Intelligent Drug Delivery Systems Research Articles

Advances in the application of logic gates in nanozymes.

Nanozymes are a class of nanomaterials with biocatalytic function and enzyme-like activity, whose advantages include high stability, low cost, and mass production. They can catalyze the substrates of natural enzymes based on specific nanostructures and serve as substitutes for natural enzymes. Their applied research involves a wide range of fields such as biomedicine, environmental governance, agriculture, and food. Molecular logic gates are a new cross-disciplinary discipline, which can simulate the function of silicon circuits on a molecular scale, perform single or multiple input logic operations, and generate logic outputs. A molecular logic gate is a binary operation that converts an input signal into an output signal according to the rules of Boolean logic, generating two signals, a high level, and a low level. The high and low levels represent the "true" and "false" values of the logic gates, and their outputs correspond to "l" and "0" of the molecular logic gates, respectively. The combination of nanozymes and logic gates is a novel and attractive research direction, and the cross-application of the two brings new opportunities and ideas for various fields, such as the construction of efficient biocomputers, intelligent drug delivery systems, and the precise diagnosis of diseases. This review describes the application of logic gates based on nanozymes, which is expected to provide a certain theoretical foundation for researchers' subsequent studies.

Thrombotic microenvironment responsive crosslinking cyclodextrin metal-organic framework nanocarriers for precise targeting and thrombolysis

Global public health is seriously threatened by thrombotic disorders because of their high rates of mortality and disability. Most thrombolytic agents, especially protein-based pharmaceuticals, have a short half-life in circulation, reducing their effectiveness in thrombolysis. The creation of an intelligent drug delivery system that delivers medication precisely and releases it under regulated conditions at nearby thrombus sites is essential for effective thrombolysis. In this article, we present a unique medication delivery system (MCRUA) that selectively targets platelets and releases drugs by stimulation from the thrombus' microenvironment. The thrombolytic enzyme urokinase-type plasminogen-activator (uPA) and the anti-inflammatory medication Aspirin (acetylsalicylic acid, ASA) are both loaded onto pH-sensitive CaCO3/cyclodextrin crosslinking metal-organic frameworks (MC) that make up the MCRUA system. c(RGD) is functionalized on the surface of MC, which is functionalized by RGD to an esterification reaction. Additionally, the thrombus site's acidic microenvironment causes MCRUA to disintegrate to release uPA for thrombolysis and aiding in vessel recanalization. Moreover, cyclodextrin-encapsulated ASA enables the treatment of the inflammatory environment within the thrombus, enhancing the antiplatelet aggregation effects and promoting cooperative thrombolysis therapy. When used for thrombotic disorders, our drug delivery system (MCRUA) promotes thrombolysis, suppresses rethrombosis, and enhances biosafety with fewer hemorrhagic side effects.

Photoinduced Metal-Free Atom Transfer Radical Polymerization for the Modification of Cellulose with Poly(N-isopropylacrylamide) to Create Thermo-Responsive Injectable Hydrogels.

Photoinduced metal-free ATRP has been successfully applied to fabricate thermo-responsive cellulose graft copolymer (PNIPAM-g-Cell) using 2-bromoisobuturyl bromide-modified cellulose as the macroinitiator. The polymerization of N-isopropylacrylamide (NIPAM) from cellulose was efficiently activated and deactivated with UV irradiation in the presence of an organic-based photo-redox catalyst. Both FTIR and 13C NMR analysis confirmed the structural similarity between the obtained PNIPAM-g-Cell and that synthesized via traditional ATRP methods. When the concentration of the PNIPAM-g-Cell is over 5% in water, it forms an injectable thermos-responsive hydrogel composed of micelles at 37 °C. Since organic photocatalysis is a metal-free ATRP, it overcomes the challenge of transition-metal catalysts remaining in polymer products, making this cellulose-based graft copolymer suitable for biomedical applications. In vitro release studies demonstrated that the hydrogel can continuously release DOX for up to 10 days, and its cytotoxicity indicates that it is highly biocompatible. Based on these findings, this cellulose-based injectable, thermo-responsive drug-loaded hydrogel is suitable for intelligent drug delivery systems.

Construction of Smart DNA-Based Drug Delivery Systems for Cancer Therapy.

Due to the disadvantages of poor targeting, slow action, and low effectiveness of current commonly used cancer treatments, including surgery, chemotherapy, and radiotherapy, researchers have turned to DNA as a biomaterial for constructing drug delivery nanocarriers. DNA is favored for its biocompatibility and programmability. In order to overcome the limitations associated with traditional drug delivery systems (DDSs), researchers have developed smart-responsive DNA DDSs that can control drug release in response to specific physical or chemical stimuli at targeted sites. In this review, a summary of multiple targeted ligand structures is provided, various shapes of stable DNA nanomaterials, and different stimuli-responsive drug release strategies in DNA DDSs. Specifically, targeted cell recognition, in vivo stable transport, and controlled drug release of smart DDSs are focused. Finally, the further development prospects and challenges of clinical application of DNA nanomaterials in the field of smart drug delivery are discussed. The objective of this review is to enhance researchers' comprehension regarding the potential application of DNA nanomaterials in precision drug delivery, with the aim of expediting the clinical implementation of intelligent DDSs.

Smart Ultrasound-responsive Polymers for Drug Delivery: An Overview on Advanced Stimuli-sensitive Materials and Techniques.

In recent years, a notable advancement has occurred in the domain of drug delivery systems via the integration of intelligent polymers that respond to ultrasound. The implementation of this groundbreaking methodology has significantly revolutionised the controlled and precise delivery of therapeutic interventions. An in-depth investigation is conducted into the most recent developments in ultrasonic stimulus-responsive materials and techniques for the purpose of accomplishing precise medication administration. The investigation begins with an exhaustive synopsis of the foundational principles underlying drug delivery systems that react to ultrasonic stimuli, focusing specifically on the complex interplay between polymers and ultrasound waves. Significant attention is devoted to the development of polymers that demonstrate tailored responsiveness to ultrasound, thereby exemplifying their versatility in generating controlled drug release patterns. Numerous classifications of intelligent polymers are examined in the discussion, including those that react to variations in temperature, pH, and enzymes. When coupled with ultrasonic stimuli, these polymers offer a sophisticated framework for the precise manipulation of drug release in terms of both temporal and spatial dimensions. The present study aims to examine the synergistic effects of responsive polymers and ultrasound in overcoming biological barriers such as the blood-brain barrier and the gastrointestinal tract. By doing so, it seeks to shed light on the potential applications of these materials in intricate clinical scenarios. The issues and future prospects of intelligent ultrasound-responsive polymers in the context of drug delivery are critically analysed in this article. The objective of this study is to offer valuable perspectives on the challenges that must be overcome to enable the effective implementation of these technologies. The primary objective of this comprehensive review is to furnish researchers, clinicians, and pharmaceutical scientists with a wealth of information that will serve as a guide for forthcoming developments in the development and enhancement of intelligent drug delivery systems that employ ultrasound-responsive polymers to attain superior therapeutic outcomes.

Preparation of pH-responsive polyurethane nano micelles and their antibacterial application

Considering the differences in pH between bacterial infection microenvironment and normal tissues, a series of pH-responsive drug-release amphiphilic polyurethane copolymers (DPU-g-PEG) have been prepared in this work. Fourier transform infrared (FT-IR) spectroscopy and 1H NMR was selected to detect the structure of the condensed polymers. The DPU-g-PEG amphiphilic copolymers could form stable micelles with a hydrophilic shell of polyethylene glycol (PEG) and a hydrophobic core of polylactic acid (PLA). We loaded a model drug called triclosan onto DPU-g-PEG micelles and studied how pH affects their particle size, Zeta potential, and drug release performance. The results revealed that when exposed to acidic conditions, the surface potential of DPU-g-PEG micelles changed, the micelles’ particle size increased, and the drug release performance was significantly enhanced. These results suggested that the micelles prepared in this study can release more antibacterial substances at sites of bacterial infection. Meanwhile, we also investigated the impact of different ratios of soft and hard segments on the properties of micelles, and the results showed that the pH responsiveness of micelles was strongest when the ratio of soft segments (PLLA diol + PEG 2000): 1,6-hexamethylene diisocyanate (HDI): 2,6-Bis-(2-hydroxy-ethyl)-pyrrolo[3,4-f]isoindole-1,3,5,7-tetraone (DMA) = 1: 1.2: 0.2. Furthermore, the results of inhibition zone test, minimum inhibitory concentration (MIC), and minimum bactericidal concentration (MBC) all confirmed the antibacterial activity of triclosan-load DPU-g-PEG micelles. In conclusion, the DPU-g-PEG micelles produced in this study have the potential to be used as intelligent drug delivery systems in the biomedical field.

Revolutionizing cancer therapy using tetrahedral DNA nanostructures as intelligent drug delivery systems

DNA nanostructures have surfaced as intriguing entities with vast potential in biomedicine, notably in the drug delivery area.

ROS-responsive polymeric micelles with aggregation-induced emission effects for drug delivery and cellular imaging

The ROS-responsive amphiphilic copolymer micelles mPEG-TK-PCL-TPE, combined with AIE properties, enable real-time drug release monitoring and intracellular tracing, and ensures stable circulation and rapid release in tumors.

Intelligent Hydrogel-Assisted Hepatocellular Carcinoma Therapy

Given the high malignancy of liver cancer and the liver’s unique role in immune and metabolic regulation, current treatments have limited efficacy, resulting in a poor prognosis. Hydrogels, soft 3-dimensional network materials comprising numerous hydrophilic monomers, have considerable potential as intelligent drug delivery systems for liver cancer treatment. The advantages of hydrogels include their versatile delivery modalities, precision targeting, intelligent stimulus response, controlled drug release, high drug loading capacity, excellent slow-release capabilities, and substantial potential as carriers of bioactive molecules. This review presents an in-depth examination of hydrogel-assisted advanced therapies for hepatocellular carcinoma, encompassing small-molecule drug therapy, immunotherapy, gene therapy, and the utilization of other biologics. Furthermore, it examines the integration of hydrogels with conventional liver cancer therapies, including radiation, interventional therapy, and ultrasound. This review provides a comprehensive overview of the numerous advantages of hydrogels and their potential to enhance therapeutic efficacy, targeting, and drug delivery safety. In conclusion, this review addresses the clinical implementation of hydrogels in liver cancer therapy and future challenges and design principles for hydrogel-based systems, and proposes novel research directions and strategies.

Doxorubicin and iron-doped mesoporous silica nanoparticles for chemodynamic therapy and chemotherapy of breast cancer

This study depicts a simple and effective strategy for designing an intelligent drug delivery system activated by the tumor-specific weakly acidic microenvironment, offering a promising biotechnological platform for combined breast cancer treatment.

Intelligent Delivery Systems in Tumor Metabolism Regulation: Exploring the Path Ahead.

Cancer metabolism plays multifaceted roles in the initiation and progression of tumors, and interventions in metabolism are considered fundamental approaches for cancer control. Within the vast metabolic networks of tumors, there exist numerous potential therapeutic targets, intricately interconnected with each other and with signaling networks related to immunity, metastasis, drug resistance, and more. Based on the characteristics of the tumor microenvironment, constructing drug delivery systems for multi-level modulation of the tumor microenvironment is proven as an effective strategy for achieving multidimensional control of cancer. Consequently, this article summarizes several features of tumor metabolism to provide insights into recent advancements in intelligent drug delivery systems for achieving multi-level regulation of the metabolic microenvironment in cancer, with the aim of offering a novel paradigm for cancer treatment.

Thermoresponsive MXene-based hydrogel for controlled anticancer drug release

The response of smart hydrogels to near-infrared (NIR) light has great potential for local drug delivery in tumor treatment. However, it is limited in biomedical applications due to low photothermal conversion rate, poor photothermal stability, and unreasonable temperature range. To solve this problem, we simply prepared a MXene/Gellan gum hydrogel (MXene@GG) by physically mixing MXene nanosheets, FeCl2 solution, and GG, which has high photothermal conversion efficiency and good photothermal stability. Importantly, MXene@GG have better photothermal properties than MXene solutions, can more effectively control drug release, and can easily control drug on/off release and kinetics. In addition, further cell experiments showed that the MXene@GG had good biocompatibility and that the drugs of doxorubicin (DOX) retained anticancer activity after rapid release from the MXene@GG hydrogel network under NIR irradiation. Thus, this newly prepared NIR responsive MXene@GG hydrogel provides a new approach for the development of intelligent drug delivery systems for local cancer treatment.

Temperature and pH-dependent nanogel for smart pesticide delivery with enhanced foliar dispersion and washout resistance can effectively control multiple plant diseases

The utilization of nanomaterials to develop a system capable of regulating pesticide release in response to environmental cues, enhancing the deposition efficacy on plant leaves, and increasing resistance against rainwater erosion holds immense significance in improving the efficiency of pesticide usage while minimizing residual pollution. Cellulose-based green nanocomposites have emerged as a promising candidate for intelligent drug delivery systems. In this study, we had successfully developed a novel biocompatible interpenetrating polymer network (IPN) gel, named SPCs, by incorporating sodium alginate (SA), polydopamine (PDA), and cellulose nanocrystal (CNC), and a stable gel-like network structure emulsion (MJ@SPCs) was achieved by coating the pesticide azoxystrobin (MJ). The resulting MJ@SPCs exhibited excellent pH responsiveness and temperature sensitivity. Compared to free MJ, MJ@SPCs exhibited improved foliar wettability, rain erosion resistance, deposition rate, and controlled release performance. The results of the bacteriostatic performance test indicated that MJ@SPCs exhibited a higher inhibitory efficiency against Gibperella zeae (GZ) than MJ at equivalent concentrations. Moreover, the in vivo biosafety evaluation of MJ@SPCs had confirmed its relative safety for aquatic zebrafish. This study offers insights into the potential applications of nanopesticides for sustainable plant protection.

The novel design of an intelligent anti-depression transdermal drug delivery system

Depression is a type of mental disorder with a significant and persistent low mood as the main clinical feature. It is often accompanied by symptoms such as slow thinking, decreased will, loss of appetite, and weight loss. The current treatment methods for depression are mainly medical treatment, psychotherapy, and physical therapy. These treatments are dependent on the patient's autonomy and the patients may suspend treatment due to forgetting or refusing. Therefore, an anti-depressant intelligent drug release system was designed, which can achieve autonomously controlled doses for the treatment of depression by transdermal drug delivery system. The work of this study is as follows:(1) The first module: the electrothermal material heating layer. Several preparation methods were screened, and multiple sets of graphene (GE) electric thermogenic layers were successfully prepared. After increasing the actual energization area to 1 cm × 1 cm, the GE electric thermogenic layer is used as the heating layer of the electrothermal material of the system, and can reach a uniform surface temperature of (45 ± 0.5) °C within 15 s at a voltage of 6 V keeping the temperature fluctuation range not exceeding ±0.03 °C, and the resistance fluctuation range not exceeding ±20 Ω, which plays a role in controlling the temperature and heat treatment of the drug loaded gel layer.(2) The second module: the drug-loaded gel layer. Based on the L16 (45) orthogonal test, the best formulation and process of N-Isopropyl acrylamide-Acrylamide copolymer (P(NIPAAm-co-AAm)) hydrogel was determined. Then, the percutaneous permeability of Selegiline liposome was studied in vitro.(3) A rat model of depression was established using chronic unpredictable mild stress (CUMS) combined with separation. From the aspects of behavior (body weight, sucrose preference test, forced swimming test, open field test) and biochemical indexes (serum proinflammatory cytokines (IL-1β, TNF-α), hippocampus HE staining observation), the therapeutic effect of hyperthermia, Selegiline oral administration and transdermal administration was discussed.

A targeted drug delivery system based on E. coli ghost for inhibiting non-Hodgkin’s lymphoma

Doxorubicin (DOX) is extensively utilized in the treatment of aggressive lymphomas, while its significant toxic side effects hamper its clinical application. Hence, there is an urgent need for a safe and effective antilymphoma drug delivery system at this stage. This study successfully developed an optimal drug delivery system (R-PEG@BGs-DOX) to safe and efficient delivery of DOX to non-Hodgkin's lymphoma site. The R-PEG@BGs-DOX was prepared by modifying polyethylene glycol (PEG) and Rituximab (R) onto the surface of bacterial ghosts (BGs), which were obtained through NaOH treatment of E. coli BL21 with modulation to achieve target structures. The prepared R-PEG@BGs exhibited efficient loading of DOX, demonstrating excellent targeting properties. The R-PEG@BGs-DOX can significantly inhibit the growth of non-Hodgkin's lymphoma cells while showing minimal toxic side effects on normal tissues. These results strongly suggest that R-PEG@BGs-DOX holds great promise as an intelligent, safe, and effective drug delivery system for anti-lymphoma treatment.

PH-responsive double emulsion system for targeted anticancer therapy based on polyacrylic acid-polyvinyl pyrrolidone containing carbon nanotubes for 5-fluorouracil as an anticancer medication

The second most significant cause of death among females is considered as breast cancer. Nowadays, many treatments are used to stop and control cancerous cells; among all, chemotherapy and anticancer medications have been applied to most patients for a long time. Although these methods successfully treat cancer, various harmful and unwanted side effects increase pain and suffering for the patients, including drug resistance, high toxicity, and non-targeting. Among different chemotherapy medications, 5-FU is one of the famous chemotherapeutic medications used to treat multiple tumors for over 70 years. With nanomaterials' help, intelligent drug delivery systems have been provided to carry different anticancer medications with minimal side effects. CNTs are well-known nanoparticles that could be used as carriers for smart drug delivery systems. Having an appropriate porosity, low toxicity, and transport, and regulating the amount of drug released make CNTs a suitable candidate as carriers in drug delivery systems. In this work, a combination of CNT nanoparticleswith PAA and PVP polymers was used to fabricate CNT/PAA/PVP nanocomposite as a drug delivery system, and 5-FU was encapsulated in the synthesized nanocarrier as an anticancer medication against MCF-7 breast cancer cell line with double emulsion technique (W-O-W). FT-IR and XRD analyses have been used to investigate different physical interactions and the crystalline behavior of the nanocomposite particles, respectively. DLS and Zeta potential identified nanoemulsions' average size distribution and surface charge. FESEM images were used to investigate the morphology features of the nanocarrier. The encapsulation and loading efficiency in CNT-PAA-PVP@5-FU nanocomposite was around 88.00 % and 45.5 %, respectively. The release pattern of 5-FU in the nanocomposite in the neutral and acidic conditions followed Korsmeyer-Peppas and Higuchi kinetic models, respectively. The pattern also proved that the release was pH-dependent and controlled in various media. MTT test verified a good cytotoxicity for the nanocomposite, and flow cytometry showed that the apoptotic percentage against MCF-7 in the nanocarrier was higher than free 5-FU. In light of these findings, the CNT-PAA-PVP@5-FU drug delivery system can be used to transport pharmaceuticals to cancerous tumors with fewer side effects compared to old treatments.

Multi-Stimuli-Responsive Nanoparticles Formed of POSS-PEG for the Delivery of Boronic Acid-Containing Therapeutics.

Polymeric vehicles often exhibit batch-to-batch variations due to polydispersity, limiting their reproducibility for biomedical applications. In contrast, polyhedral oligomeric silsesquioxane (POSS) has emerged as an attractive candidate for drug delivery due to its precise chemical structure and rigid molecular shape. A promising strategy to enhance drug efficacy while reducing systemic toxicity is the development of multi-stimuli-responsive delivery systems capable of targeted drug release at a disease site. Herein, we developed a drug delivery platform based on POSS-polymer conjugates. By functionalizing the POSS with amino groups and establishing B-N coordination with boronic acids, the nanoparticles (NPs) exhibit responsive behavior to stimuli, including adenosine-5'-triphosphate (ATP), acidic pH, and nucleophilic reagents. We successfully encapsulated two boronic acid-containing molecules: tetraphenylethylene (TPE), serving as a fluorescent probe, and bortezomib (BTZ), an anticancer drug. The TPE@NPs were employed to visualize the cellular uptake of NPs by tumor cells, while the BTZ@NPs exhibited increased cytotoxicity in tumor cells compared with normal cells. This POSS-PEG conjugate offers a nanoparticle platform for encapsulating versatile boronic acid-containing molecules, thereby enhancing drug efficacy while minimizing systemic toxicity. Given the wide-ranging applications of boronic acid-containing molecules in biomedicine, our platform holds significant promise for the development of intelligent drug delivery systems for diagnostics and therapeutics.

Shear Stress and ROS Dual-Responsive RBC-Hitchhiking Nanoparticles for Atherosclerosis Therapy.

Atherosclerosis (AS), a leading cause of death worldwide, is a chronic inflammatory disease rich in lipids and reactive oxygen species (ROS) within plaques. Therefore, lowering lipid and ROS levels is effective in treating AS and reducing AS-induced mortality. In this study, an intelligent biomimetic drug delivery system that specifically responded to both shear stress and ROS microenvironment was developed, consisting of red blood cells (RBCs) and cross-linked polyethyleneimine nanoparticles (SA PEI) loaded with a lipid-lowering drug simvastatin acid (SA), and RBCs were self-assembled with SA PEI to obtain biresponsive SA PEI@RBCs for the treatment of AS. SA PEI could achieve sustained release of SA in response to ROS and reduce ROS and lipid levels to achieve the purpose of treating AS. Shear stress model experiments showed that SA PEI@RBCs could respond to the high shear stress level (100 dynes/cm2) at plaques, realizing the desorption and enrichment of SA PEI and improving the therapeutic efficiency of SA PEI@RBCs. In vitro and in vivo experiments have confirmed that SA PEI@RBCs exhibits better in vivo safety and therapeutic efficacy than SA PEI and free SA. Therefore, shaping SA PEI@RBCs into a biomimetic drug delivery system with dual sensitivity to ROS and shear stress is an effective strategy and treatment to facilitate their delivery into plaques.

Surface activity characterization of synthesized polyvinyl alcohol-based nanogel at air-water interface under highly dynamic conditions

The ability to predict the behavior of nanogels at the air-water interface is critical for developing intelligent drug delivery systems. In this investigation, polyvinyl alcohol (PVA)-based nanogels were synthesized via the self-assembly crosslinking method employing fructose. The nanogels were characterized by means of FE-SEM, FTIR, and DLS analyses. The FE-SEM images confirmed the spherical morphology of the nanogels with an average diameter in the range of 18–30 nm. The polydispersity index of the nanogels, as assessed by the DLS test, was approximately 0.4. Subsequently, the impact of pure PVA and its produced nanogels on the hydrodynamics of a single air bubble ascending in aqueous solutions was explored, revealing that the presence of these molecules at the air-water interface results in a decrease in the local velocity profile (LVP) due to their surface activities. Finally, the results of the pendant drop measurements demonstrate that nanogels are more surface active than PVA.

Thermal-/pH-triggered hollow mesoporous carbon nanocarrier for NIR-responsive drug release

Intelligent drug-delivery systems are considered one of the most important techniques for improving cancer treatment using existing over-the-counter medicines. However, metallic materials are always accompanied by metabolism problems, whereas chemotherapy produces several side effects in humans. Carbon-based materials exhibit exceptional features such as bio-affinity and bio-degradability. Herein, hollow mesoporous carbon nanoparticles (HMCs) are reported as effective nanocarriers of anti-cancer small drug molecules. Near IR (NIR) sources, which can penetrate most organs, induce thermal effects via non-invasive pathways. NIR radiation not only provides thermal therapy but also is compatible with temperature-sensitive coated responsive polymer shells. The template method was used to synthesize HMCs with size 200 ± 50 nm, under various conditions, to obtain suitably sized and hollow structures for liver-cancer treatment. Additional pH/thermal-bi-responsive poly(N-isopropylacrylamide) (PNIPAM) shells were further coated onto the HMCs to produce multiple shells that could trigger swelling motions in PNIPAM@HMCs, as confirmed via small-angle X-ray scattering (SAXS). NIR results demonstrated an extreme increase to the ∆T of 8.7 and 14.2 °C for HMC and PNIPAM@HMCs, respectively. The SAXS spectra analyzed using SasView simulations demonstrated the multi-shell structures of synthesized HMCs and the release mechanism of PNIPAM@HMCs. Based on the model simulation of SAXS, the different rates of polymer swelling indicated the core shrinkage (229.7 to 134.2 Å) and shell expansion (324.3 to 514.3 Å) at 37 °C and 42 °C, respectively. In addition, the first-order, Higuchi, Korsmeyer–Peppas, and Weibull mathematical models were used to verify the drug-release kinetics, and the model with the highest R2 value was considered most suitable for further application. This paper presents the first SAXS study on PNIPAM@HMCs release kinetics and related mechanisms. This phenomenon indicates NIR-induced PNIPAM@HMCs as an effective strategy for cancer treatment via doxorubicin release.