title: Protease-sensitive, polymer-caged liposomes: a method for making highly targeted liposomes using triggered release.
abstract: Liposomes have become useful and well-known drug delivery vehicles because of their ability to entrap drugs without chemically modifying them and to deliver them somewhat selectively to tumorous tissue via the enhanced permeation and retention (EPR) effect. Although useful, liposome preparations are still less than ideal because of imperfect specificity, slow release kinetics in the tumor, and leakiness prior to reaching the tumor site. Cancer-associated proteases (CAPs), which are differentially expressed in tumors, have also gained traction recently as a method for tumor targeting and drug delivery. By combining the EPR effect with CAPs sensitivity, a much more specific liposome can be produced. The method described here creates an improved liposome system that can target more specifically, with faster release kinetics and lower general leaking, by deliberately producing a very unstable liposome (loaded with hyperosmotic vehicle) that is subsequently stabilized by a cross-linked polymer shell containing consensus sequences for cancer-associated proteases (protease-triggered, caged liposomes). A cholesterol-anchored, graft copolymer, composed of a short peptide sequence for urokinase plasminogen activator (uPA) and poly(acrylic acid), was synthesized and incorporated into liposomes prepared at high osmolarities. Upon cross-linking of the polymers, the protease-triggered, caged liposomes showed significant resistance to osmotic swelling and leaking of contents. Protease-triggered, caged liposomes also showed significant and substantial differential release of contents in the presence of uPA, while bare liposomes showed no differential effect in the presence of uPA. Thus a protease-sensitive liposome system with fast release kinetics was developed that could be used for more specific targeting to tumors.
authors.affiliation: Department of Chemistry, 213 CBC Building, Kansas State University, Manhattan, KS 66506, USA. mbasel@vet.ksu.edu
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Basel
authors.forename: Tej B
authors.initials: TB
authors.lastname: Shrestha
authors.forename: Deryl L
authors.initials: DL
authors.lastname: Troyer
authors.forename: Stefan H
authors.initials: SH
authors.lastname: Bossmann
mesh_terms: D003692:Delayed-Action Preparations / Q000138:chemical synthesis*; D008081:Liposomes / Q000737:chemistry*; D046911:Macromolecular Substances / Q000737:chemistry; D008422:Materials Testing; D008968:Molecular Conformation; D053769:Nanocapsules / Q000737:chemistry*; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*; D013499:Surface Properties
chemical_list: D003692:Delayed-Action Preparations; D008081:Liposomes; D046911:Macromolecular Substances; D053769:Nanocapsules; D010455:Peptides; D011108:Polymers