem@TpHResMic was able to perform a controlled Gem release in an acidic environment and to selectively target uPAR-expressing tumor cells. The Gem@TpHResMic displayed relevant cellular internalization and greater antitumor properties than free Gem in 2D and 3D models of pancreatic cancer, by generating massive damage to DNA, in terms of H2AX phosphorylation and apoptosis induction. Further investigation into the physiological model of PDAC, obtained by a co-culture of tumor spheroids and cancer-associated fibroblast (CAF), highlighted that the micellar system enhanced the antitumor potential of Gem, and was demonstrated to overcome the TME-dependent drug resistance. In vivo investigation is warranted to consider this new DDS as a new approach to overcome drug resistance in PDAC.

Strategies to Maximize Anthracycline Drug Loading in Albumin Microbubbles.

Human serum albumin (HSA) microbubbles (MBs) are attracting increasing attention as image-guided and stimuli-responsive drug delivery systems. To better understand and maximize drug encapsulation in HSA MBs, we investigated the impact of the loading strategy and the drugs' physicochemical properties on their entrapment in the MB shell. Regarding loading strategy, we explored preloading, i.e., incubating drugs with HSA prior to MB formation, as well as postloading, i.e., incubating drugs with preformed MB. Both strategies were utilized to encapsulate six anthracyclines with different physicochemical properties. We demonstrate that drug loading in the HSA MB shell profits from preloading as well as from employing drugs with high intrinsic HSA binding affinity. These findings exemplify the potential of exploiting the natural bioconjugation interactions between drugs and HSA to formulate optimally loaded MBs, and they promote the development of HSA MBs for ultrasound-triggered drug delivery.

H2O2-Responsive amphiphilic polymer with aggregation-induced emission (AIE) for DOX delivery and tumor therapy

Stimuli-responsive drug delivery systems (DDSs) based on amphiphilic polymers have attracted much attention. In this study, we reported an innovative H2O2-responsive amphiphilic polymer (TBP), bearing a H2O2-sensitive phenylboronic ester, AIE fluorophore tetraphenylethene (TPE) hydrophobic, and polyethylene glycol hydrophilic (PEG) moieties. TBP could self-assemble into micelles with an encapsulation efficiency as high as 74.9% for doxorubicin (DOX) in aqueous solution. In the presence of H2O2, TBP micelles was decomposed by oxidation, hydrolysis and rearrangement, leading to almost 80% DOX release from TBP@DOX micelles. TBP and the corresponding degradation products were biocompatible, while TBP@DOX micelles only displayed obvious toxicity toward cancer cells. Drug delivery process was clearly monitored by confocal laser scanning microscopic (CLSM) and flow cytometry (FCM) analysis. Moreover, in vivo anticancer study showed that TBP@DOX micelles were accumulated in tumor region of nude mice and effectively inhibited tumor growth. The results suggested that the reported H2O2-responsive amphiphilic polymer displayed great potential in drug delivery and tumor therapy.

The Effective Combination between 3D Cancer Models and Stimuli-Responsive Nanoscale Drug Delivery Systems.

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.

Recent advances in targeted stimuli-responsive nano-based drug delivery systems combating atherosclerosis

Atherosclerosis (AS), mainly caused by the changed immune system functions and inflammation, is the central pathogenesis of cardiovascular disease, which is a leading cause of death in the world. In modern medicine, the development of carriers precisely delivering the therapeutic agents to the target sites is the primary goal, which could minimize the potential adverse effects and be more effective in treating lesions. Due to the precise location, real-time monitoring, AS microenvironment response, and low toxicity, stimuli-responsive nano-based drug delivery systems (NDDSs) have been a promising approach in AS treatments. Herein, we will systematically summarize the recent advances in stimuli-responsive NDDSs for AS treatment, including internal stimuli (reactive oxygen species, enzyme, shear stress, and pH) and external stimuli (light, ultrasound, and magnetism) responsive NDDSs. Besides, we will also summarize in detail the classification of stimuli-responsive NDDSs for AS, such as organic NDDSs (e.g., lipid-based and polymer-based nanomaterials), inorganic NDDSs (e.g., metal-based nanoparticles and nonmetallic nanomaterials), and composite multifunctional NDDSs. Finally, the critical challenges and prospects of this field will also be proposed and discussed.

Engineered Hyaluronic Acid-Based Smart Nanoconjugates for Enhanced Intracellular Drug Delivery

Bacterial polysaccharides can be easily modified to offer dual stimuli-responsive drug delivery systems with double targeting potential. In this research work, bacterial polysaccharides hyaluronic acid (HA) were functionalized with α-tocopherol polyethylene glycol succinate (TPGS) and cholic acid (CA) to form multifunctional polysaccharides nanoconjugates (TPGS-HA-CA). Smart nanoconjugates were synthesized by forming a redox-responsive disulfide bond, and it is composed of double targeting ligands. Doxorubicin (DOX) encapsulated smart nanoconjugates were exhibited an average size of 200 nm with a uniform core-shell structure. It serves the pH-responsive side chain modulation of TPGS-HA-CA, which affords a high degree of swelling at acidic pH. Under the pH 5.0 it shows 57% of release due to the side chain modulation of C–H/N–H. Polysaccharides nanoconjugates exhibited the double stimuli-responsive drug delivery by rapid disassembly of disulfide linkage, which exhibited 72% drug release (pH 5.0+GSH 10 mM). In cytotoxic studies, DOX@TPGS-HA-CA exhibited a higher cytotoxic effect compared to DOX. Hyaluronic acid functionalization with CA, TPGS increases cell internalization, and dual stimuli activity promotes more cell death. Overall, multifunctional polysaccharides hydrogel nanoconjugates is a prospective material that has great potential for targeting breast cancer therapy.

Chemical chaperone delivered nanoscale metal–organic frameworks as inhibitor of endoplasmic reticulum for enhanced sensitization of thermo-chemo therapy

Thermotherapy and chemotherapy have received extensive attention to tumor treatment. However, thermal tolerance and drug resistance severely limit clinical effect of tumor therapy owing to endoplasmic reticulum (ER) stress. Reducing thermal tolerance and drug resistance of tumors is an urgent challenge to be solved. In this work, we design a nanoplatform of PBA-Dtxl@MIL-101 as an ER inhibitor. Amino functionalized Fe-metal organic framework (MIL-101) nanoparticles are synthesized as pH and microwave (MW) dual stimuli-responsive drug delivery system. Then, the chemical chaperones of 4-phenylbutyric acid (PBA) and antineoplastic drug Docetaxel (Dtxl) were successfully loaded into MIL-101 nanoparticles to form PBA-Dtxl@MIL-101 nanoparticles. Furthermore, PBA-Dtxl@MIL-101 nanoparticles exhibit inhibitor effect of ER stress through upregulating caspase 9 proteins and reduce thermal tolerance by downregulating HSP 90. It was demonstrated that the therapy sensitized by PBA-Dtxl@MIL-101 nanoparticles obviously destroyed tumor cells, showing simultaneously enhanced thermo-chemo therapy.

Multifunctional Size-Expandable Nanomedicines Enhance Tumor Accumulation and Penetration for Synergistic Chemo-Photothermal Therapy.

Size expansion can effectively improve tumor accumulation of nanocarriers where precise control is required. A dual-responsive nanocarrier stimulated by both endogenous pH and exogenous heat stimuli can change its size. Herein, a nanoparticle composed of poly(N,N-diethyl acrylamide) (PDEAA) and poly(2-(diisopropylamino) ethyl methacrylate) (PDPA) is developed. The antitumor drug celastrol (CLT) and the photosensitizer indocyanine green (ICG) are then loaded in it to form CIPP. ICG generates heat under near-infrared (NIR) stimulation to kill tumor cells and enhance CIPP penetration. Meanwhile, CIPP expands in response to hyperthermia and acid tumor microenvironments, preventing itself from returning to the blood flow, thus accumulating in tumor sites. Ultimately, the acidic lysosomal environment in tumor cells disintegrates CIPP to release CLT, directly inducing immunogenic cell death and sensitizing tumor cells for hyperthermia by disrupting the interaction of heat shock protein 90 and P50cdc37. Most of the tumors in B16F10-bearing mice are eradicated after single laser irradiation. The dual-responsive CIPP with multiple functions and simple design displays a synergistic antitumor effect. This study provides a basis for developing size-expandable stimulus-responsive drug delivery systems against tumors.