Antioxidant Carbon Dots Nanozyme Loaded in Thermosensitive in situ Hydrogel System for Efficient Dry Eye Disease Treatment.

Purpose: Dry eye disease (DED) is a multifactorial ocular surface disease with a rising incidence. Therefore, it is urgent to construct a reliable and efficient drug delivery system for DED treatment. Methods: In this work, we loaded C-dots nanozyme into a thermosensitive in situ gel to create C-dots@Gel, presenting a promising composite ocular drug delivery system to manage DED. Results: This composite ocular drug delivery system (C-dots@Gel) demonstrated the ability to enhance adherence to the corneal surface and extend the ocular surface retention time, thereby enhancing bioavailability. Furthermore, no discernible ocular surface irritation or systemic toxicity was observed. In the DED mouse model induced by benzalkonium chloride (BAC), it was verified that C-dots@Gel effectively mitigated DED by stabilizing the tear film, prolonging tear secretion, repairing corneal surface damage, and augmenting the population of conjunctival goblet cells. Conclusion: Compared to conventional dosage forms (C-dots), the C-dots@Gel could prolong exhibited enhanced retention time on the ocular surface and increased bioavailability, resulting in a satisfactory therapeutic outcome for DED.

Subcutaneous delivery of an antibody against SARS-CoV-2 from a supramolecular hydrogel depot.

Prolonged maintenance of therapeutically-relevant levels of broadly neutralizing antibodies (bnAbs) is necessary to enable passive immunization against infectious disease. Unfortunately, protection only lasts for as long as these bnAbs remain present at a sufficiently high concentration in the body. Poor pharmacokinetics and burdensome administration are two challenges that need to be addressed in order to make pre- and post-exposure prophylaxis with bnAbs feasible and effective. In this work, we develop a supramolecular hydrogel as an injectable, subcutaneous depot to encapsulate and deliver antibody drug cargo. This polymer-nanoparticle (PNP) hydrogel exhibits shear-thinning and self-healing properties that are required for an injectable drug delivery vehicle. In vitro drug release assays and diffusion measurements indicate that the PNP hydrogels prevent burst release and slow the release of encapsulated antibodies. Delivery of bnAbs against SARS-CoV-2 from PNP hydrogels is compared to standard routes of administration in a preclinical mouse model. We develop a multi-compartment model to understand the ability of these subcutaneous depot materials to modulate the pharmacokinetics of released antibodies; the model is extrapolated to explore the requirements needed for novel materials to successfully deliver relevant antibody therapeutics with different pharmacokinetic characteristics.

Multilayered Curcumin-Loaded Hydrogel Microcarriers with Antimicrobial Function.

The design of multifunctional microcarriers has attracted significant attention because they combine various functions within a single system. In this study, we developed a set of multilayered hydrogel microcarriers, which were first loaded with chemotherapeutic curcumin (CUR), then, using the layer-by-layer (LbL) technique, coated through a polyelectrolyte shell consisting of chitosan (CHIT) or poly(allylamine hydrochloride) (PAH). As an outer layer with antimicrobial function, newly synthesised alkylene quaternary ammonium salt functionalised polyelectrolytes (A-QAS-PEs) were applied. For this purpose, poly(acrylic acid) (PAA) was decorated with different hydrophobic side chains (n-hexane and n-dodecane side entities) and different degrees of substitution (m) of quaternary ammonium groups (abbreviated as PAA-C(O)O-(CH2)n-N+(CH3)3(m); n = 6, 12; m = 8-14%). The grafting approach of PAA with the alkylene quaternary ammonium salt moiety was performed under mild reaction conditions using Steglich esterification followed by quaternisation. The structure of antimicrobial decorated PAA was confirmed by 1H NMR and FTIR, and the mean diameter of all multifunctional microparticles was characterised by SEM. The viscoelastic properties of the functional layers were studied using quartz crystal microbalance with a dissipation (QCM-D). The release of CUR from the microcarriers was described using a hybrid model, i.e., a combination of first-order kinetics and the Korsmeyer-Peppas model. The antimicrobial activity of functionalised PAA and multilayered CUR-loaded hydrogel microcarriers with quaternary ammonium function was assessed against Staphylococcus aureus and Serratia marcescens by the agar diffusion assay method. Only a limited inhibition zone of PAA was observed, but in the case of both antimicrobial decorated PAA and the corresponding multilayered nanocarriers, the inhibitory activity increase was achieved against both strains of bacteria.

Dual-Responsive Alginate Hydrogel Constructed by Sulfhdryl Dendrimer as an Intelligent System for Drug Delivery.

Intelligent stimulus-triggered release and high drug-loading capacity are crucial requirements for drug delivery systems in cancer treatment. Based on the excessive intracellular GSH expression and pH conditions in tumor cells, a novel glutathione (GSH) and pH dual-responsive hydrogel was designed and synthesized by conjugates of glutamic acid-cysteine dendrimer with alginate (Glu-Cys-SA) through click reaction, and then cross-linked with polyethylene glycol (PEG) through hydrogen bonds to form a 3D-net structure. The hydrogel, self-assembled by the inner disulfide bonds of the dendrimer, is designed to respond to the GSH heterogeneity in tumors, with a remarkably high drug loading capacity. The Dox-loaded Glu-Cys-SA hydrogel showed controlled drug release behavior, significantly with a release rate of over 76% in response to GSH. The cytotoxicity investigation indicated that the prepared DOX-loaded hydrogel exhibited comparable anti-tumor activity against HepG-2 cells with positive control. These biocompatible hydrogels are expected to be well-designed GSH and pH dual-sensitive conjugates or polymers for efficient anticancer drug delivery.

A Rapid Self-Assembly Peptide Hydrogel for Recruitment and Activation of Immune Cells.

Self-assembly peptide nanotechnology has attracted much attention due to its regular and orderly structure and diverse functions. Most of the existing self-assembly peptides can form aggregates with specific structures only under specific conditions and their assembly time is relatively long. They have good biocompatibility but no immunogenicity. To optimize it, a self-assembly peptide named DRF3 was designed. It contains a hydrophilic and hydrophobic surface, using two N-terminal arginines, leucine, and two c-terminal aspartate and glutamic acid. Meanwhile, the c-terminal of the peptide was amidated, so that peptide segments were interconnected to increase diversity. Its characterization, biocompatibility, controlled release effect on antigen, immune cell recruitment ability, and antitumor properties were examined here. Congo red/aniline blue staining revealed that peptide hydrogel DRF3 could be immediately gelled in PBS. The stable ß-sheet secondary structure of DRF3 was confirmed by circular dichroism spectrum and IR spectra. The observation results of cryo-scanning electron microscopy, transmission electron microscopy, and atomic force microscopy demonstrated that DRF3 formed nanotubule-like and vesicular structures in PBS, and these structures interlaced with each other to form ordered three-dimensional nanofiber structures. Meanwhile, DRF3 showed excellent biocompatibility, could sustainably and slowly release antigens, recruit dendritic cells and promote the maturation of dendritic cells (DCs) in vitro. In addition, DRF3 has a strong inhibitory effect on clear renal cell carcinoma (786-0). These results provide a reliable basis for the application of peptide hydrogels in biomedical and preclinical trials.

A Novel Injectable Hydrogel Matrix Loaded With 90Y Microspheres for the Treatment of Solid Tumors.

BACKGROUND/AIM: The need to concentrate the anti-tumoral activity of 90Y only to the targeted tumor, while minimizing its off-target effects, led to the development of an innovative device (BAT-90) composed of a hydrogel matrix and 90Y microspheres. MATERIALS AND METHODS: This in vivo randomized study was planned to assess the efficacy, safety, and biodistribution of BAT-90 in 46 rabbits implanted with a VX2 tumor. The effects of BAT-90 were compared to those of 90Y microspheres and the hydrogel matrix. RESULTS: BAT-90 localized effectively the 90Y radiation in the injection site, minimizing dispersion of the microspheres in the target and distant organs of the treated animals. CONCLUSION: BAT-90 can be administered as an adjuvant treatment to clear surgical margins from any potential minimal residual disease, or as an alternative to other loco-regional treatments for non-resectable tumors.

Platforms to test the temporospatial capabilities of carrier systems in delivering growth factors to benefit vascular bioengineering.

In this study we produced a set of in vitro culture platforms to model vascular cell responses to growth factors and factor delivery vehicles. Two of the systems (whole vessel and whole lung vascular development) were supported by microfluidic systems facilitating media circulation and waste removal. We assessed vascular endothelial growth factor (VEGF) delivery by Pluronic F-127 hydrogel, 30 nm pore-sized microparticles (MPs), 60 nm pore-sized MP or a 50/50 mixture of 30 and 60 nm pore-sized MP. VEGF was delivered to porcine acellular lung vascular scaffolds (2.5 cm2 square pieces or whole 3D segments of acellular blood vessels) as well as whole acellular lung scaffolds. Scaffold-cell attachment was examined as was vascular tissue formation. We showed that a 50/50 mixture of 30 and 60 nm pore-sized silicon wafer MPs allowed for long-term release of VEGF within the scaffold vasculature and supported vascular endothelial tissue development during in vitro culture.

Microemulsion-based gel for the transdermal delivery of rasagiline mesylate: In vitro and in vivo assessment for Parkinson's therapy.

Rasagiline mesylate (RSM) is a selective and irreversible monoamine oxidase B inhibitor used for the treatment of Parkinson's disease (PD). However, its unfavorable biopharmaceutical properties, such as extensive degradation in the gastrointestinal tract and first-pass metabolism are responsible for its low oral bioavailability and suboptimal therapeutic efficacy. Here, we report the feasibility of delivering RSM via the transdermal route using RSM containing microemulsion-based gel (RSM-MEG) to achieve effective management of PD. Our in vitro skin permeation studies of RSM-MEG showed significantly higher (at least ~1.5-fold) permeation across rat skin compared to the conventional RSM hydrogel. Our skin irritation studies in rabbits showed that RSM-MEG is safe for transdermal application. Finally, using the rat model of rotenone-induced Parkinsonism, we demonstrated that the topical application of RSM-MEG was equally effective in reversing PD symptoms when compared to oral RSM therapy. Thus, our study confirmed the feasibility and potential of transdermal delivery of RSM via simple topical application of RSM-MEG, and this approach could be an alternative therapeutic intervention for the treatment of Parkinson's disease.

Hemostatic performance of chitosan-based hydrogel and its study on biodistribution and biodegradability in rats.

Hemostasis is of great significance regardless of the smooth operation or postoperative recovery. Therefore, it is urgent to develop a hemostatic material with excellent biodegradability and biocompatibility. It is well known that both carboxymethyl chitosan and hyaluronic acid with biodegradability and biocompatibility have wound healing promoting property. Here, a degradable chitosan-based hydrogel was prepared based on carboxymethyl chitosan and cross-linked by oxidized hyaluronic acid. The hemostatic performance of the hydrogel in rat liver resection injury was evaluated which results showed that the hydrogel exhibited comparable hemostatic properties compared with Fibrin Sealant. In addition, the hydrogel proved to be rapidly absorbed by the body without significant accumulation in vivo, demonstrating good biodegradability and biocompatibility. The overall results suggested the hydrogel will be a promising hemostatic hydrogel for controlling bleeding.

Hydroxyethyl cellulose hydrogel for skin delivery of khellin loaded in ascosomes: Characterization, in vitro/in vivo performance and acute toxicity.

Aim of this work was to prepare and characterize a hydroxyethyl cellulose hydrogel loaded with ascosomes, nanovesicles based on phosphatidylcholine plus ascorbyl octanoate (ASC8) or ascorbyl decanoate (ASC1), and khellin (2 mg/mL), for topical use. ASC10 vesicles were selected for the hydrogel formulation because of the best biopharmaceutical characteristics, namely size of 115 nm, PDI of 0.26, ζ-potential of -40.1 meV, EE% of 90.2%. After 24 h the in vitro release of khellin was more than 80%, while the ex-vivo skin permeation of khellin after application of the vesicles was 42% of the dose. The hydrogel formulations had a pH value of 5, viscosity properties were different according to the different temperatures and in addition, they presented characteristics of non-Newtonian fluids with a pseudoplastic shear thinning behaviour according to the Herschel-Bulkley equation. These hydrogels combine the advantages of a suitable viscosity for dermal use (hydrogel matrix) and an increased transdermal absorption (ascosome components). The best permeability of the ASC10 ascosomes, led to select the formulation for skin irritation and corrosion tests in rats. Liver and dermal histological and pathological analyses demonstrated that hydroxyethyl cellulose hydrogels based on khellin loaded in the ASC10 ascosomes have no toxic effects.

Polymer-based hydrogels with local drug release for cancer immunotherapy.

Immunotherapy that boosts the body's immune system to treat local and distant metastatic tumors has offered a new treatment option for cancer. However, cancer immunotherapy via systemic administration of immunotherapeutic agents often has two major issues of limited immune responses and potential immune-related adverse events in the clinic. Hydrogels, a class of three-dimensional network biomaterials with unique porous structures can achieve local delivery of drugs into tumors to trigger the antitumor immunity, resulting in amplified immunotherapy at lower dosages. In this review, we summarize the recent development of polymer-based hydrogels as drug release systems for local delivery of various immunotherapeutic agents for cancer immunotherapy. The constructions of polymer-based hydrogels and their local delivery of various drugs in tumors to achieve sole immunotherapy, and chemotherapy-, and phototherapy-combinational immunotherapy are introduced. Furthermore, a brief conclusion is given and existing challenges and further perspectives of polymer-based hydrogels for cancer immunotherapy are discussed.

PEG-α-CD/AM/liposome @amoxicillin double network hydrogel wound dressing-Multiple barriers for long-term drug release.

Wound infection and poor wound healing are the major challenges of wound treatment. Antibiotic drug treatment is the effective way to inhibit wound infection. It is necessary to achieve sustained release of antibiotics to get a longer treatment for wound infection. The double network hydrogels based on liposome, polyethylene glycol (PEG), α- cyclodextrin (α-CD) and acrylamide (AM) were developed, in which liposome acts as amoxicillin repository. Because the drug would release from the multiple barriers including two cavities of liposome and α-CD, as well as polyethylene glycol -α- cyclodextrin/acrylamide (PEG-CD/AM) double network, the PEG-α-CD/AM/liposome @amoxicillin double network hydrogels could achieve sustained drug release. The drug release assay showed that the dressing could release amoxicillin continuously until 12 days, than that of 8th day for single-network hydrogel releasing. The antibacterial ratio of the hydrogel could reach above 80%. What's more, the hydrogels present adjustable mechanical strength by changing the ratio of the components. The swelling ratio proved that the hydrogel had potential ability to absorb wound exudates. The cytotoxicity test of the hydrogels demonstrated excellent biocompatibility. These results indicated that this study can provide a new thought for antibacterial wound dressing and has a broad application prospect.

Drug Delivery Through Multifunctional Polypeptidic Hydrogels.

Over the last two decades, remarkable progress has been made to the discovery of novel drugs as well as their delivery systems for the treatment of cancer, the major challenge in medicine. Pharmaceutical scientists are trying to shift from traditional to novel drug delivery systems by applying nanotechnology and, in particular, polymeric carriers to medicine. In complex diseases, very sophisticated nanocarriers should be designed to encapsulate a significant quantity of drugs and bypass biological barriers with minimum cargo loss to effectively and directly deliver the encapsulated drug to the desired pathological site. One of the most promising classes of polymeric materials for drug delivery applications is polypeptides, combining the properties of the traditional polymers with the 3D structure of natural proteins, i.e., a-helices and ß-sheets. In this chapter, we present the recent progress in the synthesis of polymers that form hydrogels in aqueous solutions, based on polypeptides prepared through ring-opening polymerization of N-carboxy anhydrides and which have been loaded with anticancer drugs and studied for their functionality. Advancements in drug design and improvement of multifunctional nanocarriers from the combination of well-defined macromolecular architectures and smart materials are the future for the successful treatment of numerous lethal diseases.

Evaluation of hyaluronic acid nanoparticle embedded chitosan-gelatin hydrogels for antibiotic release.

The development of chitosan-gelatin (CS-G) hydrogels embedded with ampicillin-loaded hyaluronic acid nanoparticles (HA-NPs) for wound dressing is proposed. It was aimed to provide controlled ampicillin delivery by incorporation of HA-NPs into biocompatible CS-G hydrogel structure. According to in vitro ampicillin release studies, 55% of ampicillin was released from CS-G/HA-NPs hydrogels after 5 days. Antibacterial performance of CS-G/HA-NPs hydrogels was proven with agar disc diffusion test. For cytotoxicity assay, fibroblast cell viability increased in CS-G/HA-NPs hydrogels compared with CS-G group after 24 hr incubation. Consequently, the potential ability of CS-G/HA-NPs hydrogels as a controlled drug delivery system has been verified.

Design and in vitro antibiofilm activity of propolis diffusion-controlled biopolymers.

In this study, a novel pH-sensitive hydrogel beads that is based on gelatin/sodium alginate/chitosan (GEL/SA/CS) loaded with propolis ethanolic extracts (PE) were synthesized. The swelling behavior of GEL/SA/CS hydrogel beads was studied in different pH solutions and compared with unloaded CS (GEL/SA) hydrogel beads. The in vitro release studies have been revealed using four different pH (1.3, 5.0, 6.0, and 6.8), a saliva environment (pH 6.8), a simulated gastric fluid (SGF) (pH 1.3), and a simulated intestinal fluid (SIF) (pH 6.8) to simulate the physiological conditions in gastrointestinal (GI) tract. Propolis-loaded hydrogel beads were found to be stable at pH 1.3, 5.0, 6.0, simulated saliva, SGF, and SIF mediums, whereas the beads lose their stability at pH 6.8 buffer solution. Tested microorganisms displayed greater sensitivity to PE-loaded hydrogel beads compared with pure propolis. Contrary to antimicrobial activity results, antibiofilm activity results of PE-loaded GEL/SA and GEL/SA/CS hydrogel beads were found at low levels. According to the obtained results, the propolis-loaded GEL/SA/CS hydrogel beads synthesized within this study can be used in the treatment of GI tract diseases such as oral mucositis, gastric ulcer, ulcerative colitis, and GI cancer, as controlled releasing carriers of propolis.

Self-crosslinked chitosan/dialdehyde xanthan gum blended hypromellose hydrogel for the controlled delivery of ampicillin, minocycline and rifampicin.

The design of improved biopolymeric based hydrogel materials with high load-capacity to serve as biocompatible drug carriers is a challenging task with vital implications in health sciences. In this work, chitosan crosslinked dialdehyde xanthan gum interpenetrated hydroxypropyl methylcellulose gels were developed for the controlled delivery of different antibiotic drugs including ampicillin, minocycline and rifampicin. The prepared hydrogel scaffolds were characterized by rheology method, FTIR, SEM, TGA and compression analysis. In addition, gelation kinetics, swelling, in vitro degradation and drug release rate were studied under simulated gastrointestinal fluid conditions of pH 2.0 and 7.4 at 37 °C. Results demonstrated the gel composition and structure affected drug release kinetics. The release study showed more than 50% cumulative release within 24 h for all investigated antibiotic drugs. In vitro cell cytocompatibility using mouse embryonic fibroblast cell lines depicted ≥80% cell viability, indicating the gels are non-toxic. Finally, the antibacterial activity of loaded gels was evaluated against Gram-negative and positive bacteria (Escherichia coli, Staphylococcus aureus and Klebsiella pneumonia), which correlated well with swelling and drug release results. Overall, the present study demonstrated that the produced hydrogel scaffolds serves as promising material for controlled antibiotic delivery towards microbial growth inhibition.

Synthesis and characterization of thermosensitive hydrogel based on quaternized chitosan for intranasal delivery of insulin.

Nasal administration is a form of systemic administration in which drugs are insufflated through the nasal cavity. Steroids, nicotine replacement, antimigraine drugs, and peptide drugs are examples of the available systematically active drugs as nasal sprays. For diabetic patients who need to use insulin daily, the nasal pathway can be used as an alternative to subcutaneous injection. In this regard, intranasal insulin delivery as a user-friendly and systemic administration has recently attracted more attention. In this study, a novel formulation consists of chitosan, chitosan quaternary ammonium salt (HTCC), and gelatin (Gel) was proposed and examined as a feasible carrier for intranasal insulin administration. First, the optimization of the chitosan-HTCC hydrogel combination has done. Afterward, Gel with various amounts blended with the chitosan-HTCC optimized samples. In the next step, swelling rate, gelation time, degradation, adhesion, and other mechanical, chemical, and biological properties of the hydrogels were studied. Finally, insulin in clinical formulation and dosage was blended with optimized thermosensitive hydrogel and the release procedure of insulin was studied with electrochemiluminescence technique. The optimal formulation (consisted of 2 wt% chitosan, 1 wt% HTCC, and 0.5 wt% Gel) showed low gelation time, uniform pore structure, and the desirable swelling rate, which were resulted in the adequate encapsulation and prolonged release of insulin in 24 H. The optimal samples released 65% of the total amount of insulin in the first 24 H, which is favorable for this study.

Hybrid Hydrogels for Synergistic Periodontal Antibacterial Treatment with Sustained Drug Release and NIR-Responsive Photothermal Effect.

BACKGROUND: Periodontal pathogenic bacteria promote the destruction of periodontal tissues and cause loosening and loss of teeth in adults. However, complete removal of periodontal pathogenic bacteria, at both the bottom of the periodontal pocket and the root bifurcation area, remains challenging. In this work, we explored a synergistic antibiotic and photothermal treatment, which is considered an alternative strategy for highly efficient periodontal antibacterial therapy. METHODS: Mesoporous silica (MSNs) on the surface of Au nanobipyramids (Au NBPs) were designed to achieve the sustained release of the drug and photothermal antibacterials. The mesoporous silica-coated Au NBPs (Au NBPs@SiO2) were mixed with gelatin methacrylate (GelMA-Au NBPs@SiO2). Au NBPs@SiO2 and GelMA-Au NBPs@SiO2 hybrid hydrogels were characterized, and the drug content and photothermal properties in terms of the release profile, bacterial inhibition, and cell growth were investigated. RESULTS: The GelMA-Au NBPs@SiO2 hybrid hydrogels showed controllable minocycline delivery, and the drug release rates increased under 808 nm near-infrared (NIR) light irradiation. The hydrogels also exhibited excellent antibacterial properties, and the antibacterial efficacy of the antibiotic and photothermal treatment was as high as 90% and 66.7% against Porphyromonas gingivalis (P. gingivalis), respectively. Moreover, regardless of NIR irradiation, cell viability was over 80% and the concentration of Au NBPs@SiO2 in the hybrid hydrogels was as high as 100 µg/mL. CONCLUSION: We designed a new near-infrared light (NIR)-activated hybrid hydrogel that offers both sustained release of antibacterial drugs and photothermal treatment. Such sustained release pattern yields the potential to rapidly eliminate periodontal pathogens in the periodontal pocket, and the photothermal treatment maintains low bacterial retention after the drug treatment.

Manufacture of pH- and HAase-responsive hydrogels with on-demand and continuous antibacterial activity for full-thickness wound healing.

A kind of "intelligent" antibacterial dressing-A-HA/HA-ADH/SS hydrogel was in situ formed quickly via dynamic covalent bonds cross-linking between aldehyde hyaluronic acid (A-HA), adipic acid dihydrazide graft hyaluronic acid (HA-ADH) and sisomicin sulfate (SS). FT-IR, SEM and rheological results displayed that the hydrogels were successfully prepared. The hydrogels had good optical transmittance, injectability, self-healing ability, cytocompatibility, antioxidant activity and hemostatic performance which were beneficial to observe the wound healing condition and provide a good healing environment for wounds. In addition, the hydrogels showed a pH- and HAase- dependent degradability, which allowed them to release more SS at infected wound and then exert on-demand and sustained antibacterial effect against S. aureus and E. coli. The results of wound healing and histological examination revealed that these hydrogels have a good therapeutic effect in the full-thickness mouse skin defect wound. Thus, the hydrogels are expected to be used as potential wound dressings to improve wound healing.

Smart Hydrogels - Synthetic Stimuli-Responsive Antitumor Drug Release Systems.

Among modern drug formulations, stimuli-responsive hydrogels also called "smart hydrogels" deserve a special attention. The basic feature of this system is the ability to change their mechanical properties, swelling ability, hydrophilicity, bioactive molecules permeability, etc., influenced by various stimuli, such as temperature, pH, electromagnetic radiation, magnetic field and biological factors. Therefore, stimuli-responsive matrices can be potentially used in tissue engineering, cell cultures and technology of innovative drug delivery systems (DDSs), releasing the active substances under the control of internal or external stimuli. Moreover, smart hydrogels can be used as injectable DDSs, due to gel-sol transition connected with in situ cross-linking process. Innovative smart hydrogel DDSs can be utilized as matrices for targeted therapy, which enhances the effectiveness of tumor chemotherapy and subsequently limits systemic toxicity. External stimulus sensitivity allows remote control over the drug release profile and gel formation. On the other hand, internal factors provide drg accumulation in tumor tissue and reduce the concentration of active drug form in healthy tissue. In this report, we summarise the basic knowledge and chemical strategies for the synthetic smart hydrogel DDSs applied in antitumor therapy.