Intelligent Drug Delivery Systems Research Articles

Enhanced treatment of cerebral ischemia–Reperfusion injury by intelligent nanocarriers through the regulation of neurovascular units

Reperfusion injury is one of the major causes of disability and death caused by ischemic stroke, and drug development focuses mainly on single neuron protection. However, different kinds of cells in the neurovascular units (NVUs), including neurons, microglia and vascular endothelial cells, are pathologically changed after cerebral ischemia–reperfusion injury, resulting in an urgent need to develop a drug delivery system to comprehensively protect the kinds of cells involved in the NVU. Herein, we have constructed a c(RGDyK) peptide modified, NF-κB inhibitor caffeic acid phenethyl ester (CAPE)-loaded and reactive nitrogen species (RNS) stimuli-responsive liposomal nanocarrier (R-Lipo-CAPE) to target ischemic lesions and then remodel the NVU to reduce the progression of cerebral ischemia–reperfusion injury. The R-Lipo-CAPE liposomes were approximately 170 nm with a zeta potential of -30.8 ± 0.2 mV. The in vitro CAPE release behavior from R-Lipo-CAPE showed an RNS-dependent pattern. For in vivo studies, transient middle cerebral artery occlusion/reperfusion (MCAO) model mice treated with R-Lipo-CAPE had the least neurological impairment and decreased brain tissue damage, with an infarct area of 13%, compared with those treated with saline of 53% or free CAPE of 38%. Furthermore, microglia in the ischemic brain were polarized to the tissue-repairing M2 phenotype after R-Lipo-CAPE treatment. In addition, R-Lipo-CAPE-treated mice displayed a prominent down-regulated expression of MMP-9 and restored expression of the tight junction protein claudin-5. This proof-of-concept indicates that R-Lipo-CAPE is a promising nanomedicine for the treatment of cerebral ischemia–reperfusion injury through the regulation of neurovascular units. Statement of significanceBased on the complex mechanism and difficulty in treatment of cerebral ischemia-reperfusion injury, the overall regulation of neurovascular unit has become an extremely important target. However, little nanomedicine has been directed to remodel the neurovascular units in targeted cerebral ischemia-reperfusion injury therapy. Here, c(RGDyK) peptide modified reactive nitrogen species (RNS) stimuli-responsive liposomal nanocarrier loaded with a NF-κB inhibitor (CAPE), was designed to simultaneously regulate various cells in the microenvironment of cerebral ischemia-reperfusion injury to remodel the neurovascular units. Our in vitro and in vivo data showed that the intelligent nanocarrier exerted the ability of pathological signal stimuli-responsive drug release, cerebral ischemia-reperfusion injury site targeting and neurovascular units remodeling through reducing neuron apoptosis, regulating microglia polarization and repairing vascular endothelial cell. Overall, the intelligent liposomal drug delivery system was a promising and safe nanomedicine in the perspective of cerebral ischemia-reperfusion injury treatment.

Shape Designed Implanted Drug Delivery System for In Situ Hepatocellular Carcinoma Therapy.

In this study, an intelligent drug delivery system (DDS) based on implanted triboelectric nanogenerator (iTENG) and red blood cell (RBC) is established for in situ hepatocellular carcinoma (HCC) therapy. Apatinib (APA), as an oral antitumor drug, which can inhibit the expression of vascular endothelial growth factor receptor-2 (VEGFR2) is loaded inside RBC, realizing the transform from oral formulation to injection preparation. Multishape designed iTENG adapted for different implant sites and environments can harvest biomechanical energy efficiently. The electric field (EF) generated by the iTENG can increase the release of APA, and the release will decrease quickly when the EF disappears, which shows that the DDS is highly controllable. The controllable DDS demonstrates an exciting killing ability of HCC cells both in vitro and in vivo with strikingly reduced APA dosage. After implantation, the self-powered DDS has a prominent therapeutic effect of HCC-bearing rabbits, which is expected to be applied in clinical medicine.

Effects of pH and UV on the stability, drug-loading and release behavior of alginate-based emulsion: A coarse-grained molecular dynamics simulation and experimental study

The development of a green-friendly intelligent drug delivery system with maximum drug utilization is the hot spot in the current era of great health and the grand strategy of protecting the environment. However, the evolution of interface multi-scale structure and the micro-mechanism of drug controlled-release/extended-release in intelligent drug-loading system are still common basic research issues in related application development. Therefore, we innovatively explored the effects of pH and UV on the stability, drug-loading and release behavior of coumarin-based alginate (SA-AMC) emulsion by the scientific research method combination of computer simulation and experimental analysis. The simulation results showed that the shrinkage of SA under acidic condition and the dimerization of AMC at 365 nm UV could improve the stability of the emulsion. Meanwhile, the drug-loading capacity and extended-release effect of the emulsions were closely related to the stability of the emulsions, and the drug molecules could be controlled release under alkaline condition. The experimental results were in good consistent with the simulation results, which indicated that the computational simulation had the excellent fitting effect on the experimental conditions, and could understand the behavior of emulsifier molecules at the micro-scale while providing theoretical guidance for the design and optimization of drug delivery system for drug-loading emulsions.

Construction of Intelligent Responsive Drug Delivery System and Multi-Mode Imaging Based on Gold Nanodots.

Cancer remains a formidable global problem with a high mortality rate. There are many effective anti-cancer drugs in clinical use, among which paclitaxel (PTX) has good effects on non-small cell lung cancer, ovarian cancer, and breast cancer. However, when applied to the clinic, PTX still has many limitations, such as poor water solubility, drug resistance, and side effects on healthy tissues. A gold nanodots-paclitaxel-polylysine (AuNDs-PTX-PLL) core-shell nano-system of integrated diagnosis and treatment is constructed to achieve intelligent responsive drug delivery. On the one hand, the problem of poor water-solubility and drug resistance of PTX are solved. On the other hand,the nano-system has an excellent intelligent response effect. Drugs can only be released in the weakly acidic environment of the tumor, which reduces the damage and side effects to normal tissues. Moreover, the nano-system can be used for real-time tracking and auxiliary diagnosis for the tumor through the multi-mode imaging mode, such as fluorescence, photoacoustic, and computed tomography to achieve accurate visualization. The photothermal effect of AuNDs is beneficial to promote the release of drugs. The nano-system integrates multi-mode imaging, chemotherapy, intelligent drug release in tumor weakly acidic environment, and has excellentpractical application prospects in tumor diagnosis and treatment.

Intelligent Drug Delivery System Based on Silk Fibroin/Wool Keratin

It is critical to develop drug carriers for intelligent drug delivery systems. Normally, the drug carriers of the intelligent drug delivery system are stimulus-responsive polymers. However, as drug carriers, the biocompatibility of the materials should be the primary consideration. In this work, two smart drug systems were prepared using natural protein materials (silk and wool) as drug carriers and poly(N-isopropylacrylamide) (PNIPAM) as a functional additive material. (1) Silk fibroin (SF)/wool keratin (WK) composite films: the differences in drug release efficiency of composite films are based on the different crystallinity of composite films. Analysis of the XRD results showed that the content of the β-crystallite structure in different proportions of the composite films changed from 38.3% to 19.5%. The percentage of drugs released of the mixed films with different proportions ranged from 28% to 58% after eight hours of release, showing a gradient release. (2) SF/WK and PNIPAM composite films: the particle size of the PNIPAM microspheres changed with the temperature. The particles’ size of the prepared PNIPAM microspheres was reduced from 700 nm to 300 nm from 25°C to 35°C. After eight hours of release, the composite films with temperature-sensitive microspheres increased the percentage of drug released by up to 20% compared with the composite films without microspheres when the temperature was ranged from 25°C to 37°C. The result of drug release showed the amount of drug released could be changed with temperature stimulation, which could satisfy people’s controllable requirements for the time, location, and dose of drug release.

Controlled Release of Insulin Based on Temperature and Glucose Dual Responsive Biomicrocapsules.

The treatment of diabetes lies in developing novel functional carriers, which are expected to have the unique capability of monitoring blood glucose levels continuously and dispensing insulin correctly and timely. Hence, this study is proposing to create a smart self-regulated insulin delivery system according to changes in glucose concentration. Temperature and glucose dual responsive copolymer microcapsules bearing N-isopropylacrylamide and 3-acrylamidophenylboronic acid as main components were developed by bottom-spray coating technology and template method. The insulinoma β-TC6 cells were trapped in the copolymer microcapsules by use of temperature sensitivity, and then growth, proliferation, and glucose-responsive insulin secretion of microencapsulated cells were successively monitored. The copolymer microcapsules showed favorable structural stability and good biocompatibility against β-TC6 cells. Compared with free cells, the biomicrocapsules presented a more effective and safer glucose-dependent insulin release behavior. The bioactivity of secreted and released insulin did not differ between free and encapsulated β-TC6 cells. The results demonstrated that the copolymer microcapsules had a positive effect on real-time sensing of glucose and precise controlled release of insulin. The intelligent drug delivery system is supposed to mimic insulin secretion in a physiological manner, and further provide new perspectives and technical support for the development of artificial pancreas.

Fabrication of Laponite-Reinforced Dextran-Based Hydrogels for NIR-Responsive Controlled Drug Release.

Natural polymer gels with sensitivity to near-infrared (NIR) light have attracted the attention of scientists working on intelligent drug delivery systems. Compared to ultraviolet or visible light, NIR light has the advantages of strong trigger levels, deep penetration through affected tissues, and fewer side effects. Herein, we present a topical photothermal hydrogel for NIR-controlled drug delivery. The proposed DexIEM-GM-Laponite hydrogel was prepared through free radical polymerization of vinyl-functionalized dextran (DexIEM), vinyl-modified graphene oxide (GM), and Laponite; thereafter, the hydrogel was loaded with ciprofloxacin (CIP, an antibacterial drug) as a model drug. With the Laponite content increased, the density of crosslinking in the hydrogel increased, and its mechanical properties improved noticeably. Under NIR irradiation, the DexIEM-GM-Laponite hydrogel exhibited a photothermal property, where the surface temperature increased from 26.8 to 55.5 °C. The simulation of subcutaneous drug delivery experiments ex vivo showed that under the specified pork tissue thickness (2, 4, and 6 mm), the CIP release remained NIR-controllable. Additionally, the results of the antibacterial performance tests indicated the excellent antibacterial effect of the hydrogel, and the blood hemolysis ratio of the hydrogel was less than 5%, signifying good blood compatibility. This work will provide an avenue for the application of NIR light-responsive materials in antimicrobial therapy.

Multifunctional building elements for the construction of peptide drug conjugates

• This review presents special attention to the role and importance of structural characteristics of self-assembling peptides, transformable peptide-drug conjugates, targeting peptides and cell-penetrating peptides. • This review provides useful guidelines for the design of linker segment for intelligent and controllable cargo release. • Summarize the peptide-drug conjugates in development and clinical trials and arouse widespread attention to peptide-drug conjugate design strategies and their contribution in fighting various diseases. Engineering of smart building molecules is key basis in designing intelligent drug delivery systems. As an emerging sophisticated delivery system strategy, the powerful functions of peptide drug conjugates (PDCs) are attributed to a smart linker and multifunctional peptide domain. Peptides exhibit a wide range of functions and properties, including easy chemical synthesis and versatile modification, tunable biocompatibility, diversified self-assembled nanostructures, specific recognition/binding, and deep penetration of the cell membrane/extracellular matrix. In addition, various types of linkers enable PDCs to release drugs responsively according to the disease microenvironment or treatment needs. Owing to these inherent advantages, PDCs have been widely explored for drug delivery. Herein, the latest developments in functional peptides and linkers commonly used to construct smart PDCs are reviewed. The purpose is to bring widespread attention to PDC design strategies and their contribution to fighting various diseases, as well as to provide guidance for research on intelligent PDC drug delivery systems.

Recent Advances of Microneedles and Their Application in Disease Treatment.

For decades, scientists have been doing a lot of research and exploration to find effective long-term analgesic and/or disease-modifying treatments. Microneedles (MNs) are a simple, effective, and painless transdermal drug delivery technology that has emerged in recent years, and exhibits great promise for realizing intelligent drug delivery. With the development of materials science and fabrication technology, the MN transdermal drug delivery technology has been applied and popularized in more and more fields, including chronic illnesses such as arthritis or diabetes, cancer, dermatocosmetology, family planning, and epidemic disease prevention, and has made fruitful achievements. This paper mainly reviews the latest research status of MNs and their fabrication methodology, and summarizes the application of MNs in the treatment of various diseases, as well as the potential to use nanotechnology to develop more intelligent MNs-based drug delivery systems.

The Intracellular and Extracellular Microenvironment of Tumor Site: The Trigger of Stimuli-Responsive Drug Delivery Systems.

The tumor microenvironment (TME), including intracellular and extracellular microenvironment, contains many biochemical indicators (such as acidity/alkalinity, oxygen content, and enzymatic activity) that are different from the normal physiological environment. These abnormal biochemical indicators can accelerate the heterogeneity of tumors, but on the other hand, they also provide opportunities for the design of intelligent drug delivery systems (DDSs). The TME-responsive DDSs have shown great potential in reducing the side effects of chemotherapy and improving the curative effect of tumors. In this review, the abnormal biochemical indicators of TME are introduced in detail from both the extracellular and intracellular aspects. In view of the various physiological barriers encountered during drug delivery, the strategy of constructing TME-responsive DDSs is discussed. By summarizing the typical research progress, the authors prospect the development of TME-responsive DDS in the future.

Biodegradable bioelectronics for biomedical applications.

Biodegradable polymers have been widely used in tissue engineering with the potential to be replaced by regenerative tissue. While conventional bionic interfaces are designed to be implanted in living tissue and organs permanently, biocompatible and biodegradable electronic materials are now progressing a paradigm shift towards transient and regenerative bionic engineering. For example, biodegradable bioelectronics can monitor physiologies in a body, transiently rehabilitate disease symptoms, and seamlessly form regenerative interfaces from synthetic electronic devices to tissues by reducing inflammatory foreign-body responses. Conventional electronic materials have not readily been considered biodegradable. However, several strategies have been adopted for designing electroactive and biodegradable materials systems: (1) conductive materials blended with biodegradable components, (2) molecularly engineered conjugated polymers with biodegradable moieties, (3) naturally derived conjugated biopolymers, and (4) aqueously dissolvable metals with encapsulating layers. In this review, we endeavor to present the technical bridges from electrically active and biodegradable material systems to edible and biodegradable electronics as well as transient bioelectronics with pre-clinical bio-instrumental applications, including biodegradable sensors, neural and tissue engineering, and intelligent drug delivery systems.

Lipid-Based Intelligent Vehicle Capabilitized with Physical and Physiological Activation.

Intelligent drug delivery system based on "stimulus-response" mode emerging a promising perspective in next generation lipid-based nanoparticle. Here, we classify signal sources into physical and physiological stimulation according to their origin. The physical signals include temperature, ultrasound, and electromagnetic wave, while physiological signals involve pH, redox condition, and associated proteins. We first summarize external physical response from three main points about efficiency, particle state, and on-demand release. Afterwards, we describe how to design drug delivery using the physiological environment in vivo and present different current application methods. Lastly, we draw a vision of possible future development.

Engineered microorganism-based delivery systems for targeted cancer therapy: a narrative review.

Microorganisms with innate and artificial advantages have been regarded as intelligent drug delivery systems for cancer therapy with the help of engineering technology. Although numerous studies have confirmed the promising prospects of microorganisms in cancer, several problems such as immunogenicity and toxicity should be addressed before further clinical applications. This review aims to investigate the development of engineered microorganism-based delivery systems for targeted cancer therapy. The main types of microorganisms such as bacteria, viruses, fungi, microalgae, and their components and characteristics are introduced in detail. Moreover, the engineering strategies and biomaterials design of microorganisms are further discussed. Most importantly, we discuss the innovative attempts and therapeutic effects of engineered microorganisms in cancer. Taken together, engineered microorganism-based delivery systems hold tremendous promise for biomedical applications in targeted cancer therapy.

Temperature and pH-responsive nanogels as intelligent drug delivery systems: A comprehensive review

.Metricss { height: 500px; } @media only screen and (max-width: 768px) { .canvasjs-chart-canvas{ width:100%!important; height: 80%!important; position: inherit!important; } .metrics{ height: 75vh!important; } } .metrics{ height: 50vh; } #submitss { background-color: #2f7181; color: white; }

Multiple Stimuli-Responsive MXene-Based Hydrogel as Intelligent Drug Delivery Carriers for Deep Chronic Wound Healing.

Chronic wound healing is an important and basic issue in medical and healthcare fields. Recently, stimuli-responsive hydrogel systems have emerged as promising drug delivery carriers for wound management. However, given to the limited therapeutic outcomes, new hydrogel systems for efficient wound treatment are urgently needed. Here, the development of a 2D MXene-based hydrogel system for highly efficient photo- and magnetic-responsive drug delivery oriented to deep chronic wounds repair is presented. The intelligent responsive MXene-based hydrogel drug delivery system is composed of MXene-wrapped magnetic colloids and poly(N-isopropyl acrylamide)-alginate dual-network hydrogels. It is demonstrated that the MXene-based hydrogel system exhibits multiple response capability and controllable drug delivery ability, which can reduce the toxic side effects of drugs and promote the wound healing process as well. Notably, the practical performance of the MXene-based hydrogel drug delivery system is demonstrated by applying it to the treatment of the full-thickness cutaneous wound and subcutaneous infected wound of the rat model, which indicates the great prospect in clinical wound healing and other related biomedical fields.

Supramolecular Drug Delivery System from Macrocycle-Based Self-Assembled Amphiphiles for Effective Tumor Therapy.

Intelligent drug delivery systems (DDSs) that can improve therapeutic outcomes of antitumor agents and decrease their side effects are urgently needed to satisfy special requirements of treatment of malignant tumors in clinics. Here, the fabrication of supramolecular self-assembled amphiphiles based on the host-guest recognition between a cationic water-soluble pillar[6]arene (WP6A) host and a sodium decanesulfonate guest (G) is reported. The chemotherapeutic agent doxorubicin hydrochloride (DOX) can be encapsulated into the formed vesicle (G/WP6A) to construct supramolecular DDS (DOX@G/WP6A). WP6A affords strong affinities to G to avoid undesirable off-target leakage during delivery. Nanoscaled DOX@G/WP6A is capable of preferentially accumulating in tumor tissue via enhanced permeability and retention (EPR) effect. After internalization by tumor cells, the abundant adenosine triphosphate (ATP) binds competitively with WP6A to trigger the disintegration of self-assembled vesicles with the ensuing release of DOX. In vitro and in vivo research confirmed that DOX@G/WP6A is not only able to promote antitumor efficacy but also reduce DOX-related systemic toxicity. The above favorable findings are ascribed to the formation of ternary self-assembly, which profits from the combination of the factors of the EPR effect and the ATP-triggered release.

An intelligent responsive macrophage cell membrane-camouflaged mesoporous silicon nanorod drug delivery system for precise targeted therapy of tumors

Macrophage cell membrane-camouflaged nanocarriers can effectively reduce immune cell clearance and actively target tumors. In this study, a macrophage cell membrane-camouflaged mesoporous silica nanorod (MSNR)-based antitumor drug carrier equipped with a cationic polymer layer was developed. As drug carriers, these MSNRs were loaded with the thermosensitive phase change material L-menthol (LM), the chemotherapy drug doxorubicin (DOX) and the fluorescent molecule indocyanine green (ICG). The rod-like shape of the MSNRs was shown to enhance the penetration of the drug carriers to tumors. In the weakly acidic tumor microenvironment, the cationic polymer exhibited a proton sponge effect to trigger macrophage cell membrane coating detachment, promoting tumor cell uptake. Following nanocarrier uptake, ICG is heated by near-infrared (NIR) irradiation to make LM undergo a phase transition to release DOX and generate a synergistic effect of thermochemotherapy which kills tumor cells and inhibits tumor growth together with reactive oxygen species (ROS) produced by ICG. Overall, this nanohybrid drug delivery system demonstrates an intelligent cascade response, leads to tissue-cell specific targeting and improves drug release accuracy, thus proving to be an effective cancer therapy.Graphical

Guanidinium‐Based Ionic Covalent Organic Porous Polymer as Natamycin Delivery Agents for Anti‐Candida albicans

AbstractHere, we have strategically prepared a biodegradable ionic covalent organic porous polymers (ICOP) with dynamic double selenium bond (Se−Se) which was further used as carriers for the antifungal drug‐natamycin (NAT). ICOP presents a high drug‐loading capability (DL) of 79.33±0.12 %, as well as high encapsulation efficiency (EE) of 76.75±0.58 % to NAT. Meanwhile, owning to the simultaneous introduction of −Se−Se− bond and imine linkage, the composite drug delivery system are responsive to pH, with selective and sustained release in acidic media (pH=5.5), almost 1.34 fold as much as that in neutral conditions (pH=7.4). This special drug release behavior is consisted well with the optimum growing environment of candida albicans (pH=5.5), in which, more drugs could be released continuously, enhancing the duration of drug interactions with fungi and inhibiting the growth of fungus effectively. This novel dosing strategy is promising for the development of intelligent drug delivery system which could avoid the overdoses of drugs, and reduce the emergence of resistant strains.

The Efficiency of AuNPs in Cancer Cell Targeting Compared to Other Nanomedicine Technologies Using Fuzzy PROMETHEE.

Cancer is a disease with rare, diverse symptoms, causing abnormal cell growth in an uncontrolled way, leading to cell damage, apoptosis, and eventually death of the patient. This study uses the Fuzzy PROMETHEE technique to develop a new path for cancer treatment based on nanoparticles (NPs) applications, used in controlled anticancer drug delivery (drug release, toxicity, and unspecific site targeting) to enhance patient safety. The different nanoparticles employed in the drug delivery analysis are gold nanoparticles (AuNPs), liposomes, dendrimers, polymeric micelles (PMs), and quantum dots (QDs). Fuzzy predictable preference organization mode and evaluation multicriteria choice were used as tactics in making the best decision using the data from the factors of cost, size, shape, surface charge, ligand type, pH and temperature stimuli, biocompatibility, accumulation ratio, toxicity, specificity, stability, efficacy, adverse effect, and safety factor of the NPs. The results obtained from the total net flow of the visual PROMETHEE scenario for anticancer drug delivery, based on NPs data analysis, show that AuNPs are ranked the highest among the other NPs. The Phi values obtained for the NPs are as follows: AuNPs (0.1428), PMs (0.0280), QDs (−0.0467), dendrimers (−0.0593), and liposomes (−0.0649). This study highlights the optimal choice of NPs as an intelligent drug delivery system that facilitates therapeutic efficiency, where cancer cells are accurately targeted to enhance treatment quality and patient safety.

Electro-Mechanochemical Gating of a Metal-Phenolic Nanocage for Controlled Guest-Release Self-Powered Patches and Injectable Gels.

Recent advances have led to the development of intelligent drug-delivery systems such as microchips, micropumps, and soft devices with sensors; however, the facile preparation of transdermal and implantable systems modulable to various stimuli remains elusive. In addition, the use of a battery limits their wearable and implantable applications. Therefore, to overcome these disadvantages, we herein suggest a facile strategy to prepare electro-mechanochemically responsive soft gel composites with molecular gatekeeper-based nanocontainers. We found that a metal-phenolic coordination network can act as an efficient self-healable and adaptive gatekeeper in response to electrical and mechanical stimuli owing to the reversible dynamic bonds and adhesiveness to the silica surface. The porous channels of mesoporous silica nanoparticles are filled with guest molecules, and the exterior is wrapped with metal-tannic acid (TA) networks. Owing to the robustness of metal-phenolic network, the guest molecules are efficiently entrapped in the channels but released by electrical and ultrasound input. Voltage-dependent changes in the guest release rate provide control over the dosage on demand. The combination of hydrogel matrixes with the responsive nanocapsules enables the construction of a series of adaptive gel composites capable of successive guest release in response to electrical, ultrasound, electromechanical, and triboelectric stimuli. The Korsmeyer-Peppas model revealed that the release mechanism is non-Fickian, which indicates the presence of boundaries around the guest-loading channels (n = 0.739, R2 = 0.9574 when 2 V is applied). This study realized efficient platforms for active-type drug-delivery applications based on transdermal patches and implantable gels with remotely controllable release characteristics.