title: Use of a nanoporous biodegradable miniature device to regulate cytokine release for cancer treatment.
abstract: The clinical management of locally recurrent or unresectable malignant melanoma continues to pose a significant challenge. These lesions are typically painful and currently available treatments, such as repeated intratumoral injections of interferon-alpha (IFN-α), are costly and inconvenient. Nanotechnology offers promise as a novel means of drug delivery. A capsule-like nanoporous miniature device (NMD) based on a biodegradable polymer, poly(polycaprolactone) (PCL) was developed for controlling the local delivery of immunological agents to the tumor microenvironment. The device consists of a nanoporous release gate, a fabricated drug reservoir loaded with IFN-α and a protective layer. To improve the biocompatibility of the device, a hydrophilic poly(ethylene glycol) monoacrylate was applied to the outside wall of the device via covalent bonding techniques. Microscopic visualization of the nanoporous gate from in vitro experiments exhibited good pore stability over a two-month period. In vitro experiments demonstrated a constant release rate of IFN-α from the NMD and showed that the release rate could be regulated by the gate area. The released IFN-α was biologically functional. Cytokine-containing supernatants from release experiments phosphorylated signal transducer and activator of transcription (STAT1) in peripheral blood mononuclear cells. Subcutaneous implantation of the NMDs was well tolerated and associated with an anti-tumor effect in a human xenograft model of melanoma. There was no evidence of a significant inflammatory response to the NMD or encapsulation of the NMD by fibrosis. These experiments show that the NMD can be fabricated and employed in vivo as a versatile drug delivery platform.
authors.affiliation: Nanoscale Science and Engineering Center for Affordable Nanoengineering of Polymeric Biomedical Devices, OH, USA.
authors.forename: Hongyan
authors.initials: H
authors.lastname: He
authors.forename: Valerie
authors.initials: V
authors.lastname: Grignol
authors.forename: Volodymyr
authors.initials: V
authors.lastname: Karpa
authors.forename: Chi
authors.initials: C
authors.lastname: Yen
authors.forename: Krista
authors.initials: K
authors.lastname: LaPerle
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.forename: Natalie B
authors.initials: NB
authors.lastname: Jones
authors.forename: Margaret I
authors.initials: MI
authors.lastname: Liang
authors.forename: Gregory B
authors.initials: GB
authors.lastname: Lesinski
authors.forename: W S Winston
authors.initials: WS
authors.lastname: Ho
authors.forename: William E
authors.initials: WE
authors.lastname: Carson
authors.forename: L James
authors.initials: LJ
authors.lastname: Lee
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D001672:Biocompatible Materials / Q000009:adverse effects / Q000737:chemistry*; D002214:Capsules; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000295:instrumentation* / Q000379:methods; D005260:Female; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage* / Q000627:therapeutic use; D008546:Melanoma, Experimental / Q000188:drug therapy*; D008567:Membranes, Artificial; D051379:Mice; D016513:Mice, SCID; D008855:Microscopy, Electron, Scanning; D058608:Nanopores / Q000648:ultrastructure*; D011994:Recombinant Proteins; D012995:Solubility; D013499:Surface Properties; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001672:Biocompatible Materials; D002214:Capsules; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D008567:Membranes, Artificial; D011994:Recombinant Proteins