Stimuli-responsive Drug Delivery Research Articles

Quantum-Inspired Macromolecular Design: Harnessing Quantum Dots for Enhanced Polymer Functionality in Drug Delivery

Quantum dots (QDs) have emerged as transformative nanomaterials in drug delivery due to their unique optical and electronic properties, such as tunable fluorescence, high surface area and size-dependent emission in pharmaceutical origin. When integrated with polymers, this hybrid system offers enhanced functionality for targeted, controlled and stimuli-responsive drug delivery. This review focuses on the synthesis and application of quantum dot-polymer composites in drug delivery, emphasizing their ability to improve drug targeting, sustained release and real-time imaging in therapeutic applications. The multifunctionality of these systems enables personalized medicine approaches, particularly in cancer therapy and neurological disorders. Despite their promising potential, concerns related to toxicity and scalability pose significant challenges for their widespread clinical use. Ongoing research efforts are focused on developing more biocompatible QDs, optimizing the design of polymer-QD hybrids and addressing regulatory hurdles. This review, we believe, provides a comprehensive analysis of current advancements in quantum dot-based drug delivery systems and outlines future directions to overcome the existing limitations and enhance clinical applicability. The integration of quantum dots with polymers represents a significant leap forward in the field of nanomedicine, offering the potential for highly efficient, precise and safe drug delivery platforms.

Triggering multiple modalities of cell death via dual-responsive nanomedicines to address the narrow therapeutic window of β-lapachone

The clinical translation of the anticancer drug β-lapachone (LAP) has been limited by the narrow therapeutic window. Stimuli-responsive anticancer drug delivery systems have gained tremendous attention in recent years to alleviate adverse effects and enhance therapeutic efficacy. Here, we report a dual pH- and enzyme-responsive nanocarrier to address the above issue of LAP. In detail, the epigallocatechin gallate (EGCG) and ferric ions were employed to engineer nanoscale ferric ion-polyphenol complexes where LAP was physically encapsulated therein. The coordination bond between Fe3+ and the catechol moiety of EGCG was sensitive to the low pH, enabling the triggered cargo release in the acidic endosomes/lysosomes. Afterward, the released LAP was activated by the overexpressed NAD(P)H: quinone oxidoreductase 1 (NQO1) and ferroptosis suppressor protein 1 (FSP1) in the tumor cells, followed by the generation of reactive oxygen species (ROS), and the induction of oxidative stress and apoptotic cell death. Meanwhile, EGCG could upregulate gasdermin E (GSDME), and ferric ions were involved in the Fenton reaction. Hence, EGCG and ferric ions could sensitize the toxicity of LAP through the induction of multiple cell death pathways (e.g., pyroptosis, ferroptosis, apoptosis, and necroptosis). The current work enlarged the LAP’s therapeutic window via controlled cargo release and vehicle sensitization.

From Conventional to Cutting-edge: A Comprehensive Review on Drug Delivery Systems

: The essential need for efficacious conveyance of therapeutics to specific tissues or cells, refinement of drug formulations, and the scalability of industrial production drives the pre-sent-day demand for enhanced drug delivery systems (DDS). Newly devised drugs often exhibit suboptimal biopharmaceutical properties, resulting in diminished patient adherence and adverse side effects. The paramount importance of site-specific drug delivery lies in its capacity to facili-tate the targeted administration of diverse therapeutic agents, catering to both localized ailments and systemic treatments. Alongside targeted drug delivery strategies encompassing ligand-based targeting and stimuli-responsive systems, the advent of cutting-edge nanotechnologies such as nanoparticles, liposomes, and micelles has marked a paradigm shift. Additionally, personalized medicines have emerged as a consequential facet of drug delivery, emphasizing the customization of treatment approaches. Researchers have explored an excess of methodologies in the advance-ment of these formulation technologies, including stimuli-responsive drug delivery, 3D printing, gene delivery, and various other innovative approaches. This comprehensive review aims to pro-vide a holistic understanding of the past, present, and future of drug delivery systems, offering in-sights into the transformative potential of emerging technologies.

Self-Indicating Polymer Prodrug Nanoparticles for pH-Responsive Drug Delivery in Cancer Cells and Real-Time Monitoring of Drug Release.

Amphiphilic self-indicating and responsive polymer-based prodrugs have generated much interest as potential stimuli-responsive intelligent drug delivery systems (DDS) due to their ability to selectively deliver drugs to the cancer cells and to monitor real-time cellular uptake of the drug by imaging technique(s). In this direction, we have synthesized a new pH-responsive N-vinyl-2-pyrrolidone and coumarin-based fluorescent self-indicating polymeric prodrug (SIPD), poly(NVP)-b-poly(FPA.DOX-r-FPA-r-CA). This block copolymer prodrug self-assembled into stable micellar nanoparticles under physiological conditions that reduced undesirable drug leakage to normal cells but resulted in the release of the anticancer drug doxorubicin (DOX) in cancer cells because of acidic pH-induced cleavage of imine bonds between DOX and the copolymer. While the polymer was found to be highly biocompatible with both normal (HEK-293) cells and cancer (MCF-7) cells even at high concentrations by MTT assay, the polymer prodrug nanoparticles showed toxicity even higher than that of free DOX in cancer cells. Phase contrast microscopy also depicted the cytotoxic effects of the nanoparticles on cancer cells. The coumarin units present in the polymer served as a fluorescence resonance energy transfer (FRET) pair with the covalently attached DOX molecules, which was established by steady-state and time-resolved fluorescence spectroscopy. Furthermore, confocal microscopy results confirmed the FRET phenomenon, as the fluorescence intensity of coumarin in the micellar nanoparticles remained quenched initially in MCF-7 cells but recovered with time as the DOX molecules were released and gradually shifted toward the targeted nucleus. All of these studies implied that the synthesized prodrug nanoparticles may provide another viable option for delivering chemotherapeutic drugs into cancer cells with a capability of real-time monitoring of drug release.

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

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

Matrix metalloproteinase-responsive hydrogels with tunable retention for on-demand therapy of inflammatory bowel disease

Therapeutic options for addressing inflammatory bowel disease (IBD) include the administration of an enema to reduce intestinal inflammation and alleviate associated symptoms. However, uncontrollable retention of enemas in the intestinal tract has posed a long-term challenge for improving their therapeutic efficacy and safety. Herein we have developed a protease-labile hydrogel system as an on-demand enema vehicle with tunable degradation and drug release rates in response to varying matrix metalloproteinase-9 (MMP-9) expression. The system, composed of three tailored hydrogel networks, is crosslinked by poly (ethylene glycol) (PEG) with 2-, 4- and 8-arms through dynamic hydrazone bonds to confer injectability and generate varying network connectivity. The retention time of the hydrogels can be tuned from 12 to 36 h in the intestine due to their different degradation behaviors induced by MMP-9. The drug-releasing rate of the hydrogels can be controlled from 0.0003 mg/h to 0.278 mg/h. In addition, injection of such hydrogels in vivo resulted in significant differences in therapeutic effects including MMP-9 consumption, colon tissue repair, reduced collagen deposition, and decreased macrophage cells, for treating a mouse model of acute colitis. Among them, GP-8/5-ASA exhibits the best performance. This study validates the effectiveness of the tailored design of hydrogel architecture in response to pathological microenvironment cues, representing a promising strategy for on-demand therapy of IBD. Statement of significanceThe uncontrollable retention of enemas at the delivery site poses a long-term challenge for improving therapeutic efficacy in IBD patients. MMP-9 is highly expressed in IBD and correlates with disease severity. Therefore, an MMP-9-responsive GP hydrogel system was developed as an enema by linking multi-armed PEG and gelatin through hydrazone bonds. This forms a dynamic hydrogel characterized by in situ gelation, injectability, enhanced bio-adhesion, biocompatibility, controlled retention time, and regulated drug release. GP hydrogels encapsulating 5-ASA significantly improved the intestinal phenotype of acute IBD and demonstrated notable therapeutic differences with increasing PEG arms. This method represents a promising on-demand IBD therapy strategy and provides insights into treating diseases of varying severities using endogenous stimulus-responsive drug delivery systems.

Stimuli-responsive drug delivery system for breast cancer treatment

In the annals of cancer treatment within the domain of nanomedicine, the utilization of stimulus-response drug delivery systems has emerged as a focal point of considerable significance. While a multitude of diverse methodologies are presently employed for the treatment of tumors, the preeminent and most efficacious approach, particularly in the context of intricate scenarios, pertains to the targeted administration of therapeutic and diagnostic nanoparticles into the tumor milieu. These nanoparticles exhibit the inherent potential to acclimatize to the nuanced microenvironment of the tumor, thereby surmounting the challenges posed by tumor heterogeneity. The stimuli-responsive attributes inherent to nanoscale particles can broadly be delineated into two distinct categories: endogenous and exogenous, with a minority manifesting characteristics of both classifications. This scientific review provides an overview of the discourse surrounding exogenous drug delivery systems, which leverage ultrasound and magnetic fields as responsive stimuli, alongside endogenous drug delivery systems employing pH variations and enzymatic cues as triggering mechanisms. The findings of this review emphasize the significance of stimuli-responsive drug delivery systems as a promising strategy to enhance the specificity and efficacy within the sphere of breast cancer treatment. Finally, the review concludes with a discussion on the future directions and potential clinical applications of these systems.

Polymeric pH-Responsive Metal-Supramolecular Nanoparticles for Synergistic Chemo-Photothermal Therapy.

Stimuli-responsive drug delivery carriers, particularly those exhibiting pH sensitivity, have attracted significant scholarly interest due to their promising potential in anticancer therapeutic applications. This phenomenon can primarily be ascribed to the inherently acidic nature of tumor microenvironments. However, pH-responsive carriers frequently require the incorporation of functional groups or materials sensitive to pH changes. Given the pH-sensitive characteristics of metal coordination with natural small-molecule drugs, organometallic supramolecules present a facile and effective strategy for integrating pH-responsive behavior into these systems. Meanwhile, utilizing the natural compound luteolin in conjunction with iron ions (Fe3+) through the advanced engineering technique of flash nanoprecipitation (FNP) results in the synthesis of stable, highly loaded nanoparticles (NPs) exhibiting a supramolecular photothermal effect. Our experimental findings substantiate that the photothermal effect persists over time, even after the pH-responsive release phase has ended. Consequently, these polymeric pH-responsive metallic supramolecular nanoparticles integrate chemotherapy and photothermal therapy, creating a synergistic approach to cancer treatment. This bifunctional platform, which exhibits both pH-responsive and photothermal properties, presents a highly promising avenue for biomedical applications, particularly in the area of tumor therapies. Its dual function offers a potentially efficacious approach to tumor treatment.

In-situ forming Cu-based metal-organic framework in the presence of chitosan-Fe3O4 nanohybrids: A pH-sensitive carrier for controlled release of doxorubicin

In recent years, stimuli-responsive drug delivery systems based on pH, particularly those developed using bio-derived nanocomposite systems, have gained significant attention. In this work, a novel magnetic carrier was designed based on biopolymeric chitosan and metal-organic framework (MOF) for pH-controlling the release of anticancer drugs. To end this, an in-situ green method was performed to form Cu-based MOF in the presence of a magnetic polysaccharide synthesized by precipitation method toward the construction of CS/Fe3O4/Cu-MOF nanocomposite. The nanocomposite was immersed in an aqueous solution of a model anticancer drug, doxorubicin (DOX), and a higher loading capacity (90.1 ± 0.5 %) was achieved. The in-vitro drug release study showed low release rates in simulated physiological environments (pH 7.4, 37 °C, lower than about 20 %), but higher release rates in tumor tissue conditions (pH 4.5, 41 °C, higher than about 60 %) over 96 h, allowing for sustained and extended delivery of DOX. Additionally, the MTT assay demonstrated that the blank and DOX-loaded CS/Fe3O4/Cu-MOF had good cytocompatibility (over 80 % cell viability) and considerable cytotoxicity (lower than 40 % at 16 μg/mL) toward breast cancer (MCF-7) cell line, respectively. These results indicated that the synthesized nanocomposite with suitable pH-sensitivity has potential as a targeted anticancer agent.

Recent Progress in Multifunctional Stimuli-Responsive Combinational Drug Delivery Systems for the Treatment of Biofilm-Forming Bacterial Infections.

Drug-resistant infectious diseases pose a substantial challenge and threat to medical regimens. While adaptive laboratory evolution provides foresight for encountering such situations, it has inherent limitations. Novel drug delivery systems (DDSs) have garnered attention for overcoming these hurdles. Multi-stimuli responsive DDSs are particularly effective due to their reduced background leakage and targeted drug delivery to specific host sites for pathogen elimination. Bacterial infections create an acidic state in the microenvironment (pH: 5.0-5.5), which differs from normal physiological conditions (pH: 7.4). Infected areas are characterized by the overexpression of hyaluronidase, gelatinase, phospholipase, and other virulence factors. Consequently, several effective stimuli-responsive DDSs have been developed to target bacterial pathogens. Additionally, biofilms, structured communities of bacteria encased in a self-produced polymeric matrix, pose a significant challenge by conferring resistance to conventional antimicrobial treatments. Recent advancements in nano-drug delivery systems (nDDSs) show promise in enhancing antimicrobial efficacy by improving drug absorption and targeting within the biofilm matrix. nDDSs can deliver antimicrobials directly to the biofilm, facilitating more effective eradication of these resilient bacterial communities. Herein, this review examines challenges in DDS development, focusing on enhancing antibacterial activity and eradicating biofilms without adverse effects. Furthermore, advances in immune system modulation and photothermal therapy are discussed as future directions for the treatment of bacterial diseases.

Self-healable, stimuli-responsive bio-ionic liquid and sodium alginate conjugated hydrogel with tunable Injectability and mechanical properties for the treatment of breast cancer

Designing stimuli-responsive drug delivery vehicles with higher drug loading capacity, sustained and targeted release of anti-cancer drugs and able to mitigate the shortcomings of traditional systems is need of hour. Herein, we designed stimuli-responsive, self-healable, and adhesive hydrogel through synergetic interaction between [Cho][Gly] (Choline-Glycine) and sodium alginate (SA). The hydrogel was formed as a result of non-covalent interaction between the components of the mixture forming the fibre kind morphology; confirmed through FTIR/computational analysis and SEM/AFM images. The hydrogel exhibited excellent mechanical strength, self-healing ability, adhesive character and most importantly; adjustable injectability. In vitro biocompatibility of the hydrogel was tested on HaCaT and MCF-7 cells, showing >92 % cell viability after 48 h. The hemolysis ratio (<4 %) of the hydrogel confirmed the blood compatibility of the hydrogel. When tested for drug-loading capacity, the hydrogel show 1500 times drug loading for the 5-fluorouracil (5-FU) against the SA based hydrogel. In vitro release data indicated that 5-FU have more preference towards the cancerous cell condition, i.e. acidic pH (>85 %), whereas the drug-loaded hydrogel successfully killed the MCF-7 and HeLa cell with a <IC50–1.92 mM value. The studied hydrogel paves way towards controlled and sustained delivery of anti-cancer drug for the treatment of breast cancer.

New Zein Protein Composites with High Performance in Phosphate Removal, Intrinsic Antibacterial, and Drug Delivery Capabilities.

Herein, poly(N-(4-aminophenyl)methacrylamide)-carbon nano-onions [abbreviated as PAPMA-CNOs (f-CNOs)] integrated gallic acid cross-linked zein composite fibers (ZG/f-CNOs) were developed for the removal/recovery of phosphate from wastewater along with controlled drug delivery and intrinsic antibacterial characteristics. The composite fibers were produced by Forcespinning followed by a heat-pressure technique. The obtained ZG/f-CNOs composite fibers presented several favorable characteristics of nanoadsorbents and drug carriers. The composite fibers exhibited excellent adsorption capabilities for phosphate ions. The adsorption assessment demonstrated that composite fibers process highly selective sequestration of phosphate ions from polluted water, even in the presence of competing anions. The ZG/f-CNOs composite fibers presented a maximum phosphate adsorption capacity (qmax) of 2500 mg/g at pH 7.0. This represents the most efficient phosphate adsorption system among all of the reported nanocomposites to date. The isotherm studies and adsorption kinetics of the adsorbent showed that the adsorption experiments followed the pseudo-second-order and Langmuir isotherm model (R2 = 0.9999). After 13 adsorption/desorption cycles, the adsorbent could still maintain its adsorption efficiency of 96-98% at pH 7.0 while maintaining stability under thermal and chemical conditions. The results mark significant progress in the design of composite fibers for removing phosphates from wastewater, potentially aiding in alleviating eutrophication effects. Owing to the f-CNOs incorporation, ZG/f-CNOs composite fibers exhibited controlled drug delivery. An antibiotic azithromycin drug-encapsulated composite fibers presented a pH-mediated drug release in a controlled manner over 18 days. Furthermore, the composite fibers displayed excellent antibacterial efficiency against Gram-positive and Gram-negative bacteria without causing resistance. In addition, zein composite fibers showed augmented mechanical properties due to the presence of f-CNOs within the zein matrix. Nonetheless, the robust zein composite fibers with inherent stimuli-responsive drug delivery, antibacterial properties, and phosphate adsorption properties can be considered promising multifunctional composites for biomedical applications and environmental remediation.

Designing Dual-Responsive Drug Delivery Systems: The Role of Phase Change Materials and Metal-Organic Frameworks.

Stimuli-responsive drug delivery systems (DDSs) offer precise control over drug release, enhancing therapeutic efficacy and minimizing side effects. This review focuses on DDSs that leverage the unique capabilities of phase change materials (PCMs) and metal-organic frameworks (MOFs) to achieve controlled drug release in response to pH and temperature changes. Specifically, this review highlights the use of a combination of lauric and stearic acids as PCMs that melt slightly above body temperature, providing a thermally responsive mechanism for drug release. Additionally, this review delves into the properties of zeolitic imidazolate framework-8 (ZIF-8), a stable MOF under physiological conditions that decomposes in acidic environments, thus offering pH-sensitive drug release capabilities. The integration of these materials enables the fabrication of complex structures that encapsulate drugs within ZIF-8 or are enveloped by PCM layers, ensuring that drug release is tightly controlled by either temperature or pH levels, or both. This review provides comprehensive insights into the core design principles, material selections, and potential biomedical applications of dual-stimuli responsive DDSs, highlighting the future directions and challenges in this innovative field.

Ultrasound-guided drug delivery system utilizing piezocatalytic MoS2 nanomaterials for anti-inflammatory therapy

Traditional drug delivery systems lack the potential of controlled drug release, thereby decreasing drug utilization and release efficiency. Herein, a next generation of stimuli-responsive drug delivery platform is designed based on piezocatalytic molybdenum disulfide nanoflowers (MoS2 NFs) which can be triggered by ultrasound (US) stimulation for effective acute inflammation therapy. Under US irradiation, MoS2 NFs undergoes piezocatalysis to generate reactive oxygen species (ROS) owing to piezoelectric polarization, thus releasing loaded anti-inflammatory drug Indomethacin (IND) to the targeted inflammation site. The cumulative release of IND elevated significantly with the increase in the duration for US exposure due to the amplified ROS generation, which displayed a highly controllable nature of the as-designed drug delivery platform. For convenient applications, the IND loaded MoS2 NFs (IND@MoS2 NFs) was functionalized onto commercial dressings and their tunable in-vivo drug release performance was demonstrated in paw edema model. IND@MoS2 NFs upon US irradiation, controllably released IND into the site-specific inflamed paw which significantly inhibited 56 % of paw swelling in 6 h by suppressing the infiltration of neutrophils and expression of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α). The highly controllable drug delivery system holds great potential in facilitating personalized, user-friendly theranostic applications with improved patient outcomes.

Stimuli-sensitive biomimetic nanoparticles for the inhibition of breast cancer recurrence and pulmonary metastasis

Biomimetic nanoparticles represent a promising avenue for mitigating rapid clearance by the reticuloendothelial system (RES); however, current challenges include insufficient tumour targeting, suboptimal adhesion, and inadequate localized drug release within tumour regions. These shortcomings contribute to persistent contests, such as recurrence and pulmonary metastasis, even with advanced breast cancer therapies. Stimuli-sensitive drug release can furbish the membrane coated nanoparticles for their efficiency against the stated problems. To enhance the efficacy of biomimetic nanoparticles in addressing these issues, we proposed a versatile, stimuli-responsive drug delivery system by encapsulating doxorubicin (Dox) and perfluorohexane (PFH) within poly (lactic-co-glycolic acid) (PLGA) nanoparticles, subsequently coated with macrophage-derived cell membranes. Within this framework, PFH serves as the mediator for ultrasonic (US)-irradiation-triggered drug release specifically within tumour microenvironment, while the macrophage-derived cell membrane coating enhances cell adhesion, enables immune evasion, and natural tumour-homing ability. The characterization assays and in vitro evaluations yielded encouraging results, indicating enhanced targeting and release efficiencies. In vivo studies demonstrated marked inhibitory effects on both breast cancer recurrence and pulmonary metastasis. The resulting data indicate that these engineered nanoparticles have notable potential for targeted delivery and controlled release upon US irradiation, thereby offering significant therapeutic efficacy against primary breast cancer, pulmonary metastasis, and recurrent malignancies. Our findings lay the groundwork for a novel clinical approach, representing an intriguing direction for ongoing investigation by oncologists.

Fabrication of Rhenium Disulfide/Mesoporous Silica Core-Shell Nanoparticles for a pH-Responsive Drug Release and Combined Chemo-Photothermal Therapy.

A stimuli-responsive drug delivery nanocarrier with a core-shell structure combining photothermal therapy and chemotherapy for killing cancer cells was constructed in this study. The multifunctional nanocarrier ReS2@mSiO2-RhB entails an ReS2 hierarchical nanosphere coated with a fluorescent mesoporous silica shell. The three-dimensional hierarchical ReS2 nanostructure is capable of effectively absorbing near-infrared (NIR) light and converting it into heat. These ReS2 nanospheres were generated by a hydrothermal synthesis process leading to the self-assembly of few-layered ReS2 nanosheets. The mesoporous silica shell was further coated on the surface of the ReS2 nanospheres through a surfactant-templating sol-gel approach to provide accessible mesopores for drug uploading. A fluorescent dye (Rhodamine B) was covalently attached to silica precursors and incorporated during synthesis in the mesoporous silica walls toward conferring imaging capability to the nanocarrier. Doxorubicin (DOX), a known cancer drug, was used in a proof-of-concept study to assess the material's ability to function as a drug delivery carrier. While the silica pores are not capped, the drug molecule loading and release take advantage of the pH-governed electrostatic interactions between the drug and silica wall. The ReS2@mSiO2-RhB enabled a drug loading content as high as 19.83 mg/g doxorubicin. The ReS2@mSiO2-RhB-DOX nanocarrier's cumulative drug release rate at pH values that simulate physiological conditions showed significant pH responsiveness, reaching 59.8% at pH 6.8 and 98.5% and pH 5.5. The in vitro testing using HeLa cervical cancer cells proved that ReS2@mSiO2-RhB-DOX has a strong cancer eradication ability upon irradiation with an NIR laser owing to the combined drug delivery and photothermal effect. The results highlight the potential of ReS2@mSiO2-RhB nanoparticles for combined cancer therapy in the future.

Tumor Microenvironment-Responsive Drug Delivery Based on Polymeric Micelles for Precision Cancer Therapy: Strategies and Prospects.

In clinical practice, drug therapy for cancer is still limited by its inefficiency and high toxicity. For precision therapy, various drug delivery systems, including polymeric micelles self-assembled from amphiphilic polymeric materials, have been developed to achieve tumor-targeting drug delivery. Considering the characteristics of the pathophysiological environment at the drug target site, the design, synthesis, or modification of environmentally responsive polymeric materials has become a crucial strategy for drug-targeted delivery. In comparison to the normal physiological environment, tumors possess a unique microenvironment, characterized by a low pH, high reactive oxygen species concentration, hypoxia, and distinct enzyme systems, providing various stimuli for the environmentally responsive design of polymeric micelles. Polymeric micelles with tumor microenvironment (TME)-responsive characteristics have shown significant improvement in precision therapy for cancer treatment. This review mainly outlines the most promising strategies available for exploiting the tumor microenvironment to construct internal stimulus-responsive drug delivery micelles that target tumors and achieve enhanced antitumor efficacy. In addition, the prospects of TME-responsive polymeric micelles for gene therapy and immunotherapy, the most popular current cancer treatments, are also discussed. TME-responsive drug delivery via polymeric micelles will be an efficient and robust approach for developing clinical cancer therapies in the future.

Intelligent Drug Delivery: Pioneering Stimuli-Responsive Systems to Revolutionize Disease Management- An In-depth Exploration.

In recent years, there has been an escalating interest in stimuli-responsive drug delivery systems (SRDDS) due to their ability to revolutionize the delivery of therapeutics. SRDDSs offer a multitude of benefits in comparison to conventional drug delivery systems (DDS), including spatiotemporal control of drug release, targeted delivery, and improved therapeutic efficacy. The development of various classes of stimuli-responsive DDS, such as pH-responsive, temperature-responsive, photo-responsive, redox responsive systems, has been propelled by advances in materials science, nanotechnology, and biotechnology. These systems exploit specific environmental or physiological cues to trigger drug release in a precisely controlled manner, making them highly promising for the treatment of various diseases. In this review article, an in-depth exploration of the principles, mechanisms, and applications of SRDDS in the context of diverse pathologies such as cancer, arthritis, Alzheimer's disease, atherosclerosis and tissue engineering has been provided. Furthermore, this article delves into the discussion of recent patents, market overview and the progress of research in clinical trials. Overall, this article underscores the transformative potential of SRDDS in enabling personalized, precise, and effective drug delivery for the treatment of the above-mentioned diseases.

Polyacrylic acid/polyvinylpyrrolidone/iron oxide nanocarrier for efficient delivery of doxorubicin

Recently, stimuli-responsive drug delivery systems (DDS), especially pH-responsive ones, have drawn a lot of attention to overcome the unfavourable side effects of traditional cancer treatments. In this work, a nanocomposite hydrogel based on polyacrylic acid (PAA), polyvinylpyrrolidone (PVP), and iron oxide (hematite, Fe2O3) nanoparticles was developed using the water/oil/water emulsification technique for the efficient delivery of doxorubicin (DOX) drug. The synthesized nanocarrier was characterized via XRD, and FT-IR to get information about its crystalline structure and the interaction between the functional groups of the different constituents, respectively. Its size distribution and colloidal stability were investigated via DLS and zeta potential tests, and morphological study was carried out by FE-SEM. The nanoparticles were found to be uniform and monodisperse, with an average size of 319 nm and a surface charge of −30.4 mV. The incorporation of hematite increased the drug loading (48.5 %) and encapsulation efficiency (86.57 %) due to its high porosity and surface area. Drug release was tested at pH 7.4 and 5.4, corresponding to healthy and cancerous tissues, and the results demonstrated the pH responsiveness of the system, with faster release (54 % in 24 h) in the acid medium. MTT and flow cytometry tests corroborated its strong anticancer effect since the nano-platform significantly reduced the survival rate of cancer cells. The designed pH-responsive platform holds great potential for breast cancer therapy.

Intelligent Systems based on Cyclodextrins for the Treatment of Breast Cancer.

The incidence of breast cancer has been increasing over the last four decades, although the mortality rate has decreased. Endocrine therapy and chemotherapy are the most used options for cancer treatment but several obstacles are still attributed to these therapies. Smart materials, such as nanocarriers for targeting, delivery and release of active ingredients, sensitive to intrinsic-stimuli (pH-responsive, redox-responsive, enzyme- responsive, and thermo-responsive) and extrinsic-stimuli (ultrasound-responsive, magnetic-responsive, light-responsive) have been studied as a novel strategy in breast cancer therapy. Cyclodextrins (CDs) are used in the design of these stimuli-responsive drug carrier and delivery systems, either through inclusion complexes with hydrophobic molecules or covalent bonds with large structures to generate new materials. The present work aims to gather and integrate recent data from in vitro and in vivo preclinical studies of CD-based stimuli- responsive systems to contribute to the research in treating breast cancer. All drug carriers showed high in vitro release rates in the presence of a stimulus. The stimuli-responsive nanoplatforms presented biocompatibility and satisfactory results of IC50, inhibition of cell viability and antitumor activity against several breast cancer cell lines. Additionally, these systems led to a significant reduction in drug dosages, which encouraged possible clinical studies for better alternatives to traditional antitumor therapies.