Engineering of biomaterials for tumor modeling

Choi, Sae Rome; Yang, Yi; Huang, Kai-Yu; Kong, Hyun Joon; Flick, Matthew J.; Han, Bumsoo

doi:10.1016/j.mtadv.2020.100117

Cited by 12 publications

(8 citation statements)

References 205 publications

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“…Engineering innovative biomaterials to mimic the TME has gained great interest in the field, especially for drug screening, and to better understand cancer biology and immunology. ( 18 ) For instance, Matrigel and other biomimetic hydrogels composed of collagen and HA have been extensively investigated to recreate the tumor ECM. ( 19 ) However, such biomaterials do not display several key features of solid tumors, including control over low O 2 tension.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia-inducing cryogels uncover key cancer-immune cell interactions in an oxygen-deficient tumor microenvironment

Colombani

Rogers

Bhatt

et al. 2023

Preprint

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Hypoxia, an important feature of solid tumors, is a major factor shaping the immune landscape, and several cancer models have been developed to emulate hypoxic tumors. However, to date, they still have several limitations, such as the lack of reproducibility, inadequate biophysical cues, limited immune cell infiltration, and poor oxygen (O2) control, leading to non-pathophysiological tumor responses. As a result, it is essential to develop new and improved cancer models that mimic key features of the tumor extracellular matrix and recreate tumor-associated hypoxia while allowing cell infiltration and cancer-immune cell interactions. Herein, hypoxia-inducing cryogels (HICs) have been engineered using hyaluronic acid (HA) as macroporous scaffolds to fabricate three-dimensional microtissues and model a hypoxic tumor microenvironment. Specifically, tumor cell-laden HICs have been designed to deplete O2 locally and induce long-standing hypoxia. This state of low oxygen tension, leading to HIF-1α stabilization in tumor cells, resulted in changes in hypoxia-responsive gene expression and phenotype, a metabolic adaptation to anaerobic glycolysis, and chemotherapy resistance. Additionally, HIC-supported tumor models induced dendritic cell (DC) inhibition, revealing a phenotypic change in plasmacytoid B220+ DC (pDC) subset and an impaired conventional B220- DC (cDC) response in hypoxia. Lastly, our HIC-based melanoma model induced CD8+ T cell inhibition, a condition associated with the downregulation of pro-inflammatory cytokine secretion, increased expression of immunomodulatory factors, and decreased degranulation and cytotoxic capacity of T cells. Overall, these data suggest that HICs can be used as a tool to model solid-like tumor microenvironments and identify a phenotypic transition from cDC to pDC in hypoxia and the key contribution of HA in retaining cDC phenotype and inducing their hypoxia-mediated immunosuppression. This technology has great potential to deepen our understanding of the complex relationships between cancer and immune cells in low O2 conditions and may pave the way for developing more effective therapies.

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Section: Introductionmentioning

confidence: 99%

Hypoxia-inducing cryogels uncover key cancer-immune cell interactions in an oxygen-deficient tumor microenvironment

Colombani

Rogers

Bhatt

et al. 2023

Preprint

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“…54 However, the efficiency of this starvation therapy could be limited by the hypoxic TME caused by the insufficient O 2 supply in the solid tumor. 55,56 Therefore, the present study was conducted to explore the promising manifestations of FA−CD−(PTX−GOx) complex in delaying tumor progression via Gox-induced glucose starvation that would eventually sensitize the cancer cells to PTX chemotherapy (Scheme 2). Exposure to the FA−CD−(PTX−GOx) complex (60 μg/ mL) resulted in a time-dependent (6−12 h) enhancement in ROS generation in the TNBC cells as evident from the increased bright green fluorescence of DCF with time (Figure 7).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Simultaneously, the excessive production of H 2 O 2 of glucose oxidation results in systemic toxicity by directly damaging the cell membranes, proteins, and DNA of the cell . However, the efficiency of this starvation therapy could be limited by the hypoxic TME caused by the insufficient O 2 supply in the solid tumor. , Therefore, the present study was conducted to explore the promising manifestations of FA–CD–(PTX–GOx) complex in delaying tumor progression via Gox-induced glucose starvation that would eventually sensitize the cancer cells to PTX chemotherapy (Scheme ).…”

Section: Resultsmentioning

confidence: 99%

Folic Acid-Functionalized Carbon Dot-Enabled Starvation Therapy in Synergism with Paclitaxel against Breast Cancer

Ghosh

Chowdhury

et al. 2022

ACS Appl. Bio Mater.

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Glucose oxidase (GOx)-induced cancer starvation has recently emerged for halting the abnormal proliferation of triple-negative breast cancer (TNBC). However, monotherapy with GOx or a conventional chemotherapeutic displays suboptimal efficacy in eliminating tumors and poses impending risks to healthy tissues. To augment therapeutic efficacy and tumor selectivity, folic acid (FA)-functionalized carbon dots (CDs) embedded with GOx and paclitaxel (PTX) [FA−CD−(PTX−GOx)] was developed that showed the efficient killing of TNBC, MDA-MB-468 cells over noncancerous HEK 293 cells through synergistic effects of cancer starvation-induced oxidative stress and chemotherapy. The cargo-laden FA− CD complex resulted in a 4−8 fold increase in cancer cell death at 60 μg/mL when compared to standalone therapy with the native compounds and individually loaded cargo on FA−CD. This improved cancer cell killing efficacy of the FA−CD−(PTX−GOx) complex could be endorsed by folate receptor (FR)-mediated target-specific cellular internalization of the FA−CD complex. The antitumorigenic efficacy of the FA−CD−(PTX−GOx) complex was further validated in a three-dimensional (3D) breast tumor spheroid model. A significant 4.5-fold reduction in spheroid dimension along with antiproliferation was observed with time up to 72 h following exposure to the FA−CD−(PTX−GOx) complex. This antitumorigenic potential of FA−CD−(PTX−GOx) could be attributed to the enhanced intratumoral reactive oxygen species generation following glucose depletion by GOx that has been facilitated by the chemotherapeutic efficacy of PTX resulting in the efficient killing of cancer cells. The present study provides a novel strategy of FR-mediated fluorescent CD-enabled combined formulation of GOx and PTX for the target-specific superior killing of TNBC cells in the synergism of glucose starvation with chemotherapy.

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“…Recent studies have reported a tight correlation between the secretory activities of MSCs and their surrounding matrix, suggesting that niches that mimic native tissue are essential for the therapeutic function of MSCs 43 , 44 . Collagens and branched GAGs are the major components of ECM and provide adhesion sites necessary for cell survival 45 . In addition, the fibrous structures and pores formed by these proteins contribute to increased cell migration and cell-cell interactions 46 .…”

Section: Discussionmentioning

confidence: 99%

Combinational Treatment Involving Decellularized Extracellular Matrix Hydrogels With Mesenchymal Stem Cells Increased the Efficacy of Cell Therapy in Pancreatitis

et al. 2023

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Cell transplantation using mesenchymal stem cells (MSCs) has emerged as a promising approach to repairing and regenerating injured or impaired organs. However, the survival and retention of MSCs following transplantation remain a challenge. Therefore, we investigated the efficacy of co-transplantation of MSCs and decellularized extracellular matrix (dECM) hydrogels, which have high cytocompatibility and biocompatibility. The dECM solution was prepared by enzymatic digestion of an acellular porcine liver scaffold. It could be gelled and formed into porous fibrillar microstructures at physiological temperatures. MSCs expanded three-dimensionally in the hydrogel without cell death. Compared to the 2-dimensional cell culture, MSCs cultured in the hydrogel showed increased secretion of hepatocyte growth factor (HGF) and tumor necrosis factor-inducible gene 6 protein (TSG-6), both of which are major anti-inflammatory and anti-fibrotic paracrine factors of MSCs, under TNFα stimulation. In vivo experiments showed that the co-transplantation of MSCs with dECM hydrogel improved the survival rate of engrafted cells compared to those administered without the hydrogel. MSCs also demonstrated therapeutic effects in improving inflammation and fibrosis of pancreatic tissue in a dibutyltin dichloride (DBTC)-induced rat pancreatitis model. Combinational use of dECM hydrogel with MSCs is a new strategy to overcome the challenges of cell therapy using MSCs and can be used for treating chronic inflammatory diseases in clinical settings.

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Engineering of biomaterials for tumor modeling

Cited by 12 publications

References 205 publications

Hypoxia-inducing cryogels uncover key cancer-immune cell interactions in an oxygen-deficient tumor microenvironment

Hypoxia-inducing cryogels uncover key cancer-immune cell interactions in an oxygen-deficient tumor microenvironment

Folic Acid-Functionalized Carbon Dot-Enabled Starvation Therapy in Synergism with Paclitaxel against Breast Cancer

Combinational Treatment Involving Decellularized Extracellular Matrix Hydrogels With Mesenchymal Stem Cells Increased the Efficacy of Cell Therapy in Pancreatitis

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