title: Biomimetic Hydrogels Incorporating Polymeric Cell-Adhesive Peptide To Promote the 3D Assembly of Tumoroids.
abstract: Toward the goal of establishing physiologically relevant in vitro tumor models, we synthesized and characterized a biomimetic hydrogel using thiolated hyaluronic acid (HA-SH) and an acrylated copolymer carrying multiple copies of cell adhesive peptide (PolyRGD-AC). PolyRGD-AC was derived from a random copolymer of tert-butyl methacrylate (tBMA) and oligomeric (ethylene glycol) methacrylate (OEGMA), synthesized via atom transfer radical polymerization (ATRP). Acid hydrolysis of tert-butyl moieties revealed the carboxylates, through which acrylate groups were installed. Partial modification of the acrylate groups with a cysteine-containing RGD peptide generated PolyRGD-AC. When PolyRGD-AC was mixed with HA-SH under physiological conditions, a macroscopic hydrogel with an average elastic modulus of 630 Pa was produced. LNCaP prostate cancer cells encapsulated in HA-PolyRGD gels as dispersed single cells formed multicellular tumoroids by day 4 and reached an average diameter of ∼95 μm by day 28. Cells in these structures were viable, formed cell-cell contacts through E-cadherin (E-CAD), and displayed cortical organization of F-actin. Compared with the control gels prepared using PolyRDG, multivalent presentation of the RGD signal in the HA matrix increased cellular metabolism, promoted the development of larger tumoroids, and enhanced the expression of E-CAD and integrins. Overall, hydrogels with multivalently immobilized RGD are a promising 3D culture platform for dissecting principles of tumorigenesis and for screening anticancer drugs.
authors.affiliation: Department of Materials Science and Engineering, University of Delaware , Newark, Delaware 19716, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Hao
authors.affiliation: Department of Biomedical Engineering, University of Delaware , Newark, Delaware 19716, United States.
authors.forename: Aidan B
authors.initials: AB
authors.lastname: Zerdoum
authors.affiliation: Department of Biological Sciences, University of Delaware , Newark, Delaware 19716, United States.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Stuffer
authors.affiliation: Department of Materials Science and Engineering, University of Delaware , Newark, Delaware 19716, United States.|Department of Biological Sciences, University of Delaware , Newark, Delaware 19716, United States.|Therapy Architects, LLC, Helen F Graham Cancer Center, Newark, Delaware 19718, United States.
authors.forename: Ayyappan K
authors.initials: AK
authors.lastname: Rajasekaran
authors.affiliation: Department of Materials Science and Engineering, University of Delaware , Newark, Delaware 19716, United States.|Department of Biomedical Engineering, University of Delaware , Newark, Delaware 19716, United States.|Department of Biological Sciences, University of Delaware , Newark, Delaware 19716, United States.|Delaware Biotechnology Institute, University of Delaware , Newark, Delaware 19711, United States.
authors.forename: Xinqiao
authors.initials: X
authors.lastname: Jia
mesh_terms: D032701:Biomimetics; D063646:Carcinogenesis / Q000187:drug effects*; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry / Q000494:pharmacology; D020100:Hydrogels / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008297:Male; D008689:Methacrylates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000139:chemically induced / Q000473:pathology
chemical_list: D020100:Hydrogels; D008689:Methacrylates; D010455:Peptides; D011108:Polymers; D006820:Hyaluronic Acid