Injectable Hydrogel Based on Protein-Polyester Microporous Network as an Implantable Niche for Active Cell Recruitment

Abstract

Despite the potential of hydrogel-based localized cancer therapies, their efficacy can be limited by cancer recurrence. Therefore, it is of great significance to develop a hydrogel system that can provoke robust and durable immune response in the human body. This study has developed an injectable protein-polymer-based porous hydrogel network composed of lysozyme and poly(ε-caprolactone-co-lactide)-b-poly(ethylene glycol)-b-poly(ε-caprolactone-co-lactide (PCLA) (Lys-PCLA) bioconjugate for the active recruitment dendritic cells (DCs). The Lys-PCLA bioconjugates are prepared using thiol-ene reaction between thiolated lysozyme (Lys-SH) and acrylated PCLA (PCLA-Ac). The free-flowing Lys-PCLA bioconjugate sols at low temperature transformed to immovable gel at the physiological condition and exhibited stability upon dilution with buffers. According to the in vitro toxicity test, the Lys-PCLA bioconjugate and PCLA copolymer were non-toxic to RAW 263.7 cells at higher concentrations (1000 µg/mL). In addition, subcutaneous administration of Lys-PCLA bioconjugate sols formed stable hydrogel depot instantly, which suggested the in situ gel forming ability of the bioconjugate. Moreover, the Lys-PCLA bioconjugate hydrogel depot formed at the interface between subcutaneous tissue and dermis layers allowed the active migration and recruitment of DCs. As suggested by these results, the in-situ forming injectable Lys-PCLA bioconjugate hydrogel depot may serve as an implantable immune niche for the recruitment and modification of DCs.

Hydrogel-guided strategies to stimulate an effective immune response for vaccine-based cancer immunotherapy

“…A new type of injectable hybrid hydrogel has been recently explored based on protein-polymer networks, which can act as unique delivery vehicles for antigens/drugs because of their specific microporous structure, biodegradability of the protein, and controllable degradation rate of the polymer ( 82 , 83 ). Compared to traditional hydrogels, biocompatibility of the microporous networks, especially porous structures with interconnected long pores of the protein-polymer hydrogel, provides a niche to recruit host immune cells without any immunomodulators ( 82 , 83 ).…”

“…A new type of injectable hybrid hydrogel has been recently explored based on protein-polymer networks, which can act as unique delivery vehicles for antigens/drugs because of their specific microporous structure, biodegradability of the protein, and controllable degradation rate of the polymer ( 82 , 83 ). Compared to traditional hydrogels, biocompatibility of the microporous networks, especially porous structures with interconnected long pores of the protein-polymer hydrogel, provides a niche to recruit host immune cells without any immunomodulators ( 82 , 83 ). A hybrid hydrogel (BSA-PCLA) composed of a polymer poly(ε-caprolactone- co -lactide)- b -poly(ethylene glycol)- b -poly(ε-caprolactone- co -lactide) triblock copolymer (PCLA) conjugated with a protein, bovine serum albumin (BSA), was designed to recruit millions of cells via its microporous structure and controlled release property ( 82 ).…”

“…Subsequently, the hybrid hydrogel further increased the DC recruitment through sustained release of pDNA antigens, thus inducing a robust downstream antigen-specific immune response. Similarly, an injectable protein-polymer–based porous hydrogel network composed of lysozyme and PCLA (Lys-PCLA) bioconjugate has also shown an enhanced ability for DC recruitment ( 83 ). This unique microporous type of hydrogel provides a powerful strategy for recruiting DCs to initiate immune responses in hydrogel-based vaccines.…”

Gene Regulations upon Hydrogel-Mediated Drug Delivery Systems in Skin Cancers—An Overview

“…These high swelling properties of biocarriers have a comparable degree of elasticity to natural tissues, and can undergo gel–solid phase transitions in response to various types of stimuli such as temperature, light, pressure, electric field, magnetic field, ionic strength and pH [ 101 , 102 , 103 ]. The natural polymers have reached a considerable significance in drug delivery applications, due to their characteristics such as biocompatibility, biodegradability, bifunctionality, biochemical stability, improved drug solubility, controlled drug release, cost effectiveness and nontoxicity [ 104 , 105 , 106 , 107 ]. These advantages, identical to the native extracellular matrix (ECM), and tunable physical and mechanical properties, aid in a vast variety of biomedical applications [ 108 , 109 , 110 ].…”

Cellulose Nanocrystals-Incorporated Thermosensitive Hydrogel for Controlled Release, 3D Printing, and Breast Cancer Treatment Applications

“…Hydrogels, as viscoelastic soft materials, can absorb a large volume of water but maintain their porous structural integrity in aqueous solutions and in biological fluids. − Given this unique property and biodegradability, hydrogels have been attractive for a lot of biological applications, including controlled release, tissue engineering, 3D printing, and biosensors. − Nevertheless, weak mechanical properties of hydrogels including low tensile strength and low elastic modulus limits their applications. , Recently, the advancement for synthesis of mechanically robust hydrogels has been achieved including clay nanocomposite gels, , double network gels, and topological gels . Among them, the incorporation of nanoscale materials in the viscoelastic networks receives enormous interest because these networks mimic the structure of carbon black reinforced rubber. ,− The polymer chains are physically cross-linked in the presence of nanoscale materials, and the enhanced interactions between polymer matrix and nanoscale materials may result in the improved mechanical property that cannot be achieved by conventional hydrogels. ,− Particularly, compared with the chemical cross-linking technologies, the preparation of composite hydrogel network by incorporation of functional nanomaterials is relatively simpler with toxic-cross-linker-free simple reaction techniques. − …”