Hydrogel Drug Delivery System Research Articles

Nanofiber Hydrogel Drug Delivery System for Prevention of Postsurgical Intestinal Adhesion.

Intestinal adhesion is one of the complications that occurs more frequently after abdominal surgery. Postsurgical intestinal adhesion (PIA) can lead to a series of health problems, including abdominal pain, intestinal obstruction, and female infertility. Currently, hydrogels and nanofibrous films as barriers are often used for preventing PIA formation; however, these kinds of materials have their intrinsic disadvantages. Herein, we developed a dual-structure drug delivery patch consisting of poly lactic-co-glycolic acid (PLGA) nanofibers and a chitosan hydrogel (NHP). PLGA nanofibers loaded with deferoxamine mesylate (DFO) were incorporated into the hydrogel; meanwhile, the hydrogel was loaded with anti-inflammatory drug dexamethasone (DXMS). The rapid degradation of the hydrogel facilitated the release of DXMS at the acute inflammatory stage of the early injury and provided effective anti-inflammatory effects for wound sites. Moreover, PLGA composite nanofibers could provide sustained and stable release of DFO for promoting the peritoneal repair by the angiogenesis effects of DFO. The in vivo results indicated that NHP can effectively prevent PIA formation by restraining inflammation and vascularization, promoting peritoneal repair. Therefore, we believe that our NHP has a great potential application in inhibition of PIA.

Complex hydrogel for cartilage regeneration and anti-inflammation

With the increasing incidence of osteoarthritis (OA) in elderly patients and the challenges posed by its multifaceted pathogenesis in developing effective treatments, this study explores the effective protein loading mode of Progranulin (PGRN) and its therapeutic potential for treating OA. GelMA hydrogels prepared with different concentrations of PGRN, employing AC-PEG-NHS as a crosslinking agent for drug encapsulation, were used to test the sustained release effect of the composite hydrogel drug delivery system. Additionally, we conducted in vitro assays to investigate the regulatory effects on rat bone marrow mesenchymal atromal cells (BMSCs), chondrocytes, and mouse macrophages - focusing on cell proliferation, and differentiation. For in vivo studies, histological staining techniques were utilized to assess inflammatory cell polarization and cartilage repair in a rat knee injury model. The results demonstrated that PGRN-loaded hydrogels significantly accelerated cell proliferation, enhance differentiation of BMSCs into chondrocytes, maintained a healthy chondrocyte phenotype, and induce M2-type polarization while inhibiting M1-type polarization in macrophages. Histological analyses also showed markedly improved tissue repair in the group treated with GelMA–NHS–PGRN hydrogels. As a result, these GelMA–NHS–PGRN hydrogels present a promising therapeutic approach for OA, potentially mitigating chronic inflammation and facilitating cartilage repair through controlled release of PGRN. Key worldPGRN, Osteoarthritis, Anti-inflammatory hydrogels, Cartilage regeneration.

Injectable pathological microenvironment-responsive anti-inflammatory hydrogels for ameliorating intervertebral disc degeneration

Chronic local inflammation and resulting cellular dysfunction of nucleus pulposus (NP) cells are important pathogenic factors of intervertebral disc degeneration (IDD). Injectable pathological microenvironment-responsive hydrogels hold significant potential for treating IDD by adapting to dynamic microenvironment of IDD. Herein, we proposed an injectable gelatin-based hydrogel drug delivery system that could respond to the pathological microenvironment of IDD for controlled release of anti-inflammatory drug to promote degenerative NP repair. The hydrogel system was prepared by conjugating phenylboronic acid-modified gelatin methacryloyl (GP) with the naturally extracted anti-inflammatory drug epigallocatechin-3-gallate (EGCG) through dynamic boronic esters. The hydrogel exhibited excellent degradability, injectability, antioxidant properties, anti-inflammatory effects, and biocompatibility. It also displayed responsive-release of EGCG under high reactive oxygen species (ROS) levels and acidic conditions. The hydrogel demonstrated remarkable cytoprotective effects on NP cells in both hyperactive ROS environments and inflammatory cytokine-overexpressed environments in vitro. In vivo studies revealed that the hydrogel injected in situ could effectively ameliorate the intervertebral disc degeneration by maintaining the disc height and NP tissue structure in a rat IDD model. The hydrogel system exhibited excellent biocompatibility and responsive-release of diol-containing drugs in pathological microenvironments, indicating its potential application as a drug delivery platform.

Intramyocardial delivery of injectable hydrogel with arctigenin alleviated myocardial ischemia-reperfusion injury in rats.

Arctigenin belongs to a major bioactive component of Fructus arctii and has been found with cardioprotective effects on rats with ischemia-reperfusion (I/R) injury. The application of arctigenin is limited due to poor water solubility and low bioavailability. Hydrogel drug delivery systems can improve the efficacy and safety of drugs, increase drug utilization, and reduce side effects. We hypothesized that hydrogels containing arctigenin would facilitate the effect of arctigenin and alleviate I/R injury in the rat heart. Presently, adult Sprague-Dawley (SD) rats were subjected to 1h of I/R injury, then hydrogels comprising arctigenin were implanted into the myocardium of rats. Triphenyl tetrazolium chloride staining, hematoxylin-eosin staining, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining and Western blot were performed for evaluating the infarct size, histopathological, and vital protein alterations of hearts. It was discovered that the hydrogel combined with arctigenin abated apoptosis and reduced infarct size. In addition, the results of echocardiography and Masson staining suggested that the hydrogel with arctigenin improved cardiac function, restrained myocardial fibrosis, and activated AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1). Collectively, the injectable hydrogel delivery system enhances the effect of arctigenin, which may play a protective role in I/R injury by activating AMPK and SIRT1.

Lubricating MXenzyme-based hybrid hydrogel reverses oxidative damage to alleviate osteoarthritis

Osteoarthritis (OA) is a lubrication-deficient joint disease accompanied by persistent inflammation and progressive destruction of articular cartilage. Although the exact pathogenesis is still unclear, oxidative stress-induced metabolic imbalance and chondrocyte death are thought to take on a crucial role. Here, we present an injectable hydrogel drug delivery system based on V2C MXenzyme NS, metformin and DexMA to alleviate the progression of OA. Due to the advantageous properties of MXenzyme, MXenzyme hybrid hydrogel not only enabled the intelligent release of metformin in response to pH, but also formed a lubricant layer on the hydrogel surface for stable boundary lubrication. Moreover, MXenzyme hybrid hydrogel could scavenge excess reactive oxygen species (ROS) in chondrocytes, including H2O2 and O2−, to alleviate oxidative stress and protect mitochondrial function. Most notably, MXenzyme Hybrid Hydrogel also maintained cartilage extracellular matrix metabolic homeostasis and inhibited chondrocyte pyroptosis through activating Nrf2-ARE signaling, thereby protected cartilage tissues and mitigated the progression of OA. Collectively, the MXenzyme hybrid hydrogel is a promising nano-delivery system for the treatment of OA.

Preparation and antitumor study of intelligent injectable hydrogel: Carboxymethyl chitosan–aldehyde gum Arabic composite graphene oxide hydrogel

In this study, we used polyaldehyde gum Arabic (OGA) and carboxymethyl chitosan (CMCS) as a gel matrix to form an injectable self-healing hydrogel by Schiff-base bonding. Further, graphene oxide (GO) was loaded with doxorubicin (DOX) to the hydrogel, which resulted in a CMCS-OGA/GO@DOX hydrogel. We achieved a DOX drug loading capacity of 43.80 ± 1.13 %. Rheological studies showed that GO hydrogels have improved mechanical properties. The in vitro release profile showed pH responsiveness with 88.21 % DOX release at pH 5.5. Biocompatibility studies showed that the hydrogel composition had good cytocompatibility with L929 cells. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed a cell survival rate of 93.88 % within 48 h. The DOX-loaded hydrogel exhibited higher cell mortality in breast cancer cells (4 T1), with an inhibition rate of 79.4 % at 48 h. Acridine orange/ethidium bromide staining experiments on 4 T1 cells showed that when loaded with the same DOX concentration, the hydrogel significantly reduced the toxic effects on normal cells, whereas it had significant cytotoxic effects on cancer cells. This result indicates that the prepared GO hydrogel drug delivery system can serve as a novel approach for localized breast cancer treatment.

Tetramethylpyrazine-loaded liposomes surrounded by hydrogel based on sodium alginate and chitosan as a multifunctional drug delivery System for treatment of atopic dermatitis

Tetramethylpyrazine (TMP) has low bioavailability due to its fast metabolism and short half-life, which is not conducive to transdermal treatment of atopic dermatitis (AD). Therefore, in this study, TMP was encapsulated into liposomes (Lip) by film dispersion method, and then the surface of Lip was modified by sodium alginate (ALG) and chitosan (CS). The tetramethylpyrazine-loaded liposomes in sodium alginate chitosan hydrogel called T-Lip-AC hydrogel. In vitro experiments, we found that T-Lip-AC hydrogel not only had the antibacterial effect of CS, but also enhanced the anti-inflammatory and antioxidant effects of TMP. In addition, T-Lip-AC hydrogel could also provide a moist healing environment for AD dry skin and produce better skin permeability, and can also achieve sustained drug release, which is conducive to the treatment of AD. The lesions induced by 1-chloro-2,4-dinitrobenzene were used as the AD lesions model to test the therapeutic effect of the T-Lip-AC hydrogel on AD in vivo. The studies have showed that T-Lip-AC hydrogel could effectively promote wound healing. Therefore, we have developed a T-Lip-AC hydrogel as multifunctional hydrogel drug delivery system, which could become an effective, safe and novel alternative treatment method for treating AD.

Preparation and properties of chitosan/dialdehyde sodium alginate/dopamine magnetic drug-delivery hydrogels

The proportion of individuals with bladder cancer has drastically increased, thereby rendering bladder cancer a focus of social concern and great challenge for human health management. Hydrogels with three-dimensional network structures have attracted considerable attention in the field of drug delivery for tumor therapy. Therefore, exploring hydrogel drug-delivery systems with excellent biocompatibility and targeting ability is a current research hotspot. Herein, a chitosan/dialdehyde sodium alginate/magnetic dopamine hydrogel was investigated for this purpose. The hydrogel was prepared from chitosan using sodium dialdehyde alginate and dopamine via grafting, crosslinking, and compounding. Furthermore, characterization of the product structure, targeted adhesion, and evaluation of drug delivery properties were performed. The prepared wall-adherent hydrogel materials exhibited excellent targeted drug-delivery and controlled-release properties. In addition, the effect of dopamine dosage on the performance of drug-loaded hydrogels was examined. In conclusion, the drug-delivery materials exhibited strong organ-wall adhesion, hydrogel properties, targeting ability, antibacterial and antimicrobial abilities (98%), and biocompatibility (99%). Based on these excellent properties, the constructed targeted hydrogels demonstrate considerable potential for drug delivery and bladder cancer treatment.

Extraction, characterization and controlled release application of pectin-like/chitosan hydrogels system loaded Ciprofloxacin.

In recent decades, drug delivery applications have extensively utilized hydrogel systems based on natural polymers. Among the numerous biopolymer-based hydrogel drug delivery systems reported, a novel pectin-like substance was extracted from fig leaves and copolymerized with chitosan. The hydrogel was reformed into microspheres using glutaraldehyde (chemical cross-linker) and sodium hexametaphosphate (physical cross-linker). The extracted polysaccharide and the prepared hydrogels were characterized by FTIR, GC/MS, SEC/MALS/DRI as well as XRD, SEM, BET, and thermal analysis. SEM images revealed the formation of porous microspheres with an average size of 50 μm in diameter. Degrees of swelling in pH7 at 35°C have shown the hydrogels reached two to three times their weights. This has been reflected in their ability to load drugs or any other chemicals. The loading formula shows that hydrogels have maximum loading efficiency more than one-third of the weight of hydrogel. The antimicrobial ciprofloxacin was used as a model for loading on prepared hydrogels. The loaded hydrogels were tested for their biological activities against staphylococcus aureus (S. aureus) bacteria. The antimicrobial growth inhibition zone of the cultured (S. aureus) by ciprofloxacin-loaded hydrogel was followed, which shows controlled growth in inhibition zone sizes and for long time intervals. Results showed that the pectin-chitosan hydrogels exhibited significant antibacterial activity against gram - positive bacteria (S. aureus), with an inhibition zone of 45 mm for (CH-co-FLP)/GLU hydrogel. In vitro, the ciprofloxacin-loaded hydrogels were studied and the cumulative release of ciprofloxacin under suitable conditions was found in a controlled manner and kept release for a long time interval. Data exhibited that the cumulative release profile of ciprofloxacin from the hydrogel demonstrated sustained release over 48 hours, with a value of 6.9% released within the first 24 hours and 7.0 and 6.9% % released at the end of the study for the (CH-co-FLP)/GLU and (CH-co-FLP)/SMP hydrogels, respectively. The novel pectin-chitosan hydrogels hold the potential to enhance the quality of life for numerous patients by minimizing the need for frequent intake of chronic medications.

Treatment strategies for intrauterine adhesion: focus on the exosomes and hydrogels.

Intrauterine adhesion (IUA), also referred to as Asherman Syndrome (AS), results from uterine trauma in both pregnant and nonpregnant women. The IUA damages the endometrial bottom layer, causing partial or complete occlusion of the uterine cavity. This leads to irregular menstruation, infertility, or repeated abortions. Transcervical adhesion electroreception (TCRA) is frequently used to treat IUA, which greatly lowers the prevalence of adhesions and increases pregnancy rates. Although surgery aims to disentangle the adhesive tissue, it can exacerbate the development of IUA when the degree of adhesion is severer. Therefore, it is critical to develop innovative therapeutic approaches for the prevention of IUA. Endometrial fibrosis is the essence of IUA, and studies have found that the use of different types of mesenchymal stem cells (MSCs) can reduce the risk of endometrial fibrosis and increase the possibility of pregnancy. Recent research has suggested that exosomes derived from MSCs can overcome the limitations of MSCs, such as immunogenicity and tumorigenicity risks, thereby providing new directions for IUA treatment. Moreover, the hydrogel drug delivery system can significantly ameliorate the recurrence rate of adhesions and the intrauterine pregnancy rate of patients, and its potential mechanism in the treatment of IUA has also been studied. It has been shown that the combination of two or more therapeutic schemes has broader application prospects; therefore, this article reviews the pathophysiology of IUA and current treatment strategies, focusing on exosomes combined with hydrogels in the treatment of IUA. Although the use of exosomes and hydrogels has certain challenges in treating IUA, they still provide new promising directions in this field.

Intravesical chemotherapy synergize with an immune adjuvant by a thermo-sensitive hydrogel system for bladder cancer

Surgical resection remains the prefer option for bladder cancer treatment. However, the effectiveness of surgery is usually limited for the high recurrence rate and poor prognosis. Consequently, intravesical chemotherapy synergize with immunotherapy in situ is an attractive way to improve therapeutic effect. Herein, a combined strategy based on thermo-sensitive PLEL hydrogel drug delivery system was developed. GEM loaded PLEL hydrogel was intravesical instilled to kill tumor cells directly, then PLEL hydrogel incorporated with CpG was injected into both groins subcutaneously to promote immune responses synergize with GEM. The results demonstrated that drug loaded PLEL hydrogel had a sol-gel phase transition behavior in response to physiological temperature and presented sustained drug release, and the PLEL-assisted combination therapy could have better tumor suppression effect and stronger immunostimulating effect in vivo. Hence, this combined treatment with PLEL hydrogel system has great potential and suggests a clinically-relevant and valuable option for bladder cancer.

Investigation of the Effect of Swelling on the Diffusion Properties of Polyethylene Glycol Hydrogel for Wound Healing Applications.

The present research work aims to comprehensively analyze the effect of swelling of polyethylene glycol (PEG) hydrogel on its diffusion properties for wound healing applications. For this study, a computational model based on three fundamental theories namely, equilibrium swelling theory, rubber elasticity theory and free volume theory has been implemented to determine the diffusion parameters of PEG hydrogel having a molecular weight of 20,000 g/mol. The diffusion of two plant metabolites with inherent antimicrobial activity namely, Cinnamaldehyde and Curcumin and two synthetic antimicrobial drugs namely, Amphotericin B and Vancomycin has been simulated. The results demonstrate that the proposed theoretical framework is capable of predicting the alterations occurring in the diffusion characteristics due to the swelling of PEG hydrogel. The diffusion coefficient of the solute is found to increase with the volumetric swelling ratio (Qv), owing to the wider mesh size of the hydrogel matrix. The diffusion time of the therapeutic compounds is observed to be in the range of 2.40 - 8.30 h.Clinical Relevance- The modelling approach employed in this study will be clinically relevant for designing hydrogel drug delivery systems capable of accelerating the treatment of the infected wounds.

Latest Findings on Hydrogel Drug Delivery Systems in the Treatment of Periodontitis

Hydrogel drug delivery systems possess unique structures and properties and hence can be injected and retained in the periodontal pocket for slow and controlled release of medications with antibacterial, anti-inflammatory, and periodontal tissue regeneration-promotional effects. Due to their safety, practicability, and effectiveness, they show great potential in the treatment of periodontitis. In this paper, we gave an overview of hydrogel drug delivery systems in the treatment of periodontitis, summing up the classification and forms of the drugs delivered and the strengths and weaknesses of common types of hydrogel matrixes. In addition, we discussed properties required for hydrogel drug delivery systems applicable in the treatment of periodontitis, including a certain level of viscosity, suitable degradation cycle, and temperature sensitivity. Finally, we summarized the stimulus responsiveness types of hydrogel drug delivery systems applicable in the treatment of periodontitis, including pH-responsiveness, enzyme-responsiveness, reactive oxygen species-responsiveness, light-responsiveness, and sugar-responsiveness. In the future, researchers should make further investigation into the clinical efficacy of hydrogel drug delivery systems and promote their translation into clinical applications. Additionally, hydrogel drug delivery systems carrying biologic drugs could be further investigated to promote advancement in the field of periodontal tissue regeneration. Furthermore, the response sources, realization strategies, and safe preparation methods of smart hydrogel drug delivery systems should also be further clarified and explored to achieve drug delivery of better efficiency and safety. In addition to drug delivery, hydrogel matrixes with medicinal values also show great promises.

Polymer-Based Hydrogels Applied in Drug Delivery: An Overview.

Polymer-based hydrogels are hydrophilic polymer networks with crosslinks widely applied for drug delivery applications because of their ability to hold large amounts of water and biological fluids and control drug release based on their unique physicochemical properties and biocompatibility. Current trends in the development of hydrogel drug delivery systems involve the release of drugs in response to specific triggers such as pH, temperature, or enzymes for targeted drug delivery and to reduce the potential for systemic toxicity. In addition, developing injectable hydrogel formulations that are easily used and sustain drug release during this extended time is a growing interest. Another emerging trend in hydrogel drug delivery is the synthesis of nano hydrogels and other functional substances for improving targeted drug loading and release efficacy. Following these development trends, advanced hydrogels possessing mechanically improved properties, controlled release rates, and biocompatibility is developing as a focus of the field. More complex drug delivery systems such as multi-drug delivery and combination therapies will be developed based on these advancements. In addition, polymer-based hydrogels are gaining increasing attention in personalized medicine because of their ability to be tailored to a specific patient, for example, drug release rates, drug combinations, target-specific drug delivery, improvement of disease treatment effectiveness, and healthcare cost reduction. Overall, hydrogel application is advancing rapidly, towards more efficient and effective drug delivery systems in the future.

Supramolecular Polymer-Nanomedicine Hydrogel Loaded with Tumor Associated Macrophage-Reprogramming polyTLR7/8a Nanoregulator for Enhanced Anti-Angiogenesis Therapy of Orthotopic Hepatocellular Carcinoma.

Anti-angiogenic therapies targeting inhibition of vascular endothelial growth factor (VEGF) pathway show clinical benefit in hypervascular hepatocellular carcinoma (HCC) tumors. However, HCC expresses massive pro-angiogenic factors in the tumor microenvironment (TME) in response to anti-angiogenic therapy, recruiting tumor-associated macrophages (TAMs), leading to revascularization and tumor progression. To regulate cell types in TME and promote the therapeutic efficiency of anti-angiogenic therapy, a supramolecular hydrogel drug delivery system (PLDX-PMI) co-assembled by anti-angiogenic nanomedicines (PCN-Len nanoparticles (NPs)) and oxidized dextran (DX), and loaded with TAMs-reprogramming polyTLR7/8a nanoregulators (p(Man-IMDQ) NRs) is developed for orthotopic liver cancer therapy. PCN-Len NPs target tyrosine kinases of vascular endothelial cells and blocked VEGFR signaling pathway. p(Man-IMDQ) NRs repolarize pro-angiogenic M2-type TAMs into anti-angiogenic M1-type TAMs via mannose-binding receptors, reducing the secretion of VEGF, which further compromised the migration and proliferation of vascular endothelial cells. On highly malignant orthotopic liver cancer Hepa1-6 model, it is found that a single administration of the hydrogel formulation significantly decreases tumor microvessel density, promotes tumor vascular network maturation, and reduces M2-subtype TAMs, thereby effectively inhibiting tumor progression. Collectively, findings in this work highlight the great significance of TAMs reprogramming in enhancing anti-angiogenesis treatment for orthotopic HCC, and provides an advanced hydrogel delivery system-based synergistic approach for tumor therapy.

Ferroptosis-Enhanced Immunotherapy with an Injectable Dextran-Chitosan Hydrogel for the Treatment of Malignant Ascites in Hepatocellular Carcinoma.

Malignant ascites in advanced hepatocellular carcinoma (HCC) is a complex clinical problem that lacks effective treatments. Due to the insensitivity of advanced HCC cells to traditional chemotherapies, low drug accumulation, and limited drug residence time in the peritoneal cavity, the therapeutic effects of malignant ascites in HCC are not satisfactory. In this study, an injectable hydrogel drug delivery system based on chitosan hydrochloride and oxidized dextran (CH-OD) is designed to load sulfasalazine (SSZ), an FDA-approved drug with ferroptosis-inducing ability, for effective tumor-killing and activation of anti-tumor immunity. Compared to free SSZ, SSZ-loaded CH-OD (CH-OD-SSZ) hydrogel exhibits greater cytotoxicity and induces higher levels of immunogenic ferroptosis. In the preclinical model of hepatoma ascites, intraperitoneal administration of CH-OD-SSZ hydrogel can significantly suppress tumor progression and improve the immune landscape. Both in vitro and in vivo, CH-OD-SSZ hydrogel induces the repolarization of macrophages to an M1-like phenotype and promotes the maturation and activation of dendritic cells. Combination treatment with CH-OD-SSZ hydrogel and anti-programmed cell death protein 1 (PD-1) immunotherapy achieves more than 50% ascites regression and generates long-term immune memory. Collectively, CH-OD-SSZ hydrogel exhibits promising therapeutic potential in the treatment of peritoneal dissemination and malignant ascites in advanced HCC, especially when combined with anti-PD-1 immunotherapy.

Hydrogel Drug Delivery Systems for Bone Regeneration.

With the in-depth understanding of bone regeneration mechanisms and the development of bone tissue engineering, a variety of scaffold carrier materials with desirable physicochemical properties and biological functions have recently emerged in the field of bone regeneration. Hydrogels are being increasingly used in the field of bone regeneration and tissue engineering because of their biocompatibility, unique swelling properties, and relative ease of fabrication. Hydrogel drug delivery systems comprise cells, cytokines, an extracellular matrix, and small molecule nucleotides, which have different properties depending on their chemical or physical cross-linking. Additionally, hydrogels can be designed for different types of drug delivery for specific applications. In this paper, we summarize recent research in the field of bone regeneration using hydrogels as delivery carriers, detail the application of hydrogels in bone defect diseases and their mechanisms, and discuss future research directions of hydrogel drug delivery systems in bone tissue engineering.

Biodegradable Microspheres and Hydrogel Drug Delivery System of Tumor Necrosis Factor (TNF) Inhibitor and Growth Differentiation Factor 5 (GDF5) Reduces Disk Inflammation in the Rabbit Model.

Preclinical study. Develop and test a drug delivery system (DDS) composed of anti-inflammatories and growth factors in the rabbit disk injury model. Biological therapies that inhibit inflammation or enhance cell proliferation can alter intervertebral disk (IVD) homeostasis to favor regeneration. As biological molecules have short half-lives and one molecule may not cover multiple disease pathways, effective treatments may require a combination of growth factors and anti-inflammatory agents delivered in a sustained manner. Biodegradable microspheres were generated separately to encapsulate tumor necrosis factor alpha (TNFα) inhibitors [etanercept (ETN)] or growth differentiation factor 5 (GDF5) and were embedded into a thermoresponsive hydrogel. Release kinetics and activity of ETN and GDF5 were measured in vitro . For in vivo testing, New Zealand White rabbits (n=12) underwent surgery for disk puncture and treatment with blank-DDS, ETN-DDS, or ETN+GDF5-DDS at levels L34, L45, and L56. Radiographic and magnetic resonance images of the spines were obtained. The IVDs were isolated for histologic and gene expression analyses. ETN and GDF5 were encapsulated into poly (L-lactide-co-glycolide) microspheres and had average initial bursts of 2.4±0.1 and 11.2±0.7μg from DDS, respectively. In vitro studies confirmed that ETN-DDS inhibited TNFα-induced cytokine release and GDF5-DDS induced protein phosphorylation. In vivo studies showed that rabbit IVDs treated with ETN+GDF5-DDS had better histologic outcomes, higher levels of extracellular, and lower levels of inflammatory gene expression than IVDs treated with blank-DDS or ETN-DDS. This pilot study demonstrated that DDS can be fabricated to deliver sustained and therapeutic dosages of ETN and GDF5. In addition, ETN+GDF5-DDS may have greater anti-inflammatory and regenerative effects than ETN-DDS alone. Thus, intradiscal injection of controlled release TNF-α inhibitors and growth factors may be a promising treatment to reduce disk inflammation and back pain.

A topical thermosensitive hydrogel system with cyclosporine A PEG-PCL micelles alleviates ulcerative colitis induced by TNBS in mice.

Ulcerative colitis (UC) is an idiopathic, chronic, relapsing disease. In most cases, only the distal colon is affected, and the colonic stasis or fast colonic transit through the inflamed colon usually results in reduced exposure of the distal inflamed colon. Although the immunosuppressant cyclosporine A (CsA) has been used in patients with severe colitis who do not respond to corticosteroids, the clinical application of CsA remains limited due to the systemic toxicities and insufficient accumulation at the site of action for the intravenous and oral routes. In this study, we loaded CsA into the amphipathic poly(ethylene glycol)-poly(ε-caprolactone) (PEG-PCL) micelles and then embedded them in hydrogels consisting of chitosan, poloxamer 188, and poloxamer 407 to construct a thermosensitive and mucoadhesive hydrogel drug delivery system (PLCP). The PLCP presented a high drug-loading capacity and showed a stable and rapid gelation rate after rectal administration into the body. Compared to CsA-loaded micelles and Sandimmun (Neoral®), the developed thermosensitive gel exhibited prolonged retention on the inflamed colon, as seen from in vitro adhesion and in vivo distribution experiments. It also fast mitigated colitis symptoms in TNBS-treated mice by regulating the expression levels of proinflammatory cytokines (TNF-α, IL-1β, COX-2, and iNOS2), anti-inflammatory cytokines (IL-10, Nrf2, NQO1, and HO-1), and other relevant biochemical factors. Our results suggested that CsA-loaded micelle thermal hydrogel system could be a promising strategy by enhancing the retention in the diseased colon and promoting the relief and recovery of UC.

Therapeutic Delivery of Tumor Suppressor miRNAs for Breast Cancer Treatment.

The death rate from breast cancer (BC) has dropped due to early detection and sophisticated therapeutic options, yet drug resistance and relapse remain barriers to effective, systematic treatment. Multiple mechanisms underlying miRNAs appear crucial in practically every aspect of cancer progression, including carcinogenesis, metastasis, and drug resistance, as evidenced by the elucidation of drug resistance. Non-coding RNAs called microRNAs (miRNAs) attach to complementary messenger RNAs and degrade them to inhibit the expression and translation to proteins. Evidence suggests that miRNAs play a vital role in developing numerous diseases, including cancer. They affect genes critical for cellular differentiation, proliferation, apoptosis, and metabolism. Recently studies have demonstrated that miRNAs serve as valuable biomarkers for BC. The contrast in the expression of miRNAs in normal tissue cells and tumors suggest that miRNAs are involved in breast cancer. The important aspect behind cancer etiology is the deregulation of miRNAs that can specifically influence cellular physiology. The main objective of this review is to emphasize the role and therapeutic capacity of tumor suppressor miRNAs in BC and the advancement in the delivery system that can deliver miRNAs specifically to cancerous cells. Various approaches are used to deliver these miRNAs to the cancer cells with the help of carrier molecules, like nanoparticles, poly D, L-lactic-co-glycolic acid (PLGA) particles, PEI polymers, modified extracellular vesicles, dendrimers, and liposomes. Additionally, we discuss advanced strategies of TS miRNA delivery techniques such as viral delivery, self-assembled RNA-triple-helix hydrogel drug delivery systems, and hyaluronic acid/protamine sulfate inter-polyelectrolyte complexes. Subsequently, we discuss challenges and prospects on TS miRNA therapeutic delivery in BC management so that miRNAs will become a routine technique in developing individualized patient profiles.