title: Biodistribution of biodegradable polymeric nano-carriers loaded with busulphan and designed for multimodal imaging.
abstract: BACKGROUND
  Multifunctional nanocarriers for controlled drug delivery, imaging of disease development and follow-up of treatment efficacy are promising novel tools for disease diagnosis and treatment. In the current investigation, we present a multifunctional theranostic nanocarrier system for anticancer drug delivery and molecular imaging. Superparamagnetic iron oxide nanoparticles (SPIONs) as an MRI contrast agent and busulphan as a model for lipophilic antineoplastic drugs were encapsulated into poly (ethylene glycol)-co-poly (caprolactone) (PEG-PCL) micelles via the emulsion-evaporation method, and PEG-PCL was labelled with VivoTag 680XL fluorochrome for in vivo fluorescence imaging.
  
  
  RESULTS
  Busulphan entrapment efficiency was 83% while the drug release showed a sustained pattern over 10 h. SPION loaded-PEG-PCL micelles showed contrast enhancement in T2*-weighted MRI with high r2* relaxivity. In vitro cellular uptake of PEG-PCL micelles labeled with fluorescein in J774A cells was found to be time-dependent. The maximum uptake was observed after 24 h of incubation. The biodistribution of PEG-PCL micelles functionalized with VivoTag 680XL was investigated in Balb/c mice over 48 h using in vivo fluorescence imaging. The results of real-time live imaging were then confirmed by ex vivo organ imaging and histological examination. Generally, PEG-PCL micelles were highly distributed into the lungs during the first 4 h post intravenous administration, then redistributed and accumulated in liver and spleen until 48 h post administration. No pathological impairment was found in the major organs studied.
  
  
  CONCLUSIONS
  Thus, with loaded contrast agent and conjugated fluorochrome, PEG-PCL micelles as biodegradable and biocompatible nanocarriers are efficient multimodal imaging agents, offering high drug loading capacity, and sustained drug release. These might offer high treatment efficacy and real-time tracking of the drug delivery system in vivo, which is crucial for designing of an efficient drug delivery system.
authors.affiliation: Division of Functional Materials (FNM), Department of Materials and Nanophysics, Royal Institute of Technology (KTH), 164 40, Stockholm, Sweden.|Division of Experimental Cancer Medicine (ECM), Department of Laboratory Medicine (LABMED), Karolinska Institutet (KI), 141 86, Stockholm, Sweden.
authors.forename: Heba
authors.initials: H
authors.lastname: Asem
authors.affiliation: Division of Experimental Cancer Medicine (ECM), Department of Laboratory Medicine (LABMED), Karolinska Institutet (KI), 141 86, Stockholm, Sweden.|Clinical Research Center (KFC), Karolinska University Hospital Huddinge, 141 86, Stockholm, Sweden.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Division of Experimental Cancer Medicine (ECM), Department of Laboratory Medicine (LABMED), Karolinska Institutet (KI), 141 86, Stockholm, Sweden.
authors.forename: Fei
authors.initials: F
authors.lastname: Ye
authors.affiliation: Division of Experimental Cancer Medicine (ECM), Department of Laboratory Medicine (LABMED), Karolinska Institutet (KI), 141 86, Stockholm, Sweden.
authors.forename: Åsa
authors.initials: Å
authors.lastname: Barrefelt
authors.affiliation: Division of Experimental Cancer Medicine (ECM), Department of Laboratory Medicine (LABMED), Karolinska Institutet (KI), 141 86, Stockholm, Sweden.
authors.forename: Manuchehr
authors.initials: M
authors.lastname: Abedi-Valugerdi
authors.affiliation: Division of Experimental Cancer Medicine (ECM), Department of Laboratory Medicine (LABMED), Karolinska Institutet (KI), 141 86, Stockholm, Sweden.
authors.forename: Ramy
authors.initials: R
authors.lastname: El-Sayed
authors.affiliation: Division of Experimental Cancer Medicine (ECM), Department of Laboratory Medicine (LABMED), Karolinska Institutet (KI), 141 86, Stockholm, Sweden.
authors.forename: Ibrahim
authors.initials: I
authors.lastname: El-Serafi
authors.affiliation: Department of Nanomedicine, King Abdullah International Medical Research Center, King Abdulaziz Medical City, PO Box 22490, Riyadh, 11426, Saudi Arabia.
authors.forename: Khalid M
authors.initials: KM
authors.lastname: Abu-Salah
authors.affiliation: PerkinElmer, 68 Elm St., Hopkinton, MA, 01748, USA.
authors.forename: Jörg
authors.initials: J
authors.lastname: Hamm
authors.affiliation: Division of Functional Materials (FNM), Department of Materials and Nanophysics, Royal Institute of Technology (KTH), 164 40, Stockholm, Sweden.
authors.forename: Mamoun
authors.initials: M
authors.lastname: Muhammed
authors.affiliation: Division of Experimental Cancer Medicine (ECM), Department of Laboratory Medicine (LABMED), Karolinska Institutet (KI), 141 86, Stockholm, Sweden. Moustapha.Hassan@ki.se.|Clinical Research Center (KFC), Karolinska University Hospital Huddinge, 141 86, Stockholm, Sweden. Moustapha.Hassan@ki.se.
authors.forename: Moustapha
authors.identifier: http://orcid.org/0000-0003-1927-5859
authors.initials: M
authors.lastname: Hassan
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D002066:Busulfan / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D003911:Dextrans / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry*; D018922:HL-60 Cells; D006207:Half-Life; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000378:metabolism / Q000502:physiology; D058185:Magnetite Nanoparticles / Q000737:chemistry / Q000648:ultrastructure; D051379:Mice; D008807:Mice, Inbred BALB C; D008823:Micelles; D010316:Particle Size; D011091:Polyesters / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D003911:Dextrans; D004337:Drug Carriers; D058185:Magnetite Nanoparticles; D008823:Micelles; D011091:Polyesters; D011092:Polyethylene Glycols; D002066:Busulfan; C065507:ferumoxides
keywords: Biodegradable polymer; Biodistribution; Busulphan; Cancer; Drug delivery; In vivo fluorescence imaging; Magnetic resonance imaging