title: HPMA-based block copolymers promote differential drug delivery kinetics for hydrophobic and amphiphilic molecules.
abstract: We describe a method how polymeric nanoparticles stabilized with (2-hydroxypropyl)methacrylamide (HPMA)-based block copolymers are used as drug delivery systems for a fast release of hydrophobic and a controlled release of an amphiphilic molecule. The versatile method of the miniemulsion solvent-evaporation technique was used to prepare polystyrene (PS) as well as poly-d/l-lactide (PDLLA) nanoparticles. Covalently bound or physically adsorbed fluorescent dyes labeled the particles' core and their block copolymer corona. Confocal laser scanning microscopy (CLSM) in combination with flow cytometry measurements were applied to demonstrate the burst release of a fluorescent hydrophobic drug model without the necessity of nanoparticle uptake. In addition, CLSM studies and quantitative calculations using the image processing program Volocity® show the intracellular detachment of the amphiphilic block copolymer from the particles' core after uptake. Our findings offer the possibility to combine the advantages of a fast release for hydrophobic and a controlled release for an amphiphilic molecule therefore pointing to the possibility to a 'multi-step and multi-site' targeting by one nanocarrier.
  
  
  CONCLUSIONS
  We describe thoroughly how different components of a nanocarrier end up in cells. This enables different cargos of a nanocarrier having a consecutive release and delivery of distinct components. Most interestingly we demonstrate individual kinetics of distinct components of such a system: first the release of a fluorescent hydrophobic drug model at contact with the cell membrane without the necessity of nanoparticle uptake. Secondly, the intracellular detachment of the amphiphilic block copolymer from the particles' core after uptake occurs. This offers the possibility to combine the advantages of a fast release for a hydrophobic substance at the time of interaction of the nanoparticle with the cell surface and a controlled release for an amphiphilic molecule later on therefore pointing to the possibility to a 'multi-step and multisite' targeting by one nanocarrier. We therefore feel that this could be used for many cellular systems where the combined and orchestrated delivery of components is prerequisite in order to obtain the highest efficiency.
authors.affiliation: Max Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany; University Medicine of the Johannes Gutenberg University, Dermatology Clinic, Langenbeckstr. 1, 55131 Mainz, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Tomcin
authors.affiliation: Johannes Gutenberg University Mainz, Institute of Organic Chemistry, Duesbergweg 10-14, 55128 Mainz, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Kelsch
authors.affiliation: Max Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany.
authors.forename: Roland H
authors.initials: RH
authors.lastname: Staff
authors.affiliation: Max Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Landfester
authors.affiliation: Johannes Gutenberg University Mainz, Institute of Organic Chemistry, Duesbergweg 10-14, 55128 Mainz, Germany.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Zentel
authors.affiliation: Max Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany; University Medicine of the Johannes Gutenberg University, Dermatology Clinic, Langenbeckstr. 1, 55131 Mainz, Germany. Electronic address: volker.mailaender@unimedizin-mainz.de.
authors.forename: Volker
authors.initials: V
authors.lastname: Mailänder
mesh_terms: D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods*; D065546:Drug Liberation; D005455:Fluorescent Antibody Technique; D006367:HeLa Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D066292:Lipid Droplets / Q000737:chemistry; D008689:Methacrylates / Q000737:chemistry*; D053758:Nanoparticles / Q000737:chemistry; D011091:Polyesters / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D011137:Polystyrenes / Q000737:chemistry; D013501:Surface-Active Agents / Q000008:administration & dosage*
chemical_list: D004337:Drug Carriers; D008689:Methacrylates; D011091:Polyesters; D011108:Polymers; D011137:Polystyrenes; D013501:Surface-Active Agents; C033616:poly(lactide); C032802:hydroxypropyl methacrylate
keywords: Drug release; HPMA; Miniemulsion; Nanoparticles; PDLLA