Versatile click alginate hydrogels crosslinked via tetrazine–norbornene chemistry

Desai, Rajiv M.; Koshy, Sandeep T.; Hilderbrand, Scott A.; Mooney, David J.; Joshi, Neel

doi:10.1016/j.biomaterials.2015.01.048

Cited by 247 publications

(221 citation statements)

References 57 publications

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“…S7A). This could be explained by stress relaxation of hydrogels followed by the loss of structural integrity, which is typical of ionically cross-linked hydrogels as cells proliferate (28). Histological observations suggest a qualitative trend where fewer stromal-like cells may be present with Ara-C compared with vehicle control, but more dead hematopoietic cells are visible in stiff matrices compared with soft (Fig.…”

Section: Matrix Stiffness Controls the Growth Kinetics And Resistance Tomentioning

confidence: 94%

Extracellular matrix stiffness causes systematic variations in proliferation and chemosensitivity in myeloid leukemias

Shin

Mooney

2016

Proc. Natl. Acad. Sci. U.S.A.

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124

102

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Extracellular matrix stiffness influences biological functions of some tumors. However, it remains unclear how cancer subtypes with different oncogenic mutations respond to matrix stiffness. In addition, the relevance of matrix stiffness to in vivo tumor growth kinetics and drug efficacy remains elusive. Here, we designed 3D hydrogels with physical parameters relevant to hematopoietic tissues and adapted them to a quantitative high-throughput screening format to facilitate mechanistic investigations into the role of matrix stiffness on myeloid leukemias. Matrix stiffness regulates proliferation of some acute myeloid leukemia types, including MLL-AF9 + MOLM-14 cells, in a biphasic manner by autocrine regulation, whereas it decreases that of chronic myeloid leukemia BCR-ABL + K-562 cells.Although Arg-Gly-Asp (RGD) integrin ligand and matrix softening confer resistance to a number of drugs, cells become sensitive to drugs against protein kinase B (PKB or AKT) and rapidly accelerated fibrosarcoma (RAF) proteins regardless of matrix stiffness when MLL-AF9 and BCR-ABL are overexpressed in K-562 and MOLM-14 cells, respectively. By adapting the same hydrogels to a xenograft model of extramedullary leukemias, we confirm the pathological relevance of matrix stiffness in growth kinetics and drug sensitivity against standard chemotherapy in vivo. The results thus demonstrate the importance of incorporating 3D mechanical cues into screening for anticancer drugs.matrix stiffness | systems pharmacology | biomaterials | drug screening | cancer M yeloid leukemias originate from the hematopoietic stem cell compartment in bone marrow (BM) after oncogenic mutations. For instance, a translocation between parts of the human chromosome 22 and 9 results in the BCR-ABL fusion gene that causes chronic myeloid leukemia (CML) (1). Some translocations involving the mixed lineage leukemia (MLL) gene in the human chromosome 11, band q23, such as the MLL-AF9 fusion gene, are involved in acute myeloid leukemia (AML) (2). In addition to mutations, hematopoietic microenvironments can contribute to pathogenesis and progression of myeloid leukemias (3). Both oncoproteins and cell-extrinsic factors are known to perturb various signaling pathways that regulate key biological processes in cancer. For instance, AKT/PKB (protein kinase B) is a major signaling node downstream of activated tyrosine kinases and phosphatidylinositol 3-kinase and has been targeted by a number of drugs to inhibit cancer cell survival and growth (4). Recently, physical cues from microenvironments have emerged as important regulators of tumor biology, such as extracellular matrix stiffness and collagen architecture (5, 6). Matrix stiffness also regulates normal hematopoiesis (7,8). However, the relevance of physical cues to blood cancer remains largely unclear. Importantly, how different cancer subtypes with distinct oncogenic mutations respond to matrix stiffness also remains to be investigated.Recent studies highlight the utility of adapting 3D culture into a high-throughput ...

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Section: Matrix Stiffness Controls the Growth Kinetics And Resistance Tomentioning

confidence: 94%

Extracellular matrix stiffness causes systematic variations in proliferation and chemosensitivity in myeloid leukemias

Shin

Mooney

2016

Proc. Natl. Acad. Sci. U.S.A.

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124

102

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“…Certain pre-gel solutions may require monomers or catalysts that are harmful to cells and tissues, which provides a strong impetus to develop bio-orthogonal cross-linking reactions such as copper-free click reactions for gelation (FIG. 2b) 38–40 . Click chemistry provides high specificity, quantitative conversion and modest gelation kinetics that are tuneable from a few minutes to one hour, with no side reactions with biomolecules in the body.…”

Section: Macroscopic Design and Delivery Routesmentioning

confidence: 99%

Designing hydrogels for controlled drug delivery

2016

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Hydrogel delivery systems can leverage therapeutically beneficial outcomes of drug delivery and have found clinical use. Hydrogels can provide spatial and temporal control over the release of various therapeutic agents, including small-molecule drugs, macromolecular drugs and cells. Owing to their tunable physical properties, controllable degradability and capability to protect labile drugs from degradation, hydrogels serve as a platform in which various physiochemical interactions with the encapsulated drugs control their release. In this Review, we cover multiscale mechanisms underlying the design of hydrogel drug delivery systems, focusing on physical and chemical properties of the hydrogel network and the hydrogel–drug interactions across the network, mesh, and molecular (or atomistic) scales. We discuss how different mechanisms interact and can be integrated to exert fine control in time and space over the drug presentation. We also collect experimental release data from the literature, review clinical translation to date of these systems, and present quantitative comparisons between different systems to provide guidelines for the rational design of hydrogel delivery systems.

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“…7,8,9,10,11 Light initiated modifications to hydrogels are an ideal method to spatiotemporally control properties. Through light sensitive chemistries and photopatterning, removal of crosslinks and molecules of interest have controlled physical and chemical properties as well as the subsequent direction of cell behavior.…”

Section: Introductionmentioning

confidence: 99%

Spatiotemporal Modification of Stimuli-Responsive Hyaluronic Acid/Poly(N-isopropylacrylamide) Hydrogels

Dadoo

Gramlich

2016

ACS Biomater. Sci. Eng.

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Current methods to spatiotemporally modify stimuli response in hydrogels are typically subtractive and lead to a decrease in response. To increase the breadth of hydrogel applications and biomedical systems, new formulations are needed that can introduce and increase stimuli response spatiotemporally in hydrogels. In this work, the light induced thiol-norbornene click chemistry reaction was used to modify the stimuli response of robust hyaluronic acid hydrogels through an additive process in spatiotemporal fashion, overcoming this limitation. These stimuli responsive hydrogels were made from norbornene functionalized hyaluronic acid (NorHA) crosslinked with thermo-responsive dithiol-terminated poly(N-isopropylacrylamide) (DTPN).Varying crosslinker molecular weight and gelation conditions led to a range of compression modulus (5 to 54 kPa) and mass loss (9 to 33%) upon heating to 37 °C while retaining a majority NorHA in the hydrogel. The thermo-response of these hydrogels could not only be controlled by the crosslink density, but also by heating to 55 °C to increase the dewatering of the hydrogels.The stimuli response of the hydrogels were temporally increased by introducing additional DTPN and UV-initiator to an original hydrogel with subsequent irradiation. This modification was extended to spatiotemporally changing the stimuli response by photopatterning DTPN into a NorHA hydrogel, yielding a hydrogel that changed shape and topology through heating.Furthermore, human mesenchymal stem cells could adhere and proliferate on the DTPN patterned surface, demonstrating that the materials could be used for studies where cells are present.

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Versatile click alginate hydrogels crosslinked via tetrazine–norbornene chemistry

Cited by 247 publications

References 57 publications

Extracellular matrix stiffness causes systematic variations in proliferation and chemosensitivity in myeloid leukemias

Extracellular matrix stiffness causes systematic variations in proliferation and chemosensitivity in myeloid leukemias

Designing hydrogels for controlled drug delivery

Spatiotemporal Modification of Stimuli-Responsive Hyaluronic Acid/Poly(N-isopropylacrylamide) Hydrogels

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