Injectable, Adhesive Albumin Nanoparticle-Incorporated Hydrogel for Sustained Localized Drug Delivery and Efficient Tumor Treatment.

Injectable hydrogels are receiving increasing attention as local depots for sustained anticancer drug delivery. However, most current hydrogel-based carriers lack tissue-adhesive ability, a property that is important for the immobilization of drug-loaded systems at tumor sites to increase local drug concentration. In this study, we developed a paclitaxel (PTX)-loaded injectable hydrogel with firm tissue adhesion for localized tumor therapy. PTX-loaded bovine serum albumin (BSA) nanoparticles (PTX@BN) were prepared, and the drug-loaded hydrogel was then fabricated by cross-linking PTX@BN with o-phthalaldehyde (OPA)-terminated 4-armed poly(ethylene glycol) (4aPEG-OPA) via a condensation reaction between OPA and the amines in BSA. The hydrogel showed firm adhesion to various organs and tumor tissues ex vivo due to the condensation reaction of unreacted OPA groups and amines in the tissues. The PTX-loaded nanocomposite hydrogels sustained PTX release over 30 days following the Korsmeyer-Peppas model and exhibited notable inhibition activities against mouse C26 colon and 4T1 breast cancer cells in vitro. Following peritumoral injection into mice with C26 or 4T1 tumors, the PTX@BN-loaded hydrogel significantly enhanced the antitumor efficacy and prolonged animal survival time compared to free PTX solutions with low systemic toxicity. Therefore, the adhesive, PTX-loaded nanocomposite hydrogels have the potential for efficient localized tumor therapy.

Designing Hydrogels for Immunomodulation in Cancer Therapy and Regenerative Medicine.

The immune system not only acts as a defense against pathogen and cancer cells, but also plays an important role in homeostasis and tissue regeneration. Targeting immune systems is a promising strategy for efficient cancer treatment and regenerative medicine. Current systemic immunomodulation therapies are usually associated with low persistence time, poor targeting to action sites, and severe side effects. Due to their extracellular matrix-mimetic nature, tunable properties and diverse bioactivities, hydrogels are intriguing platforms to locally deliver immunomodulatory agents and cells, as well as provide an immunomodulatory microenvironment to recruit, activate, and expand host immune cells. In this review, the design considerations, including polymer backbones, crosslinking mechanisms, physicochemical nature, and immunomodulation-related components, of the hydrogel platforms, are focused on. The immunomodulatory effects and therapeutic outcomes in cancer therapy and tissue regeneration of different hydrogel systems are emphasized, including hydrogel depots for delivery of immunomodulatory agents, hydrogel scaffolds for cell delivery, and immunomodulatory hydrogels depending on the intrinsic properties of materials. Finally, the remained challenges in current systems and future development of immunomodulatory hydrogels are discussed.

Intratympanic injection of hydrogel nanodrug for the prevention and treatment of sensorineural hearing loss.

Safe and efficient drug delivery to the inner ear has always been the focus of prevention and treatment of sensorineural deafness. The rapid development of nanodrug delivery systems based on hydrogel has provided a new opportunity. Among them, thermo-sensitive hydrogels promote the development of new dosage form for intratympanic injection. This smart biomaterial could transform to semisolid phase when the temperature increased. Thermo-sensitive hydrogel nanodrug delivery system is expected to achieve safe, efficient, and sustained inner ear drug administration. This article introduces the key techniques and the latest progress in this field.

Stimuli-Responsive Hydrogel Adhesives for Wound Closure and Tissue Regeneration.

Sutures and staplers, as gold standards for clinical wound closure, usually cause secondary tissue injury and require professional technicians and equipment. The noninvasive hydrogel adhesives are used in various biomedical applications, such as wound closure, tissue sealing, and tissue regeneration, due to their remarkable properties. Recently-developed hydrogel adhesives, especially stimuli-responsive hydrogels, have shown great potential owing to their advantages in regulating their performance and functions according to the wound situations or external conditions, thus allowing the wounds to heal gradually. However, comprehensive summary on stimuli-responsive hydrogels as tissue adhesives is rarely reported to date. This review focuses on the advances in the design of various stimuli-responsive hydrogel adhesives over the past decade, including the systems responsive to pH, temperature, photo, and enzymes. Their potential biomedical applications, such as skin closure, cardiovascular and liver hemostasis, and gastrointestinal sealing, are emphasized. Meanwhile, the challenges and future development of stimuli-responsive hydrogel adhesives are discussed. This review aims to provide meaningful insights for the further design of next-generation of hydrogel adhesives for wound closure and tissue regeneration.

Injectable, self-healing hydrogel adhesives with firm tissue adhesion and on-demand biodegradation for sutureless wound closure.

Tissue adhesives have garnered extensive interest as alternatives and supplements to sutures, whereas major challenges still remain, including weak tissue adhesion, inadequate biocompatibility, and uncontrolled biodegradation. Here, injectable and biocompatible hydrogel adhesives are developed via catalyst-free o-phthalaldehyde/amine (hydrazide) cross-linking reaction. The hydrogels demonstrate rapid and firm adhesion to various tissues, and an o-phthalaldehyde-mediated tissue adhesion mechanism is established. The hydrogel adhesives show controlled degradation profiles of 6 to 22 weeks in vivo through the incorporation of disulfide bonds into hydrogel network. In liver and blood vessel injury, the hydrogels effectively seal the incisions and rapidly stop bleeding. In rat and rabbit models of full-thickness skin incision, the hydrogel adhesives quickly close the incisions and accelerate wound healing, which exhibit efficacies superior to those of commercially available fibrin glue and cyanoacrylate glue. Thus, the hydrogel adhesives show great potential for sutureless wound closure, hemostasis sealing, and prevention of leakage in surgical applications.

Injectable antibacterial tissue-adhesive hydrogel based on biocompatible o-phthalaldehyde/amine crosslinking for efficient treatment of infected wounds.

Injectable antibacterial hydrogels have attracted considerable attention in wound management. However, the development of injectable hydrogels with excellent antibacterial activity, good biocompatibility, and strong tissue adhesion remains a challenge. In this study, an antibacterial tissue-adhesive hydrogel was developed based on a catalyst-free o-phthalaldehyde (OPA)/amine reaction by simply mixing OPA-terminated four-arm poly(ethylene glycol) (4aPEG-OPA) and ε-poly-l-lysine (ε-PLL) solutions. The hydrogel showed tunable gelation time, storage moduli, and degradation rate depending on the polymer concentration and 4aPEG-OPA/ε-PLL mass ratio. The hydrogel exhibited nearly 100% bacterial inhibition rates in-vitro against Gram-negative E. coli and Gram-positive S. aureus, while maintaining good biocompatibility. The hydrogel matched well in shape and tightly adhered to the tissue after in-situ formation at the wound sites. Following the treatment of rat models of full-thickness skin incisions and round wounds, the hydrogel effectively closed the wounds and promoted wound healing. Moreover, after administering to S. aureus infected full-thickness skin wounds, the hydrogel exhibited remarkable efficacy in inhibiting wound infection with a bacterial inhibition rate over 99.94%, achieving a significantly accelerated wound healing compared with the commercially available Prontosan® gel. Therefore, the hydrogel exhibits great potential as a wound dressing for infection prevention and promotion of healing.

Thermo-induced physically crosslinked polypeptide-based block copolymer hydrogels for biomedical applications.

Stimuli-responsive synthetic polypeptide-containing block copolymers have received considerable attention in recent years. Especially, unique thermo-induced sol-gel phase transitions were observed for elaborately-designed amphiphilic diblock copolypeptides and a range of poly(ethylene glycol) (PEG)-polypeptide block copolymers. The thermo-induced gelation mechanisms involve the evolution of secondary conformation, enhanced intramolecular interactions, as well as reduced hydration and increased chain entanglement of PEG blocks. The physical parameters, including polymer concentrations, sol-gel transition temperatures and storage moduli, were investigated. The polypeptide hydrogels exhibited good biocompatibility in vitro and in vivo, and displayed biodegradation periods ranging from 1 to 5 weeks. The unique thermo-induced sol-gel phase transitions offer the feasibility of minimal-invasive injection of the precursor aqueous solutions into body, followed by in situ hydrogel formation driven by physiological temperature. These advantages make polypeptide hydrogels interesting candidates for diverse biomedical applications, especially as injectable scaffolds for 3D cell culture and tissue regeneration as well as depots for local drug delivery. This review focuses on recent advances in the design and preparation of injectable, thermo-induced physically crosslinked polypeptide hydrogels. The influence of composition, secondary structure and chirality of polypeptide segments on the physical properties and biodegradation of the hydrogels are emphasized. Moreover, the studies on biomedical applications of the hydrogels are intensively discussed. Finally, the major challenges in the further development of polypeptide hydrogels for practical applications are proposed.

A Multifunctional Nanoparticle Mitigating Cytokine Storm by Scavenging Multiple Inflammatory Mediators of Sepsis.

Sepsis is a disease caused by infection, which is characterized by a dysregulated immune response in the host and affects more than 30 million people worldwide each year. However, the current single therapeutic approaches are not effective in controlling the progression of sepsis. Here, we synthesize a nanoparticle (TMP) containing tannic acid (TA), Polymyxin B (PMB), and Mn2+ (Mn) by a simple one-pot method. TMP has the following characteristics: (1) All components have good biocompatibility; (2) simple preparation process without subsequent processing; (3) antibacterial and remove multiple inflammatory mediators; and (4) effectively mitigating cytokine storm both in the acute lung injury (ALI) and the cecal ligation and puncture (CLP) model. Our results demonstrate the critical role of targeting multiple mediators to mitigate cytokine storms for the treatment of sepsis.

A facile theragnostic nano-platform for the effective treatment and real-time imaging of acute liver injury.

Acute liver injury (ALI), induced by an imbalance of pro-inflammatory and anti-inflammatory processes, remains a major concern for disease detection and drug screening. However, current clinical blood tests for ALI diagnostics are limited by delayed estimation, invasive and non-comprehensive visualization and false results from non-specific biomarkers. Moreover, it is difficult to give timely therapy to inhibit its progression and adjust treatment regimens in time. Herein, this study developed a facile theragnostic nano-platform (BLD NP) for effective treatment and real-time imaging of acute liver injury (ALI). BLD NPs comprise peptide-caged NIR probes (CyGbF) for real-time imaging and a small molecular drug (dexamethasone sodium phosphate, Dsp) for timely treatment of ALI, in which CyGbF was conjugated and Dsp was electrostatically complexed with fluorinated polyethylene (LPOF), respectively. After systemic administration, BLD NPs passively target liver tissue and react with ALI-associated protease to in situ activate the NIR signaling moiety for non-invasive longitudinal imaging of ALI progression, while Dsp is released timely for ALI treatments, serving as a theragnostic platform and providing comprehensive estimations for ALI, comparable to standard methods including blood tests and flow cytometric analysis. Therefore, BLD NPs hold great promise for early real-time imaging, timely therapeutic treatment and prediction of the progression of ALI.

pH- and Temperature-responsive Hydrogels Based on Tertiary Amine-modified Polypeptides for Stimuli-responsive Drug Delivery.

pH- and temperature-responsive hydrogels have attracted considerable attention due to their responsiveness to dual physiologically-relevant stimuli. In this study, we developed stimuli-responsive hydrogels based on monomethoxy poly(ethylene glycol) (mPEG)-polypeptide block copolymers containing various tertiary amine pendants (EEP-TAs). The EEP-TAs were synthesized via ring-opening copolymerization of α-amino acid N-carboxyanhydrides, and further modified post-polymerization with click chemistry. The EEP-TAs exhibited an α-helix-to-ß-sheet transition when the pH was increased from 4.0 to 7.4. At elevated polymer concentrations, aqueous solutions of the EEP-TAs underwent thermo-induced sol-gel phase transitions, which were dependent on the pH. The hydrogels almost fully degraded within 3 weeks in the subcutaneous layer of mice and exhibited good histocompatibility in vivo. Additionally, doxorubicin (DOX)-loaded hydrogels exhibited pH-responsive drug release profiles in vitro, which were composed of rapid release at acidic pH and more sustained release at neutral pH. Thus, these polypeptide hydrogels hold potential as depots for environment-responsive delivery of therapeutic agents.

Injectable Polypeptide Hydrogel Depots Containing Dual Immune Checkpoint Inhibitors and Doxorubicin for Improved Tumor Immunotherapy and Post-Surgical Tumor Treatment.

In this work, we developed a strategy for local chemo-immunotherapy through simultaneous incorporation of dual immune checkpoint blockade (ICB) antibodies, anti-cytotoxic T-lymphocyte-associated protein 4 (aCTLA-4) and anti-programmed cell death protein 1 (aPD-1), and a chemotherapy drug, doxorubicin (Dox), into a thermo-gelling polypeptide hydrogel. The hydrogel encapsulating Dox or IgG model antibody showed sustained release profiles for more than 12 days in vitro, and the drug release and hydrogel degradation were accelerated in the presence of enzymes. In comparison to free drug solutions or hydrogels containing Dox or antibodies only, the Dox/aCTLA-4/aPD-1 co-loaded hydrogel achieved improved tumor suppression efficiency, strengthened antitumor immune response, and prolonged animal survival time after peritumoral injection into mice bearing B16F10 melanoma. Additionally, after injection of Dox/aCTLA-4/aPD-1 co-loaded hydrogel into the surgical site following tumor resection, a significantly enhanced inhibition on tumor reoccurrence was demonstrated. Thus, the polypeptide hydrogel-based chemo-immunotherapy strategy has potential in anti-tumor therapy and the prevention of tumor reoccurrence.

Mucoadhesive, Antibacterial, and Reductive Nanogels as a Mucolytic Agent for Efficient Nebulized Therapy to Combat Allergic Asthma.

Asthma is an intractable disease involving the infiltration of inflammatory cells and mucus plugging. Despite small molecular mucolytics having the ability to break the disulfide bonds of mucins, offering a potential way to overcome the airflow obstruction and airway infection, these mucolytics have limited therapeutic effects in vivo. Therefore, in this work, arginine-grafted chitosan (CS-Arg) is ionically cross-linked with tris(2-carboxyethyl)phosphine (TCEP) to obtain nanogels as a mucolytic agent. The positively charged nanogels effectively inhibit the formation of large aggregates of mucin in vitro, probably thanks to the formation of an ionic interaction between CS-Arg and mucin, as well as the breakage of disulfide bonds in mucin by the reductive TCEP. Moreover, the nanogels show good cytocompatibility at concentrations up to 5 mg mL-1, exhibiting effective inhibitory effects against the proliferation of both Staphylococcus aureus and Escherichia coli at 5 mg mL-1. After the administration of the nanogels by nebulization into a Balb/c mouse model with allergic asthma, they can efficiently reduce the mucus obstruction in bronchioles and alveoli and relieve airway inflammation. Therefore, these CS-Arg/TCEP nanogels potentially represent a promising mucolytic agent for the efficient treatment of allergic asthma and other muco-obstructive diseases.

Biomedical polymers: synthesis, properties, and applications.

Biomedical polymers have been extensively developed for promising applications in a lot of biomedical fields, such as therapeutic medicine delivery, disease detection and diagnosis, biosensing, regenerative medicine, and disease treatment. In this review, we summarize the most recent advances in the synthesis and application of biomedical polymers, and discuss the comprehensive understanding of their property-function relationship for corresponding biomedical applications. In particular, a few burgeoning bioactive polymers, such as peptide/biomembrane/microorganism/cell-based biomedical polymers, are also introduced and highlighted as the emerging biomaterials for cancer precision therapy. Furthermore, the foreseeable challenges and outlook of the development of more efficient, healthier and safer biomedical polymers are discussed. We wish this systemic and comprehensive review on highlighting frontier progress of biomedical polymers could inspire and promote new breakthrough in fundamental research and clinical translation.

Effect of Polymer Topology and Residue Chirality on Biodegradability of Polypeptide Hydrogels.

Polypeptide-based injectable hydrogels have attracted the attention of biomedical researchers due to their unique biocompatibility and biodegradability, tunable residue chirality, and secondary conformation of polypeptide chains. In the present study, four types of poly(ethylene glycol)-block-poly(glutamic acid)s with different topological structures and residue chirality of polypeptide segments were developed, which were grafted with tyramine side groups for further cross-linking. The results demonstrated that the covalent conjugation between the tyramine groups in the presence of horseradish peroxidase and hydrogen peroxide could form porous hydrogels rapidly. Additionally, the gelation time and mechanical strength of the hydrogels were measured. All the polymer precursors and hydrogels exhibited good cytocompatibility in vitro. Further assessment of the enzymatic degradability of the hydrogels and copolymers in vitro revealed that the degradation rate was influenced by the adjustment of polymer topology or residue chirality of polypeptide copolymers. Subsequently, the effect of copolymer topology and polypeptide chirality on in vivo biodegradability and biocompatibility was assessed. This study will provide insights into the relationship between copolymer structures and hydrogel properties and benefit future polypeptide-based hydrogel studies in biomedical applications.

A fast and versatile cross-linking strategy via o-phthalaldehyde condensation for mechanically strengthened and functional hydrogels.

Fast and catalyst-free cross-linking strategy is of great significance for construction of covalently cross-linked hydrogels. Here, we report the condensation reaction between o-phthalaldehyde (OPA) and N-nucleophiles (primary amine, hydrazide and aminooxy) for hydrogel formation for the first time. When four-arm poly(ethylene glycol) (4aPEG) capped with OPA was mixed with various N-nucleophile-terminated 4aPEG as building blocks, hydrogels were formed with superfast gelation rate, higher mechanical strength and markedly lower critical gelation concentrations, compared to benzaldehyde-based counterparts. Small molecule model reactions indicate the key to these cross-links is the fast formation of heterocycle phthalimidine product or isoindole (bis)hemiaminal intermediates, depending on the N-nucleophiles. The second-order rate constant for the formation of phthalimidine linkage (4.3 M-1 s-1) is over 3000 times and 200 times higher than those for acylhydrazone and oxime formation from benzaldehyde, respectively, and comparable to many cycloaddition click reactions. Based on the versatile OPA chemistry, various hydrogels can be readily prepared from naturally derived polysaccharides, proteins or synthetic polymers without complicated chemical modification. Moreover, biofunctionality is facilely imparted to the hydrogels by introducing amine-bearing peptides via the reaction between OPA and amino group.

Crucial Impact of Residue Chirality on the Gelation Process and Biodegradability of Thermoresponsive Polypeptide Hydrogels.

Thermosensitive polypeptide hydrogels have gained considerable attention in potential biomedical applications, of which the polymer structure may be tuned by residue chirality. In this study, polypeptide-based block copolymers with different chiralities were synthesized by ring-opening polymerization of γ-ethyl-l-glutamate N-carboxyanhydride and/or γ-ethyl-d-glutamate N-carboxyanhydride using amino-terminated monomethoxy poly(ethylene glycol) as a macroinitiator. All mPEG-polypeptide copolymers underwent sol-gel transition with an increase in temperature. The block copolymers with mixed enantiomeric residues of γ-ethyl-l-glutamate (ELG) and γ-ethyl-d-glutamate (EDG) in the polypeptide blocks exhibited lower critical gelation concentrations and lower critical gelation temperatures compared with those composed of pure ELG or EDG residues. We established that the difference in gelation properties between the copolymers was derived from the distinction of the secondary structures. We further demonstrated the influence of polypeptide chirality on the degradability and biocompatibility of hydrogels in vivo. Our findings provide insights into the design of hydrogels having tailored secondary conformation, gelation property, and biodegradability.

A pH-Triggered Self-Unpacking Capsule Containing Zwitterionic Hydrogel-Coated MOF Nanoparticles for Efficient Oral Exendin-4 Delivery.

Oral peptide or protein delivery is considered a revolutionary alternative to daily subcutaneous injection; however, major challenges remain in terms of impediments of the gastrointestinal environment and the intestinal epithelium consisting of mucus and the epithelial cell layer, leading to low bioavailability. To protect against gastrointestinal degradation and promote penetration across the intestinal mucosa, a pH-triggered self-unpacking capsule encapsulating zwitterionic hydrogel-coated metal-organic framework (MOF) nanoparticles is engineered. The MOF nanoparticles possess a high exendin-4 loading capacity, and the zwitterionic hydrogel layer imparts unique capability of permeation across the mucus layer and effective internalization by epithelial cells to the nano-vehicles. In addition to the gastro-resistant feature, the pH-responsive capsules are dissociated drastically in the intestinal environment due to the rapid generation of abundant CO2 bubbles, which triggers a sudden release of the nanoparticles. After oral administration of the capsules containing exendin-4-loaded nanoparticles into a diabetes rat model, markedly enhanced plasma exendin-4 levels are achieved for over 8 h, leading to significantly increased endogenous insulin secretion and a remarkable hypoglycemic effect with a relative pharmacological availability of 17.3%. Owing to the low risk of hypoglycemia, this oral exendin-4 strategy will provide a vast potential for daily and facile diabetes treatment.

Localized Chemotherapy Based on Injectable Hydrogel Boosts the Antitumor Activity of Adoptively Transferred T Lymphocytes In Vivo.

The adoptive transfer of antigen-specific T cells has been successfully applied in the treatment of hematological malignancies. However, its application in the treatment of solid tumors has been overshadowed by the immunosuppressive tumor microenvironment. In this context, a preprocessing strategy is developed to reprogram the immunosuppressive tumor microenvironment using a thermoresponsive hydrogel loaded with doxorubicin (DOX@Gel). Compared with hydrogel-based chemotherapy alone or adoptive T cell therapy alone, this combination exhibits enhanced anti-tumor efficacy. In addition to the direct killing of tumor cells, the local chemotherapy releases tumor-associated antigens which enhance the proliferation and effector function of endogenous and adoptively transferred T cells. Moreover, DOX@Gel significantly reduces the numbers of both myeloid derived suppressor cells and Tregs in tumor microenvironment. It is suggested that DOX@Gel promotes the efficacy of adoptively transferred T cells against solid tumors, overcoming the key limitations of adoptive T cell therapy.

Rapidly Thermoreversible and Biodegradable Polypeptide Hydrogels with Sol-Gel-Sol Transition Dependent on Subtle Manipulation of Side Groups.

Thermoreversible hydrogels are attractive materials for biomedical applications, but their applications are still limited by nonbiodegradability and/or slow temperature-dependent gel-to-sol transition rates. In this research, we prepared a range of amphiphilic diblock, triblock, and four-armed star block copolymers composed of poly(ethylene glycol) (PEG) and poly(γ-(2-(2-ethoxyethoxy)ethyl)-l-glutamate) (P(EEO2LG)) segments, which can form rapidly thermoreversible hydrogels at physiological temperature. Intriguingly, the obtained hydrogels can transform from gel to sol within 10-70 s in response to the temperature decrease from 37 to 0 °C. The thermosensitive sol-gel-sol transitions are markedly faster than previously reported thermoreversible PEG-poly(l-glutamate) derivative hydrogels with subtle differences in the side groups and a widely studied poly(d,l-lactide-co-glycolide)-b-PEG-b-poly(d,l-lactide-co-glycolide) (PLGA-PEG-PLGA) hydrogel that required a much longer time of 40∼150 min. Further investigation of the relationship between the hydrogel property and polymer structure is performed, and the self-assembly mechanisms of different copolymers are proposed. Cytotoxicity assays and subcutaneous degradation experiments reveal that the PEG/P(EEO2LG) block copolymers are biocompatible and biodegradable. The polypeptide hydrogel can therefore be used as a three-dimensional platform for facile cell culture and collection by regulating the temperature.

Design of an Injectable Polypeptide Hydrogel Depot Containing the Immune Checkpoint Blocker Anti-PD-L1 and Doxorubicin to Enhance Antitumor Combination Therapy.

Combination therapy can be used to enhance the therapeutic response and decrease side effects during cancer treatment. In this study, a system is developed to locally deliver the immune checkpoint blockade antibody targeting programmed death-ligand 1 (anti-PD-L1 or aPD-L1) and doxorubicin (Dox), by an injectable, biocompatible polypeptide hydrogel as a drug depot. The localized and sustained release of Dox after the intratumoral injection of the co-loaded hydrogel induces immunogenic tumor cell death, thus promoting an antitumor immunological response. The tumor inhibitory effect is significantly enhanced by the simultaneous release of aPD-L1 at the tumor site thanks to its action on the inhibition of the PD-1/PD-L1 pathway and restoration of the tumor-killing effect of cytotoxic T cells. Treatment of the B16F10 melanoma model with the aPD-L1 and Dox co-loaded hydrogel leads to a remarkable inhibition of tumor progression and prolongation of animal survival.