Modular and Adaptable Tumor Niche Prepared from Visible Light Initiated Thiol-Norbornene Photopolymerization

Adv Healthcare Materials

2018

Photoresponsive hydrogels have become invaluable 3D culture matrices for mimicking aspects of the extracellular matrix. Recent efforts have focused on using ultraviolet (UV) light exposure and multifunctional macromers to induce secondary hydrogel crosslinking and dynamic matrix stiffening in the presence of cells. This contribution reports the design of a novel yet simple dynamic poly(ethylene glycol)–peptide hydrogel system through flavin mononucleotide (FMN) induced di‐tyrosine crosslinking. These di‐tyrosine linkages effectively increase hydrogel crosslinking density and elastic modulus. In addition, the degree of stiffening in hydrogels at a fixed PEG macromer content can be readily tuned by controlling FMN concentration or the number of tyrosine residues built‐in to the peptide linker. Furthermore, tyrosine‐bearing pendant biochemical motifs can be spatial‐temporally patterned in the hydrogel network via controlling light exposure through a photomask. The visible light and FMN‐induced tyrosine dimerization process produces a cytocompatible and physiologically relevant degree of stiffening, as shown by changes of cell morphology and gene expression in pancreatic cancer and stromal cells. This new dynamic hydrogel scheme should be highly desirable for researchers seeking a photoresponsive hydrogel system without complicated chemical synthesis and secondary UV light irradiation.

Section: Resultssupporting

confidence: 91%

Dynamic PEG–Peptide Hydrogels via Visible Light and FMN‐Induced Tyrosine Dimerization

Liu

Nguyen

Adv Healthcare Materials

2018

“…This is consistent with our previous report exploring the effect of matrix stiffness on COLO-357 cell spheroid sizes. 47 This can be attributed to the increased density of the polymer network. Notably, both initial crosslinking and subsequent stiffening occurred without causing cell damage.…”

Section: Discussionmentioning

confidence: 99%

Orthogonal enzymatic reactions for rapid crosslinking and dynamic tuning of PEG–peptide hydrogels

Arkenberg

2017

Biomater. Sci.

Self Cite

Stiffening of the extracellular matrix is a hallmark in cancer progression, embryonic development, and wound healing. To mimic this dynamic process, our work explored orthogonal enzymatic reactions capable of modulating the properties of poly(ethylene glycol) (PEG)-peptide hydrogels. A hepta-mutant bacterial transpeptidase sortase A (SrtA) was used to ligate two PEG-peptide macromers (i.e., PEG-YLPRTG and NH-GGGG-PEG) into a primary hydrogel network. The hydrogels were dynamically stiffened using mushroom tyrosinase (MT), which oxidized tyrosine residues into di-tyrosine and led to increased matrix stiffness. After confirming the expression and enhanced catalytic activity of SrtA, we investigated the cytocompatibility of the enzymatic reaction with a mouse insulinoma cell line, MIN6. In addition, we altered peptide substrate concentrations and evaluated their influence on primary hydrogel network properties and MT-triggered stiffening. Using a pancreatic cancer cell line, COLO-357, the effect of MT-triggered stiffening on spheroid formation was investigated. We found that cell spheroids formed in hydrogels that were exposed to MT were significantly smaller than spheroids formed without MT incubation, suggesting that matrix stiffening played a crucial role in the sizes of cancer cell spheroids. Through utilizing highly specific and orthogonal enzymatic reactions, this hydrogel platform permits rapid and mild in situ cell encapsulation, as well as dynamic control of matrix stiffness for investigating the role of matrix stiffening on cell fate processes.

“…The use of HA hydrogels as scaffold for 3D culture of PCCs did not receive significant attention until recently. We have developed HA-gelatin hydrogels via visible light based thiol-norbornene photopolymerization [53]. Specifically, thiolated HA (THA) and norbornene-modified gelatin (GelNB) were modularly crosslinked into hydrogels within minutes by means of visible light irradiation.…”

Section: D Culture Of Pdac Cells With Ecm-derived Hydrogelsmentioning

confidence: 99%

“…In a separate study, we designed a pathophysiologically relevant dynamic biomimetic hydrogel system where the gels were crosslinked by thiolated HA (THA) and norbornene/hydroxyphenylacetic acid dually-functionalized gelatin (i.e., GelNB-HPA). [66]The initial gel network was formed by orthogonal thiol-norbornene photopolymerization of GelNB, GelNB-HPA, THA, and inert macromer PEG-tetra-thiol (PEG4SH) [53]. With this hybrid dynamic hydrogel system, the effects of matrix biochemical and biophysical cues were easily decoupled for gaining new insights into the effects of matrix compositions on PDAC cell fate processes.…”

Section: Dynamic Hydrogels To Probe Pdac Cell Fatementioning

confidence: 99%

Designer hydrogels: Shedding light on the physical chemistry of the pancreatic cancer microenvironment

Korc

2018

Cancer Letters

Self Cite

Pancreatic ductal adenocarcinoma (PDAC) is currently the third leading cause of cancer mortality in the United States, with a 5-year survival of ∼8%. PDAC is characterized by a dense and hypo-vascularized stroma consisting of proliferating cancer cells, cancer-associated fibroblasts, macrophages and immune cells, as well as excess matrices including collagens, fibronectin, and hyaluronic acid. In addition, PDAC has increased interstitial pressures and a hypoxic/acidic tumor microenvironment (TME) that impedes drug delivery and blocks cancer-directed immune mechanisms. In spite of increasing options in targeted therapy, PDAC has mostly remained treatment recalcitrant. Owing to its critical roles on governing PDAC progression and treatment outcome, TME and its interplay with the cancer cells are increasingly studied. In particular, three-dimensional (3D) hydrogels derived from or inspired by components in the TME are progressively developed. When properly designed, these hydrogels (e.g., Matrigel, collagen gel, hyaluronic acid-based, and semi-synthetic hydrogels) can provide pathophysiologically relevant compositions, conditions, and contexts for supporting PDAC cell fate processes. This review summarizes recent efforts in using 3D hydrogels for fundamental studies on cell-matrix or cell-cell interactions in PDAC.