Injectable Thermoresponsive Hydrogel Research Articles

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

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

Thermoresponsive Injectable Hydrogel To Mimic the Heat- and Strain-Stiffening Behavior of Biopolymers toward Muscle Cell Proliferation.

Injectable hydrogels with nonlinear mechanical attributes to emulate natural biopolymers hold paramount significance in tissue engineering, offering the potential to create scaffolds that seamlessly mimic the biomechanical intricacies of living tissues. Herein, we unveil a synthetic design strategy employing Schiff base chemistry to furnish a peptide-polymer hierarchical contractile injectable hydrogel network. This innovative design demonstrates cross-linking of supramolecular peptide nanostructures such as nanofibers, 1NF, and twisted bundles, 1TB, with a thermosensitive aldehyde-functionalized polymer, PCHO. These networks exhibit interesting nonlinear mechanical stiffening responses to temperature and external stress. Furthermore, the hydrogels transform into a gel state at physiological temperature to exhibit injectable behavior and demonstrate compression load-bearing capabilities. Finally, the hydrogel network exhibits excellent biocompatibility and cell proliferation toward fibroblast, L929, and myoblast, C2C12, to validate their use as potential extracellular matrix mimetic injectable scaffolds.

Thermo-responsive injectable hydrogels from linear and star-shaped block copolymers composed of amino acid-derived vinyl polymer and poly(ethylene glycol) for biomedical applications

Injectable hydrogels were developed from linear and star-shaped thermo-responsive amino acid-derived vinyl polymer/polyethylene glycol block copolymers, and revealing their usefulness as three-dimensional scaffolds for biological applications.

Local Spinal Cord Injury Treatment Using a Dental Pulp Stem Cell Encapsulated H2S Releasing Multifunctional Injectable Hydrogel.

Spinal cord injury (SCI) commonly induces nerve damage and nerve cell degeneration. In this work, a novel dental pulp stem cells (DPSCs) encapsulated thermoresponsive injectable hydrogel with sustained hydrogen sulfide (H2S) delivery is demonstrated for SCI repair. For controlled and sustained H2S gas therapy, a clinically tested H2S donor (JK) loaded octysilane functionalized mesoporous silica nanoparticles (OMSNs) are incorporated into the thermosensitive hydrogel made from Pluronic F127 (PF-127). The JK-loaded functionalized MSNs (OMSF@JK) promote preferential M2-like polarization of macrophages and neuronal differentiation of DPSCs in vitro. OMSF@JK incorporated PF-127 injectable hydrogel (PF-OMSF@JK) has a soft consistency similar to that of the human spinal cord and thus, shows a high cytocompatibility with DPSCs. The cross-sectional micromorphology of the hydrogel shows a continuous porous structure. Last, the PF-OMSF@JK composite hydrogel considerably improves the in vivo SCI regeneration in Sprague-Dawley rats through a reduction in inflammation and neuronal differentiation of the incorporated stem cells as confirmed using western blotting and immunohistochemistry. The highly encouraging in vivo results prove that this novel design on hydrogel is a promising therapy for SCI regeneration with the potential for clinical translation.

Abstract 16714: An Injectable Thermo-Responsive Hydrogel as a Tool for Cardiac Tissue Engineering Efforts: In vitro and in vivo Biocompatibility Assessment

Background: Heart failure (HF) is a major contributor to the global burden of cardiovascular disease. Current treatments for HF do not regenerate muscle nor function and so cardiac transplantation remains the only definitive treatment for HF. Thus, novel therapies for HF are still needed. To overcome this limitation, we engineered an injectable thermo-responsive hydrogel that transitions from a liquid-solution to a gel-based matrix upon reaching body temperature allowing for a liquid injection rapidly followed by gel localization. Previously, we demonstrated the potential of our hydrogel for cardiac tissue applications using primary cardiomyocytes. Goal: The goal of this project is to assess the biocompatibility of the thermo-responsive hydrogel with human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) and its effect on mice heart tissue. Methods: 3D cell culture: 9x104 hiPSC-CM were encapsulated for 21 days using 150μl of hydrogel solution (1.5% w/w) and cell function was assessed afterwards. Mouse intracardial injection: a left thoracotomy was performed via the fourth intercostal space in an adult C57BL/6 mouse model. Then, three injections of 10 μl of either (i) lipofectamine, (ii) hydrogel (1% w/w) or (ii) saline were injected into the left ventricle anterior wall. After injections, the thoracotomy site was closed, and the animals recovered. Four weeks post inject the tissues were harvested and prepared for studies. Results: We found that our hydrogel promotes hiPSC-CMs alignment, elongation with increased Cx43 localization and improved contraction function when compared with traditional 2D fibronectin controls. Furthermore, the in-vivo biocompatibility in mice (intracardial injection) proved that our hydrogel is well tolerated by cardiac tissue. Conclusion: Our results indicated that the injectable thermos-responsive hydrogel is a biocompatible material with potential to be used in cardiac tissue engineering efforts.

In situ injectable thermoresponsive nanocomposite hydrogel based on hydroxypropyl chitosan for precise synergistic calcium-overload, photodynamic and photothermal tumor therapy

Traditional therapies have poor accuracy and significant toxic side effects in the process of tumor treatment. The non-traditional treatment methods with high accuracy and efficacy are worth exploring and investigating. Herein, a strategy that enables precise and synergistic therapies of calcium-overload, photodynamic, and photothermal through facile near infrared (NIR) irradiation was carried out base on the injectable and self-healable hydrogel encapsulating indocyanine green (ICG)-loaded and bovine serum albumin (BSA)-modified calcium peroxide (CaO2) nanoparticles (ICG@CaO2-BSA NPs) and bismuth sulfide (Bi2S3) nanorods. The hydrogel fabricated through the dynamic Schiff-base bonds between hydroxypropyl chitosan (HPCS) and aldehyde-modified Pluronic F127 (F127-CHO) as the delivery substrate for functional substances could adhere and grip tumor tissues due to the adhesion of hydroxyl groups in HPCS and the hydrophobic aggregation caused by thermoresponsiveness of F127-CHO. CaO2 in ICG@CaO2-BSA NPs decomposed in the tumor micro-acidic environment to produce calcium ions (Ca2+) and hydrogen peroxide (H2O2), while ICG generated reactive oxygen species (ROS) under NIR irradiation, the photothermal effect of Bi2S3 nanorods and ICG under NIR irradiation could increase the temperature of tumor tissues and ultimately achieve precise tumor cell destruction. Therefore, this strategy will provide promising prospects for precise and efficient treatment of tumors.

Dendronized chitosan hydrogel with GIT1 to accelerate bone defect repair through increasing local neovascular amount

Bone defects have long been a major healthcare issue because of the difficulties in regenerating bone mass volume and the high cost of treatment. G protein-coupled receptor kinase 2 interacting protein 1 (GIT1) has been proven to play an important role both in vascular development and in bone fracture healing. In this study, a type of thermoresponsive injectable hydrogel from oligoethylene glycol-based dendronized chitosan (G1-CS) was loaded with GIT1-plasmids (G1-CS/GIT1), and used to fill unicortical bone defects. RT-PCR analysis confirmed that G1-CS/GIT1 enhanced DNA transfection in MSCs both in vitro and in vivo. From the results of micro-CT, RT-PCR and histological analysis, it can be concluded that G1-CS/GIT1 accelerated the bone healing rate and increased the amount of neovascularization around the bone defects. In addition, an adeno-associated virus (AAV)-GIT1 was constructed to transfect mesenchymal stem cells. The results of capillary tube formation assay, immunofluorescence staining and western blot analysis proved that high expression of GIT1 induces mesenchymal stem cells to differentiate into endothelial cells. RT-PCR analysis and capillary tube formation assay confirmed that the Notch signaling pathway was activated in the differentiation process. Overall, we developed an efficient strategy through combination of injectable hydrogel and G1T1 for bone tissue engineering.

Thermo-Responsive Injectable Hydrogels Formed by Self-Assembly of Alginate-Based Heterograft Copolymers.

Polysaccharide-based graft copolymers bearing thermo-responsive grafting chains, exhibiting LCST, have been designed to afford thermo-responsive injectable hydrogels. The good performance of the hydrogel requires control of the critical gelation temperature, Tgel. In the present article, we wish to show an alternative method to tune Tgel using an alginate-based thermo-responsive gelator bearing two kinds of grafting chains (heterograft copolymer topology) of P(NIPAM86-co-NtBAM14) random copolymers and pure PNIPAM, differing in their lower critical solution temperature (LCST) about 10 °C. Interestingly, the Tgel of the heterograft copolymer is controlled from the overall hydrophobic content, NtBAM, of both grafts, implying the formation of blended side chains in the crosslinked nanodomains of the formed network. Rheological investigation of the hydrogel showed excellent responsiveness to temperature and shear. Thus, a combination of shear-thinning and thermo-thickening effects provides the hydrogel with injectability and self-healing properties, making it a good candidate for biomedical applications.

Penetrative and Sustained Drug Delivery Using Injectable Hydrogel Nanocomposites for Postsurgical Brain Tumor Treatment

Postsurgical treatment of glioblastoma multiforme (GBM) by systemic chemotherapy and radiotherapy is often inefficient. Tumor cells infiltrating deeply into the brain parenchyma are significant obstacles to the eradication of GBM. Here, we present a potential solution to this challenge by introducing an injectable thermoresponsive hydrogel nanocomposite. As a liquid solution that contains drug-loaded micelles and water-dispersible ferrimagnetic iron oxide nanocubes (wFIONs), the hydrogel nanocomposite is injected into the resected tumor site after surgery. It promptly gelates at body temperature to serve as a soft, deep intracortical drug reservoir. The drug-loaded micelles target residual GBM cells and deliver drugs with a minimum premature release. Alternating magnetic fields accelerate diffusion through heat generation from wFIONs, enabling penetrative drug delivery. Significantly suppressed tumor growth and improved survival rates are demonstrated in an orthotopic mouse GBM model. Our system proves the potential of the hydrogel nanocomposite platform for postsurgical GBM treatment.

Growth Factor Loaded Thermo-Responsive Injectable Hydrogel for Enhancing Diabetic Wound Healing

Background: Diabetic wound (DW) is the most devastating complication resulting in significant mortality and morbidity in diabetic patients. The objective of the current study was to formulate Epidermal Growth Factor loaded Chitosan nanoparticle impregnated with thermos-responsive injectable hydrogel with protease inhibitor. EGF, shown in all stages of wound healing from inflammation to proliferation and remodelling, combined with Doxycycline, a well-known anti-inflammatory and anti-bacterial drug, could be a better strategy in diabetic wound healing. However, EGF's low stability makes it difficult to use. Methodology: The nanoparticles were prepared using the ionic gelation method. The prepared nanoparticles were evaluated for particle size, zeta potential, entrapment efficiency, and SEM studies. Further, the optimized nanoparticle batch was loaded into hydrogel with a protease inhibitor. The hydrogel was evaluated for morphology, protease degradation, in vitro drug release, anti-bacterial activity, cell migration, in vitro cell biocompatibility, and in vivo wound healing studies. Results and Conclusion: The particle size analysis of nanoparticles revealed the size (203 ± 1.236 nm), Zeta potential (+28.5 ± 1.0 mV), and entrapment efficiency of 83.430 ± 1.8%, respectively. The hydrogel showed good porous morphology, injectability, thermo-responsive, biocompatibility, and controlled drug release. In vitro anti-bacterial studies revealed the potential anti-bacterial activity of doxycycline against various microbes. In vivo data indicated that combining EGF and DOX considerably reduced inflammation time-dependent than single-agent treatment. Furthermore, histological studies corroborated these findings. After topical application of hydrogel, histopathology studies revealed significant collagen synthesis and a fully regenerated epithelial layer and advancement in all three stages (proliferation, remodelling, and maturation), which are required to improve the diabetic wound healing process by any dressing. These findings demonstrated that hydrogel promoted cutaneous wound healing in STZ-induced rats by suppressing inflammation at the wound site. Furthermore, histological studies corroborated these findings. After topical application of hydrogel, histopathology studies revealed significant collagen synthesis, a fully regenerated epithelial layer, and advancement in all three stages (proliferation, remodelling, and maturation), which are required to improve the diabetic wound healing process by any dressing. These findings demonstrated that hydrogel promoted cutaneous wound healing in STZ-induced rats by suppressing inflammation at the wound site.

A MgFe-LDH Nanosheet-Incorporated Smart Thermo-Responsive Hydrogel with Controllable Growth Factor Releasing Capability for Bone Regeneration.

Although growth factor (GF)-loaded hydrogels have been explored as promising materials in repairing bone defects, it still remains challenging to construct smart hydrogels with excellent gelation/mechanical properties as well as controllable GF releasing capability. Herein, the incorporation of bone morphogenetic protein 2 (BMP-2)-functionalized MgFe-layered double hydroxide (LDH) nanosheets into chitosan/silk fibroin (CS) hydrogels loaded with platelet-derived growth factor-BB (PDGF-BB) to construct a smart injectable thermo-responsive hydrogel (denoted as CSP-LB), which can achieve a burst release of PDGF-BB and a sustained release of BMP-2, for highly efficient bone regeneration is reported. The incorporation of MgFe-LDH in CS hydrogel not only shortens the gelation time and decreases sol-gel transition temperature, but also enhances the mechanical property of the hydrogel. Because of the sequential release of dual-GFs and sustained release of bioactive Mg2+ /Fe3+ ions, the in vitro experiments prove that the CSP-LB hydrogel exhibits excellent angiogenic and osteogenic properties compared with the CS hydrogel. In vivo experiments further prove that the CSP-LB hydrogel can significantly enhance bone regeneration with higher bone volume and mineral density than that of the CS hydrogel. This smart thermo-sensitive CSP-LB hydrogel possesses excellent gelation capability and angiogenic and osteogenic properties, thus providing a promising minimally invasive solution for bone defect treatment.

Chitosan and carboxymethyl cellulose-based 3D multifunctional bioactive hydrogels loaded with nano-curcumin for synergistic diabetic wound repair

Biopolymer-based thermoresponsive injectable hydrogels with multifunctional tunable characteristics containing anti-oxidative, biocompatibility, anti-infection, tissue regeneration, and/or anti-bacterial are of abundant interest to proficiently stimulate diabetic wound regeneration and are considered as a potential candidate for diversified biomedical application but the development of such hydrogels remains a challenge. In this study, the Chitosan-CMC-g-PF127 injectable hydrogels are developed using solvent casting. The Curcumin (Cur) Chitosan-CMC-g-PF127 injectable hydrogels possess viscoelastic behavior, good swelling properties, and a controlled release profile. The degree of substitution (% DS), thermal stability, morphological behavior, and crystalline characteristics of the developed injectable hydrogels is confirmed using nuclear magnetic resonance (1H NMR), thermogravimetric analysis, scanning electron microscopy (SEM), and x-ray diffraction analysis (XRD), respectively. The controlled release of cur-micelles from the hydrogel is evaluated by drug release studies and pharmacokinetic profile (PK) using high-performance liquid chromatography (HPLC). Furthermore, compared to cur micelles the Cur-laden injectable hydrogel shows a significant increase in half-life (t1/2) up to 5.92 ± 0.7 h, mean residence time (MRT) was 15.75 ± 0.76 h, and area under the first moment curve (AUMC) is 3195.62 ± 547.99 μg/mL*(h)2 which reveals the controlled release behavior. Cytocompatibility analysis of Chitosan-CMC-g-PF127 hydrogels using 3T3-L1 fibroblasts cells and in vivo toxicity by subcutaneous injection followed by histological examination confirmed good biocompatibility of Cur-micelles loaded hydrogels. The histological results revealed the promising tissue regenerative ability and shows enhancement of fibroblasts, keratinocytes, and collagen deposition, which stimulates the epidermal junction. Interestingly, the Chitosan-CMC-g-PF127 injectable hydrogels ladened Cur exhibited a swift wound repair potential by up-surging the cell migration and proliferation at the site of injury and providing a sustained drug delivery platform for hydrophobic moieties.

The osteogenesis and the biologic mechanism of thermo-responsive injectable hydrogel containing carboxymethyl chitosan/sodium alginate nanoparticles towards promoting osteal wound healing

With the development of minimally invasive orthopedics, injectable materials for bone repair are attracted more attention, especially for those wound with a small external mouth and sizeable internal cavity. In this work, the hydrogel with features of thermo-responsiveness, degradability and injectability was designed and fabricated. The hydrogel, named as FHCS, is composed of Pluronic F-127 (F127) loaded with carboxymethyl chitosan/sodium alginate nanoparticles (nCS) and nanohydroxyapatite (nHA). The hydrogel FHCS was non-toxic and good hemocompatible. It can enhance the ALP activity and extracellular matrix calcification of MC3T3-E1 due to the chitosan-based nanoparticle components (nCS). Moreover, FHCS-5 (containing 5 mg/mL nCS) showed relative high expression of osteogenic genes and protein markers. Osteal regeneration was observed treated by FHCS-5 hydrogel in a critical-size rat calvarial bone defect model. CT scanning showed that the whole defect was basically covered by new bone after FHCS-5 hydrogel. The results of H&E staining and Masson's trichrome staining on histological sections further confirmed that FHCS-5 hydrogel promoted new osteal formation and maturation, which up regulated the osteogenic related genes and proteins of ALP, OCN, OPN through BMP/Smad signaling pathway. Hence, this study suggests that FHCS-5 hydrogels have a promising application for non-loading bone regeneration.

An injectable thermosensitive Pluronic F127/hyaluronic acid hydrogel loaded with human umbilical cord mesenchymal stem cells and asiaticoside microspheres for uterine scar repair

Uterine scar was one of the long-term complications cesarean section. In this study, an thermo-responsive injectable hydrogel loaded with human umbilical cord mesenchymal stem cells (UCMSCs) and asiaticoside microspheres (AMs) was used for uterine scar repair, which was prepared by optimizing the mixed ratio of aldehyde-functionalized Pluronic F127 (F127-CHO) and adipic dihydrazide-modified hyaluronic acid (AHA). The asiaticoside was loaded in Poly (DL-lactide-co-gycolide) (PLGA) by emulsion- diffusion-evaporation method. The hydrogel had appropriate pore size, good mechanical property, and slow release ability of asiaticoside. In vitro cell experiments demonstrated that F127-CHO/AHA/AMs could effectively promote stem cell adhesion and proliferation, promote angiogenesis, and provide a suitable microenvironment for cell survival. The F127-CHO/AHA/AMs/UCMSCs hydrogel was further used to repair uterine scar in female SD rats. The results showed that the prepared hydrogel could promote the proliferation of rat endometrial cells, promote the regeneration of glands, reduce the degree of endometrial fibrosis and restore the morphology of uterine cavity. The hydrogel could upregulate expression of Ki67 and IGF-1, downregulate TGF-β1 expression and promote M1-M2 transition of macrophages. This study confirmed that the prepared hydrogel could be used as an effective transplantation strategy, which could be expected to achieve clinical transformation of uterine scar repair.

An Injectable Hydrogel for Treatment of Chronic Neuropathic Pain

Current treatments for chronic neuropathic pain often fall short. A small-molecular compound ZL006 can suppress N-Methyl-d-aspartate receptor (NMDAR)-mediated neuropathic pain behaviors without blocking essential NMDAR function and brings new hope for neuropathic pain therapy. The persistent nature of neuropathic pain mandates the long-term treatment. However, similar to existing analgesics, ZL006 has only a short duration of action. To unleash the therapeutic potential of ZL006, the stability of ZL006 in aqueous solutions is investigated, and a ZL006-incorporated P407-based thermoresponsive injectable hydrogel is developed. The computational analysis is performed to help achieve the desired ZL006-loaded hydrogel system and elucidate the gelation mechanism. The hydrogel matrix can be loaded with ZL006 in an aqueous phase at room temperature without costly specialized equipment and no organic solvent, where the sol is formed and injectable. On subcutaneous administration and subsequent rapid warming to physiological temperature, the sol is converted to a gel. The thermoresponsive hydrogel at body temperature enables the extended release of encapsulated ZL006, and therefore a single subcutaneous injection of ZL006-hydrogel produces a prolonged and stable analgesic action in mice with spinal nerve ligation. The study provides a practical chronic neuropathic pain therapy and a new perspective on future applications of ZL006.

Transdermal Photothermal-Pharmacotherapy to Remodel Adipose Tissue for Obesity and Metabolic Disorders.

Despite the increasing prevalence of obesity, the current medications, which act indirectly on the central nervous system to suppress appetite or on the gastrointestinal tract to inhibit fat absorption, suffer from poor effectiveness and side effects. Here, we developed a transdermal mild photothermal therapy directly acting on the root of evil (subcutaneous white adipose depot) to induce its ameliorating remodeling (browning, lipolysis, and apoptosis), based on the injectable thermoresponsive hydrogel encapsulated with copper sulfide nanodots. Further, combining pharmaceutical therapy with codelivery of mirabegron leads to a strong therapeutic synergy. This method not only ensures high effectiveness and low side effects due to localized and targeted application but also remotely creates significant improvements in systemic metabolism. Specifically, as compared to the untreated group, it totally inhibits obesity development in high-fat-diet fed mice (15% less in body weight) with decreased masses of both subcutaneous (40%) and visceral fats (54%), reduced serum levels of cholesterol (54%)/triglyceride (18%)/insulin (74%)/glucose (45%), and improved insulin sensitivity (65% less in insulin resistance index). This self-administrable method is amenable for long-term home-based treatment. Finally, multiple interconnected signaling pathways are revealed, providing mechanistic insights to develop effective strategies to combat obesity and associated metabolic disorders.

Subcutaneous Delivery of Albumin: Impact of Thermosensitive Hydrogels.

Albumin demonstrates remarkable promises as a versatile carrier for therapeutic and diagnostic agents. However, noninvasive delivery of albumin-based therapeutics has been largely unexplored. In this study, injectable thermosensitive hydrogels were evaluated as sustained delivery systems for Cy5.5-labeled bovine serum albumin (BSA-Cy5.5). These hydrogels were prepared using aqueous solutions of Poloxamer 407 (P407) or poly(lactide-co-glycolide)-block-poly(ethylene glycol)-block-poly(lactide-co-glycolide) (PLGA-PEG-PLGA), which could undergo temperature-triggered phase transition and spontaneously solidify into hydrogels near body temperature, serving as in situ depot for tunable cargo release. In vitro, these hydrogels were found to release BSA-Cy5.5 in a sustained manner with the release half-life of BSA-Cy5.5 from P407 and PLGA-PEG-PLGA hydrogels at 16 h and 105 h, respectively. Without affecting the bioavailability, subcutaneous administration of BSA-Cy5.5-laden P407 hydrogel resulted in delayed BSA-Cy5.5 absorption, which reached the maximum plasma level (Tmax) at 24 h, whereas the Tmax for subcutaneously administered free BSA-Cy5.5 solution was 8 h. Unexpectedly, subcutaneously injected BSA-Cy5.5-laden PLGA-PEG-PLGA hydrogel did not yield sustained BSA-Cy5.5 plasma level, the bioavailability of which was significantly lower than that of P407 hydrogel (p < 0.05). The near-infrared imaging of BSA-Cy5.5-treated mice revealed that a notable portion of BSA-Cy5.5 remained trapped within the subcutaneous tissues after 6 days following the subcutaneous administration of free solution or hydrogels, suggesting the discontinuation of BSA-Cy5.5 absorption irrespective of the formulations. These results suggest the opportunities of developing injectable thermoresponsive hydrogel formulations for subcutaneous delivery of albumin-based therapeutics.

An injectable thermo-responsive hydrogel based cellulose-brush derivative for the sustained release of doxorubicin

A cellulose-grafted-poly(N-isopropylacrylamide) (cellulose-g-PNIPAAm) copolymer with thermo-responsivity was synthesized using homogeneous activators regenerated by electron transfer for atom transfer radical polymerization (ARGET-ATRP). The prepared copolymer dispersed at low concentration in water or phosphate-buffered saline (PBS) at 25 °C could self-assembly into micelles at 37 °C. The size and morphology of these micelles were determined by dynamic light scattering and transmission electron microscopy. The copolymer at a concentration over 4.2% by weight in water formed an injectable thermo-responsive hydrogel that was composed of micelles when the temperature increased to 37 °C. This hydrogel was used to load the anticancer drug doxorubicin (DOX). In vitro release studies demonstrated that this hydrogel released DOX in a sustained manner. Furthermore, this cellulose-based injectable thermo-responsive hydrogel was used in cytotoxicity tests, revealing that it was very biocompatible. Based on the above results, this cellulose-g-PNIPAAm injectable thermo-responsive hydrogel has strong potential for application in smart drug delivery systems.

Intraarticular Injection of Infliximab-Loaded Thermosensitive Hydrogel Alleviates Pain and Protects Cartilage in Rheumatoid Arthritis.

PurposePain and cartilage destruction caused by rheumatoid arthritis (RA) are major challenges during clinical treatment. Traditional systemic administration not only has obvious side effects but also provides limited relief for local symptoms in major joints. Local delivery of therapeutics for RA treatment is a potential strategy but is limited by rapid intraarticular release.Materials and MethodsIn this study, we prepared a thermoresponsive injectable hydrogel by mixing pluronic F127 (F127) and hyaluronic acid (HA) with poly (γ-glutamic acid) (PGA) incorporating infliximab (IFX), a new generation monoclonal antibody drug. We investigated the biocompatibility of the hydrogel and its IFX release profile. In vivo, we studied the clinical manifestations (articular skin temperature and joint diameter), detected cytokines in the synovial fluid and cartilage, performed behavioral studies on pain relief, and evaluated the cartilage protection effect.ResultsA thermoresponsive hydrogel was successfully prepared by mixing F127, HA, and PGA with injectable properties. The F127-HA-PGA hydrogel had a porous structure with interconnected pores. The infliximab-loaded thermosensitive hydrogel exhibited good biocompatibility and biodegradability and sustained release properties. Intraarticular injection of the IFX-loaded F127-HA-PGA hydrogel could alleviate the expression of inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and interleukin-17 (IL-17), in the synovial fluid and cartilage as well as relieve pain and inhibit cartilage destruction in RA.ConclusionThe double effect on pain relief and cartilage protection indicated the significant potential of the IFX-loaded injectable hydrogel for RA treatment in major joint lesions.

Abstract 2881: Injectable thermoresponsive hydrogel for the sustained delivery of triptolide in breast cancer treatment

Abstract To avoid the narrow therapeutic window and take advantage of the anticancer efficacy of triptolide (TP), a major active component of Tripterygium wilfordii Hook.F., a novel thermo-responsive nano-micelle hydrogel was fabricated in present study for the sustained release of TP in breast tumor tissue. Briefly, the amphiphilic poloxamer 188-g-poly (N-isopropylacrylamide-co-acrylic acid) copolymer was synthesized by atomic transfer radical polymerization reaction and self-assembled into micelles in aqueous solution with CMC value of 2.6×10-3 mg/mL. TP encapsulated nanogel (TP/F68-g-(PNIPAAm-co-AAC)) exhibited the sol-gel phase transition at 32°C with a narrow size distribution (about 50.16 nm) and sustained drug release in vitro. And then, the TP-loaded nanogel significantly inhibited the cell proliferation against human breast cancer MDA-MB-231 and MCF-7 cells, as well as the induction of cell apoptosis and cell cycle arrest activity. Moreover, we also found the superior anti-angiogenic activities of TP nanogel in both HUVEC and rat aortic ring model when compared to free TP. As expected, mediated by the 4T1 mouse breast cancer model, we demonstrated that a single injection of the TP-loaded nanogel system resulted in the long detention time in tumor tissue due to its thermo-responsive capacity. Moreover, the novel nanogel remarkably enhanced anticancer efficacy and reduced the side effects, when compared with the multiple injections of free TP. Therefore, the injectable thermo-responsive nanogel provided a potential strategy for the efficient delivery of TP with a sustained release manner in breast cancer treatment. Citation Format: Jingjing Li, Jinming Zhang, George Pak-Heng Leung. Injectable thermoresponsive hydrogel for the sustained delivery of triptolide in breast cancer treatment [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2881.