Recent advances on thermosensitive hydrogels-mediated precision therapy

Precision therapy has become the preferred choice attributed to the optimal drug concentration in target sites,increased therapeutic efficacy,and reduced adverse effects.Over the past few years,sprayable or injectable thermosensitive hydrogels have exhibited high therapeutic potential.These can be applied as cell-growing scaffolds or drug-releasing reservoirs by simply mixing in a free-flowing sol phase at room temperature.Inspired by their unique properties,thermosensitive hydrogels have been widely applied as drug delivery and treatment platforms for precision medicine.In this review,the state-of-theart developments in thermosensitive hydrogels for precision therapy are investigated,which covers from the thermo-gelling mechanisms and main components to biomedical applications,including wound healing,anti-tumor activity,osteogenesis,and periodontal,sinonasal and ophthalmic diseases.The most promising applications and trends of thermosensitive hydrogels for precision therapy are also discussed in light of their unique features.

Chitosan-based thermosensitive hydrogel with long-term release of murine nerve growth factor for neurotrophic keratopathy

Neurotrophic keratopathy is a persistent defect of the corneal epithelium,with or without stromal ulceration,due to corneal nerve deficiency caused by a variety of etiologies.The treatment options for neurotrophic keratopathy are limited.In this study,an ophthalmic solution was constructed from a chitosan-based thermosensitive hydrogel with long-term release of murine nerve growth factor(CTH-mNGF).Its effectiveness was evaluated in corneal denervation(CD)mice and patients with neurotrophic keratopathy.In the preclinical setting,CTH-mNGF was assessed in a murine corneal denervation model.CTH-mNGF was transparent,thermosensitive,and ensured sustained release of mNGF for over 20 hours on the ocular surface,maintaining the local mNGF concentration around 1300 pg/mL in vivo.Corneal denervation mice treated with CTH-mNGF for 10 days showed a significant increase in corneal nerve area and total corneal nerve length compared with non-treated and CTH treated mice.A subsequent clinical trial of CTH-mNGF was conducted in patients with stage 2 or 3 neurotrophic keratopathy.Patients received topical CTH-mNGF twice daily for 8 weeks.Fluorescein sodium images,Schirmer’s test,intraocular pressure,Cochet-Bonnet corneal perception test,and best corrected visual acuity were evaluated.In total,six patients(total of seven eyes)diagnosed with neurotrophic keratopathy were enrolled.After 8 weeks of CTH-mNGF treatment,all participants showed a decreased area of corneal epithelial defect,as stained by fluorescence.Overall,six out of seven eyes had fluorescence staining scores<5.Moreover,best corrected visual acuity,intraocular pressure,Schirmer’s test and Cochet-Bonnet corneal perception test results showed no significant improvement.An increase in corneal nerve density was observed by in vivo confocal microscopy after 8 weeks of CTH-mNGF treatment in three out of seven eyes.This study demonstrates that CTH-mNGF is transparent,thermosensitive,and has sustained-release properties.Its effectiveness in healing corneal epithelial defects in all eyes with neurotrophic keratopathy suggests CTH-mNGF has promising application prospects in the treatment of neurotrophic keratopathy,being convenient and cost effective.

Immobilization of insulin-like growth factor-1 onto thermosensitive hydrogels to enhance cardiac progenitor cell survival and differentiation under ischemic conditions

Stem cell therapy is a promising approach to treat myocardial infarction. However, direct delivery of stem cells into hearts experiences poor cell engraftment and differentiation, due to ischemic conditions （low nutrient and oxygen） in the infarct hearts. Development of suitable cell carriers capable of supporting cell survival and differentiation under these harsh conditions is critical for improving the efficacy of current stem cell therapy. In this work, we created a family of novel cell carriers based on thermosensitive hydrogels and insulin-like growth factor 1 （IGF-1）, and investigated if these cell carriers can improve cell sur- vival and differentiation under ischemic conditions. The thermosensitive hydrogels were synthesized from N-isopropylacryla- mide, acrylic acid, acrylic acid N-bydroxysuccinicimide ester, and 2-hydroxyethyl methacrylate-oligo（hydroxybutyrate）. The hydrogel solutions can be readily injected through 26G needles, and can quickly solidify at 37 ~C to form highly flexible hy- drogels. IGF-I was immobilized into the hydrogels in order to support long-term cell survival and differentiation. Different amount of IGF- 1 was immobilized by using hydrogels with different content of N-hydroxysuccinicimide ester groups. Cardio- sphere derived cells were encapsulated in the hydrogels and cultured under ischemic conditions. The results demonstrated that a significant improvement of cell survival and differentiation was achieved after IGF-1 immobilization. These IGF-1 immobi- lized hydrogels have the potential to improve cell survival and differentiation in infarct hearts.

Injectable and thermosensitive hydrogels mediating a universal macromolecular contrast agent with radiopacity for noninvasive imaging of deep tissues

It is very challenging to visualize implantable medical devices made of biodegradable polymers in deep tissues.Herein,we designed a novel macromolecular contrast agent with ultrahigh radiopacity(iodinate content>50%)via polymerizing an iodinated trimethylene carbonate monomer into the two ends of poly(ethylene glycol)(PEG).A set of thermosensitive and biodegradable polyester-PEG-polyester triblock copolymers with varied polyester compositions synthesized by us,which were soluble in water at room temperature and could spontaneously form hydrogels at body temperature,were selected as the demonstration materials.The addition of macromolecular contrast agent did not obviously compromise the injectability and thermogelation properties of polymeric hydrogels,but conferred them with excellent X-ray opacity,enabling visualization of the hydrogels at clinically relevant depths through X-ray fluoroscopy or Micro-CT.In a mouse model,the 3D morphology of the radiopaque hydrogels after injection into different target sites was visible using Micro-CT imaging,and their injection volume could be accurately obtained.Furthermore,the subcutaneous degradation process of a radiopaque hydrogel could be non-invasively monitored in a real-time and quantitative manner.In particular,the corrected degradation curve based on Micro-CT imaging well matched with the degradation profile of virgin polymer hydrogel determined by the gravimetric method.These findings indicate that the macromolecular contrast agent has good universality for the construction of various radiopaque polymer hydrogels,and can nondestructively trace and quantify their degradation in vivo.Meanwhile,the present methodology developed by us affords a platform technology for deep tissue imaging of polymeric materials.

In vitro Evaluation of Lysozyme-loaded Microspheres in Thermosensitive Methylcellulose-based Hydrogel

Long-terrn injectable microspheres have some inherent disadvantages such as migration of microspheres from the originalsite an.d the burst effect. In order to avoid these problems, microsphere-loaded thermosensitive, hydrogel system was designed and expected to achieve a zero-order release Of biomolecular drugs in relativehigh initial drug loadings. Lysozyme, an antibacterial protein usually used to reduce prosthetic valve endocarditis,was selected as the model drug. Poly （DL-lactide-co-glycolide） （PLGA） microspheres, prepared by solvent evaporation method, were employee to encapsulate lysozyme and dispersed into thermosensitive pre-gel solution containing methylcellulose （MC）, polyethylene glycol （PEG）, sodium citrate （SC）, and sodium alginate （SA）. The mixture could act asadrug reservoir by.performing sol-gel transition rapidly if the temperature was raised from roomtemperature to 37℃. The in vitro release results showed that the burst effect was avoided due to strengthening ofdiffusion resistance in the gel. The formulation was able.to deliver lysozy.me for over.30 daysin a nearly zero-order release profile with a rate of 32.8μg.d^-1 which exhibits its remarkable potential for effective aoolication in long-term drug delivery.

Dynamic culture of a thermosensitive collagen hydrogel as an extracellular matrix improves the construction of tissue-engineered peripheral nerve

Tissue engineering technologies offer new treatment strategies for the repair of peripheral nerve injury, hut cell loss between seeding and adhesion to the scaffold remains inevitable. A thermosensitive collagen hydrogel was used as an extracellular matrix in this study and combined with bone marrow mesenchymal stem cells to construct tissue-engineered peripheral nerve composites in vitro. Dynamic culture was performed at an oscillating frequency of 0.5 Hz and 35° swing angle above and below the horizontal plane. The results demonstrated that bone marrow mesenchymal stem cells formed membrane-like structures around the poly-L-lactic acid scaffolds and exhibited regular alignment on the composite surface. Collagen was used to fill in the pores, and seeded cells adhered onto the poly-L-lactic acid fibers. The DNA content of the bone marrow mesenchymal stem cells was higher in the composites constructed with a thermosensitive collagen hydrogel compared with that in collagen I scaffold controls. The cellular DNA content was also higher in the thermosensitive collagen hydrogel composites constructed with the thermosensitive collagen hydrogel in dynamic culture than that in static culture. These results indicate that tissue-engineered composites formed with thermosensitive collagen hydrogel in dynamic culture can maintain larger numbers of seeded cells by avoiding cell loss during the initial adhe-sion stage. Moreover, seeded cells were distributed throughout the material.

Bioinspired metal-organic framework nanozyme reinforced with thermosensitive hydrogel for regulating inflammatory responses in Parkinson’s disease

Parkinson’s disease(PD)is a prevalent neurodegenerative disorder accompanied by movement disorders and neuroinflammatory injury.Anti-inflammatory intervention to regulate oxidative stress in the brain is beneficial for managing PD.However,traditional natural antioxidants have failed to meet the clinical treatment demands due to insufficient activity and sustainability.Herein,Cu-doping zeolite imidazolate framework-8(ZIF-8)nanozyme is designed to simulate Cu/Zn superoxide dismutase(SOD)by biomimetic mineralization.The nanozyme composite is then integrated into thermosensitive hydrogel(poly(lactic-co-glycolic acid)-poly(ethylene glycol)-poly(lactic-co-glycolic acid)(PLGA-PEG-PLGA))to form an effective antioxidant system(Cu-ZIF@Hydrogel).The thermosensitive hydrogel incorporating nanozymes demonstrate distinct viscoelastic properties aimed at enhancing local nanozyme adhesion,prolonging nanozyme retention time,and modulating antioxidant activity,thus significantly improving the bioavailability of nanozymes.At the cellular and animal levels of PD,we find that Cu-ZIF@Hydrogel bypass the blood-brain barrier and efficiently accumulate in the nerve cells.Moreover,the Cu-ZIF@Hydrogel significantly alleviate the PD’s behavioral and pathological symptoms by reducing the neuroinflammatory levels in the lesion site.Therefore,the hydrogel-incorporating nanozyme system holds great potential as a simple and reliable avenue for managing PD.

Injectable thermosensitive microsphere-hydrogel composite system:combined therapy of hepatocellular carcinoma by remodeling tumor immune microenvironment

Advanced hepatocellular carcinoma(HCC)is one of the most prevalent malignancies,and the clinical treatment outcomes are not satisfactory.Due to the complexity,heterogeneity,and immunosuppressive microenvironment of HCC,monotherapies have limited effects.Therefore,combined therapy may effectively enhance antitumor treatment by remodeling the tumor immune microenvironment.This study reports an injectable thermosensitive microsphere-hydrogel composite system for local co-delivery of the targeted drug sorafenib(SOR)and immunomodulatory cytokines for the combined therapy of HCC.The delivery system exhibited superior properties such as dual-drug delivery,sustained and slow release,local injectability,thermosensitivity,and low side effects.Moreover,it successfully remodeled the immune microenvironment of HCC by increasing the infiltration of CD8^(+)T cells and natural killer cells while decreasing the infiltration of immunosuppressive Treg cells,thereby achieving a potent synergistic effect with SOR.This safe composite delivery system can remodel the tumor microenvironment and enhance anti-tumor treatment,providing a valuable option for the treatment of HCC.

Synergistic injection of the thermosensitive hydrogel and Bi-based alloy bone cement for orthopaedic repair

Low-melting-point alloys have the advantages of good biocompatibility, plasticity, and near-bone mechanical strength, making them suitable as bone defect-filling materials for direct injection into defective bone sites. However, using low-melting-point alloys for orthopedic implants poses the challenge of causing thermal damage to the surrounding bone tissue during injection. In this study, a thermosensitive hydrogel is prepared and synergistically injected into the bone defect site with BiInSn. BiInSn solidifies and releases heat during injection, while the thermosensitive hydrogel absorbs heat and transforms into a gel state,encapsulating BiInSn. Therefore, the surrounding bone tissue is effectively protected from thermal damage. When BiInSn and the thermosensitive hydrogel were injected synergistically, in vitro thermal experiments revealed that the maximum temperature of the surrounding bone tissue reached 42℃. This temperature is below the 47℃ threshold, which causes permanent damage to bone tissues. In vivo experiments demonstrated that rats in the BiInSn-thermosensitive hydrogel group exhibited better recovery at the bone defect sites. These results suggest that the synergistic injection of Bi-based alloy and thermosensitive hydrogel is beneficial in reducing thermal damage to bone tissue, guiding bone tissue growth, and effectively facilitating the repair of bone defects.

A novel sprayable thermosensitive hydrogel coupled with zinc modified metformin promotes the healing of skin wound

A novel sprayable adhesive is established(ZnMet-PF127)by the combination of a thermosensitive hydrogel(Pluronic F127,PF127)and a coordination complex of zinc and metformin(ZnMet).Here we demonstrate that ZnMet-PF127 potently promotes the healing of traumatic skin defect and burn skin injury by promoting cell proliferation,angiogenesis,collagen formation.Furthermore,we find that ZnMet could inhibit reactive oxygen species(ROS)production through activation of autophagy,thereby protecting cell from oxidative stress induced damage and promoting healing of skin wound.ZnMet complex exerts better effects on promoting skin wound healing than ZnCl2 or metformin alone.ZnMet complex also displays excellent antibacterial activity against Staphylococcus aureus or Escherichia coli,which could reduce the incidence of skin wound infections.Collectively,we demonstrate that sprayable PF127 could be used as a new drug delivery system for treatment of skin injury.The advantages of this sprayable system are obvious:(1)It is convenient to use;(2)The hydrogel can cover irregular skin defect sites evenly in a liquid state.In combination with this system,we establish a novel sprayable adhesive(ZnMet-PF127)and demonstrate that it is a potential clinical treatment for traumatic skin defect and burn skin injury.

Thermosensitive injectable hydrogel loaded with hypoxia-induced exosomes maintains chondrocyte phenotype through NDRG3-mediated hypoxic response

Current clinical treatments cannot effectively delay the progression of osteoarthritis(OA).Consequently,joint replacement surgery is required for late-stage OA when patients cannot tolerate pain and joint dysfunction.Therefore,the prevention of OA progression in the early and middle stages is an urgent clinical problem.In a previous study,we demonstrated that NDRG3-mediated hypoxic response might be closely related to the development and progression of OA.In this study,an injectable thermosensitive hydrogel was established by cross-linking Pluronic F-127 and hyaluronic acid(HA)for the sustained release of hypoxia-induced exosomes(HExos)derived from adipose-derived mesenchymal stem cells.We demonstrated that for OA at the early and middle stages,the HExos-loaded HP hydrogel could maintain the chondrocyte phenotype by enhancing chondrocyte autophagy,reducing chondrocyte apoptosis,and promoting chondrocyte activity and proliferation through the NDRG3-mediated hypoxic response.This novel composite hydrogel,which could activate the NDRG3-mediated hypoxic response,may provide new ideas and a theoretical basis for the treatment of early-and mid-stage OA.

Regulated extravascular microenvironment via reversible thermosensitive hydrogel for inhibiting calcium influx and vasospasm

Arterial vasospasm after microsurgery can cause severe obstruction of blood flow manifested as low tissue temperature,leading to tissue necrosis.The timely discovery and synchronized treatment become pivotal.In this study,a reversible,intelligent,responsive thermosensitive hydrogel system is constructed employing both the gel–sol transition and the sol–gel transition.The“reversible thermosensitive(RTS)”hydrogel loaded with verapamil hydrochloride is designed to dynamically and continuously regulate the extravascular microenvi-ronment by inhibiting extracellular calcium influx.After accurate implantation and following in situ gelation,the RTS hydrogel reverses to the sol state causing massive drug release to inhibit vasospasm when the tissue tem-perature drops to the predetermined transition temperature.Subsequent restoration of the blood supply allevi-ates further tissue injury.Before the temperature drops,the RTS hydrogel maintains the gel state as a sustained-release reservoir to prevent vasospasm.The inhibition of calcium influx and vasospasm in vitro and in vivo is demonstrated using vascular smooth muscle cells,mice mesenteric arterial rings,and vascular ultrasonic Doppler detection.Subsequent animal experiments demonstrate that RTS hydrogel can promote tissue survival and alleviate tissue injury responding to temperature change.Therefore,this RTS hydrogel holds therapeutic po-tential for diseases requiring timely detection of temperature change.

MiRNA 24-3p-rich exosomes functionalized DEGMA-modified hyaluronic acid hydrogels for corneal epithelial healing

The damage of corneal epithelium may lead to the formation of irreversible corneal opacities and even blindness.The migration rate of corneal epithelial cells directly affects corneal repair.Here,we explored ocu-microRNA 24-3p(miRNA 24-3p)that can promote rabbit corneal epithelial cells migration and cornea repair.Exosomes,an excellent transport carrier,were exacted from adipose derived mesenchymal stem cells for loading with miRNA 24-3p to prepare miRNA 24-3p-rich exosomes(Exos-miRNA 24-3p).It can accelerate corneal epithelial migration in vitro and in vivo.For application in cornea alkali burns,we further modified hyaluronic acid with di(ethylene glycol)monomethyl ether methacrylate(DEGMA)to obtain a thermosensitive hydrogel,also reported a thermosensitive DEGMA-modified hyaluronic acid hydrogel(THH)for the controlled release of Exos-miRNA 24-3p.It formed a highly uniform and clear thin layer on the ocular surface to resist clearance from blinking and extended the drug-ocular-epithelium contact time.The use of THH-3/Exos-miRNA 24-3p for 28 days after alkali burn injury accelerated corneal epithelial defect healing and epithelial maturation.It also reduced corneal stromal fibrosis and macrophage activation.MiRNA 24-3p-rich exosomes functionalized DEGMA-modified hyaluronic acid hydrogel as a multilevel delivery strategy has a potential use for cell-free therapy of corneal epithelial regeneration.

Custom-design of intrinsically antimicrobial polyurethane hydrogels as multifunctional injectable delivery systems for mini-invasive wound treatment

Effective management of hard-to-close skin wounds is a challenging issue due to several co-morbidities in affected patients.Particularly,infections represent a major obstacle in wound healing.The design of efficient wound treatments thus represents an urgent need.Injectable drug delivery hydrogels with intrinsic antimicrobial and antifungal properties were herein designed for perspective application in the mini-invasive treatment of hard-to-close wounds.First,an amphiphilic polyurethane was synthesized from Poloxamer■407 macrodiol and N-Boc diethanolamine chain extender(DHP407,M_(w)=33 kDa).Chain-extension reaction step was optimized to maximize the formation of-NH groups along the polymer chains(4.5×10^(20)±1.8×10^(19)-NH groups/g polymer),after Boc-caging group removal(D-DHP407).DHP407 and D-DHP407 water-based solutions were thermosensitive with slightly different Critical Micellar Concentration(17.5μg/mL vs.19.7μg/mL)and cluster hydrodynamic diameter(235.6±19.9 nm vs.260.1±20.5 nm),and similar Critical Micellar Temperature(22.5℃ vs.23.1℃).A polyurethane solution concentration(15%w/V)was selected by tube-inverting test and rheological analysis showing injectability,as evidenced by sol-to-gel transition at 27.7±0.6℃ for DHP407 and 29.7±0.6℃ for D-DHP407,within few minutes,at similar gelation kinetics.DHP407 and D-DHP407 hydrogels showed controlled release of Bovine Serum Albumin(BSA)model protein(1 mg/mL),with no burst phenomena.BSA released from DHP407 and D-DHP407 hydrogels at 24 h was 33.7±5.0% and 24.6±1.2%,respectively.D-DHP407 hydrogel was biocompatible and able to support NIH-3T3 cell proliferation.Furthermore,D-DHP407 hydrogel showed intrinsic antifungal and antibacterial activity against C.albicans and Gram-positive S.aureus and Gram-negative E.coli bacteria,injectability and capability to retain shape post-injection,making it promising for future use in the management of hard-to-close skin wounds.

In vivo retention of poloxamer-based in situhydrogels for vaginal application in mouse and rat models

The purpose of this study is to evaluate the in vivo retention capabilities of poloxamer-based in situ hydrogels for vaginal application with nonoxinol-9 as the model drug. Two in situ hydrogel formulations, which contained 18% poloxamer 407 plus 1% poloxamer 188 (GEL1, relative hydrophobic) or 6% poloxamer 188 (GEL2, relative hydrophilic), were compared with respect to the rheological properties, in vitro hydrogel erosion and drug release. The vaginal retention capabilities of these hydrogel formulations were further determined in two small animal models, including drug quantitation of vaginal rinsing fluid in mice and isotope tracing with 99mTc in rats. The two formulations exhibited similar phase transition temperatures ranging from 27 to 32 °C. Increasing the content of poloxamer 188 resulted in higher rheological moduli under body temperature, but slightly accelerated hydrogel erosion and drug release. When compared in vivo, GEL1 was eliminated significantly slower in rat vagina than GEL2, while the vaginal retention of these two hydrogel formulations behaved similarly in mice. In conclusion, increases in the hydrophilic content of formulations led to faster hydrogel erosion, drug release and intravaginal elimination. Rats appear to be a better animal model than mice to evaluate the in situ hydrogel for vaginal application.

Controlled WISP-1 shRNA Delivery Using Thermosensitive Biodegradable Hydrogel in the Treatment of Osteoarthritis

This paper presents a new method of delivering shRNA with biodegradable, thermosensitive PLGA-PEG-PLGA hydrogels for gene treatment of osteoarthritis （OA）. OA is a chronic debilitating disease. Without the proper treatment and prognosis, it may result in the loss of joint function in aged people. Currently, gene therapy targeted on WISP-1 has emerged as an alternative method for OA treatment. In order to constantly release shRNA at 37.0 ℃, we synthetized the hydrogels via ring-opening copolymerization of lactide （LA） and glycolide （GA） using Polyethylene glycol （PEG Mn = 1000） and stannous octoate （Sn（Oct）2, 95%） as the macroinitiator and catalyst. First, the PLGA-PEG-PLGA copolymer was mixed with WISP- 1 shRNA and PEI-Lys in distilled water at 4.0 ℃. Then, the WISP-lshRNA/PEI-Lys loaded hydrogel was formed after incubation of the mixed solution at 37.0 ℃. During tests, the plasmid was released from this hydrogel complex constantly, and enhanced the transfection efficiency of WISP-1 shRNA. In addition, silencing WISP-1 results to lower expression of MMP-3 and ADAMTS, and the accumulation of HBP 1 in synoviocytes. Therefore, the hydrogel containing WISP-1 shRNA is demonstrated an efficient way for the treatment of OA.

Camptothecin@HMSNs/thermosensitive hydrogel composite for applications in preventing local breast cancer recurrence

Camptothecin has a strong tumor killing ability for a variety of tumor cells with its special anti-cancer mechanism including the breast cancer. However, because of its infinite hydrophobic property, its clinical application has been greatly limited. Early prevention of loco regional recurrence for the breast cancer is critical for patients who have undergone breast-conserving therapy. In the study,CPT was used for the inhibition of the recurrence after the operation. The hollow mesoporous silica nanoparticles were used as the carrier to improve the hydrophilic property and increase its bioavailability with the high loading capacity. The ability of the cellular uptake and antitumor activity was increased. Hydrogel was the ideal carrier for local therapy, so the CPT@HMSNs were loaded into the PLEL thermo sensitive hydrogel to be injected into the tumor sites after the tumor was resected. The recurrence was reduced in the group of CPT-HMSNs-PLEL and the side effect of CPT was decreased. They exhibit distinguished potential as drug carrier for local delivery.

Design and evaluation of chitosan-amino acid thermosensitive hydrogel

Chitosan/glycerophosphate thermosensitive hydrogel crosslinked physically was a potential drug delivery carrier;however, long gelation time limits its application. Here, chitosan-amino acid (AA) thermosensitive hydrogels were prepared from chitosan (CS), αβ-glycerophosphate (GP), and L-lysine (Lys) or L-glutamic acid (Glu). The prepared CS-Lys/GP and CS-Glu/GP hydrogel showed good thermosensitivity and could form gels in a short time. The optimal parameters of CS-Lys/GP hydrogel were that the concentration of CS-Lys was 2.5%, the ratio of CS/Lys was 3.5/1.0, the ratio of CS-Lys/GP was 4.5/1.0. The optimal parameters of CS-Glu/GP hydrogel were that the concentration of CS-Glu was 3.0%, the ratio of CS/Glu was 2.0/1.0, and the ratio of CS-Glu/GP was 4.0/1.5. Chitosan-amino acid (CS-AA) thermosensitive hydrogel had a three-dimensional network structure. The addition of model drug tinidazole (TNZ) had no obvious effect on the structure of hydrogel. The results of infrared spectroscopy showed that there were hydrogen bonds between amino acids and chitosan. In vitro release results showed that CS-Lys/GP and CS-Glu/GP thermosensitive hydrogels had sustained release effects. Thus, the chitosan-amino acid thermosensitive hydrogels hold great potential as a sustained release drug delivery system.

Local sustained release of PD-1 monoclonal antibody and lenvatinib by thermo-sensitive hydrogel for improving tumor immunotherapy

In clinic,the combination of intravenous pembrolizumab(PD-1 monoclonal antibody)with oral Lenvatinib(LEN)exhibited an enhanced synergistic benefit for cancer therapy.However,the clinical outcomes were always limited by the problems of inconsistent pharmacokinetic profiles of two drugs,lower drug accumulation in tumor and obvious side effects during the combination therapy.Here,in situ-forming thermosensitive hydrogels based on PLGA-PEG-PLGA triblock copolymers were prepared for local administration of anti-PD1 and LEN(P&L@Gel)to improve therapeutic efficacy and safety.After peritumoral or surgical resection site injection,the significant increased concentrations of both drugs in tumor were observed with the local sustained release of P&L@Gel.In comparison with the group of intraperitoneal anti-PD1 plus oral LEN(P-ip&L-po),significantly higher tumor inhibition efficiency on CT26 tumor models could be obtained in P&L@Gel group,even at the dose of one-eighth of the former,same tumorinhibition effects could be achieved.The enhanced antitumor efficacy of P&L@Gel group was probably associated with the 2.2 folds of increased level of CD8+T cells and the polarization of tumor associated macrophage from M2 to M1 along with the increased drug accumulation.Moreover,compared with the obvious side effects of P-ip&L-po group,no significant changes of PLT,ALT and UA in blood,as well as IL-1αand IL-1βin mice paws were observed between P&L@Gel group and untreated group.These results suggested that local administration of anti-PD1 and LEN with thermosensitive hydrogel could offer a potential strategy for tumors or tumor postoperative adjuvant treatment.

Engineering of a NIR-activable hydrogel-coated mesoporous bioactive glass scaffold with dual-mode parathyroid hormone derivative release property for angiogenesis and bone regeneration

Osteogenesis,osteoclastogenesis,and angiogenesis play crucial roles in bone regeneration.Parathyroid hormone(PTH),an FDA-approved drug with pro-osteogenic,pro-osteoclastogenic and proangiogenic capabilities,has been employed for clinical osteoporosis treatment through systemic intermittent administration.However,the successful application of PTH for local bone defect repair generally requires the incorporation and delivery by appropriate carriers.Though several scaffolds have been developed to deliver PTH,they suffer from the weaknesses such as uncontrollable PTH release,insufficient porous structure and low mechanical strength.Herein,a novel kind of NIR-activable scaffold(CBP/MBGS/PTHrP-2)with dual-mode PTHrP-2(a PTH derivative)release capability is developed to synergistically promote osteogenesis and angiogenesis for high-efficacy bone regeneration,which is fabricated by integrating the PTHrP-2-loaded hierarchically mesoporous bioactive glass(MBG)into the N-hydroxymethylacrylamide-modified,photothermal agent-doped,poly(N-isopropylacrylamide)-based thermosensitive hydrogels through assembly process.Upon on/off NIR irradiation,the thermoresponsive hydrogel gating undergoes a reversible phase transition to allow the precise control of on-demand pulsatile and long-term slow release of PTHrP-2 from MBG mesopores.Such NIR-activated dual-mode delivery of PTHrP-2 by this scaffold enables a well-maintained PTHrP-2 concentration at the bone defect sites to continually stimulate vascularization and promote osteoblasts to facilitate and accelerate bone remodeling.In vivo experiments confirm the significant improvement of bone reparative effect on critical-size femoral defects of rats.This work paves an avenue for the development of novel dual-mode delivery systems for effective bone regeneration.