title: Fragmentation of Injectable Bioadhesive Hydrogels Affords Chemotherapeutic Macromolecules.
abstract: Implantation of drug delivery depots into or proximal to targeted tissue is an effective method to deliver anticancer drugs in a sustained localized manner. Herein, syringe-injectable polydextran aldehyde (PDA)-based bioadhesive gels are prepared that can locally deliver cytotoxins upon their hydrolytic fragmentation. Adhesive gels are formed by mixing doxorubicin (DOX)-functionalized PDA (DOX-PDA) and bovine serum albumin (BSA) using a dual-barrel syringe. Upon mixing and delivery, the DOX-PDA reacts with the cross-linker BSA as well as the extracellular matrix via imine bond formation to define the cohesive and adhesive properties of the gel, respectively. Resulting gels are mechanically rigid (∼10 kPa) and adherent (adhesive stress ∼ 4 kPa). Once formed, the DOX-PDA-BSA gels undergo slow hydrolytic degradation (>2 months) locally releasing free DOX and DOX-PDA as expected. Surprisingly, we found that macromolecules composed of DOX, PDA, and BSA are also released from the bulk material. These DOX-PDA-BSA macromolecules, along with free DOX and DOX-PDA conjugate, are internalized by A549 lung carcinoma cells, resulting in potent cell death.
authors.affiliation: Chemical Biology Laboratory, National Cancer Institute, National Institutes of Health , Frederick, Maryland 21701, United States.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Yamada
authors.affiliation: Chemical Biology Laboratory, National Cancer Institute, National Institutes of Health , Frederick, Maryland 21701, United States.
authors.forename: Joel P
authors.initials: JP
authors.lastname: Schneider
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology*; D016503:Drug Delivery Systems; D006801:Humans; D020100:Hydrogels / Q000737:chemistry*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology*; D046911:Macromolecular Substances / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*; D012710:Serum Albumin, Bovine / Q000737:chemistry*; D014407:Tumor Cells, Cultured
chemical_list: D000903:Antibiotics, Antineoplastic; D020100:Hydrogels; D046911:Macromolecular Substances; D011108:Polymers; D012710:Serum Albumin, Bovine; D004317:Doxorubicin