title: Hierarchical self-assembly of magnetic nanoclusters for theranostics: Tunable size, enhanced magnetic resonance imagability, and controlled and targeted drug delivery.
abstract: Nanoparticle-based imaging and therapy are of interest for theranostic nanomedicine. In particular, superparamagnetic iron oxide (SPIO) nanoparticles (NPs) have attracted much attention in cancer imaging, diagnostics, and treatment because of their superior imagability and biocompatibility (approved by the Food and Drug Administration). Here, we developed SPIO nanoparticles (NPs) that self-assembled into magnetic nanoclusters (SAMNs) in aqueous environments as a theranostic nano-system. To generate multi-functional SPIO NPs, we covalently conjugated β-cyclodextrin (β-CD) to SPIO NPs using metal-adhesive dopamine groups. Polyethylene glycol (PEG) and paclitaxel (PTX) were hosted in the β-CD cavity through high affinity complexation. The core-shell structure of the magnetic nanoclusters was elucidated based on the condensed SPIO core and a PEG shell using electron microscopy and the composition was analyzed by thermogravimetric analysis (TGA). Our results indicate that nanocluster size could be readily controlled by changing the SPIO/PEG ratio in the assemblies. Interestingly, we observed a significant enhancement in magnetic resonance contrast due to the large cluster size and dense iron oxide core. In addition, tethering a tumor-targeting peptide to the SAMNs enhanced their uptake into tumor cells. PTX was efficiently loaded into β-CDs and released in a controlled manner when exposed to competitive guest molecules. These results strongly indicate that the SAMNs developed in this study possess great potential for application in image-guided cancer chemotherapy.
  
  
  CONCLUSIONS
  In this study, we developed multi-functional SPIO NPs that self-assembled into magnetic nanoclusters (SAMNs) in aqueous conditions as a theranostic nano-system. The beta-cyclodextrin (β-CD) was immobilized on the surfaces of SPIO NPs and RGD-conjugated polyethylene glycol (PEG) and paclitaxel (PTX) were hosted in the β-CD cavity through high affinity complexation. We found that nanocluster size could be readily controlled by varying the SPIO/PEG ratio in the assemblies, and also demonstrated significant improvement of the functional nanoparticles for theranostic systems; enhanced magnetic resonance, improved cellular uptake, and efficient PTX loading and sustained release at the desired time point. These results strongly indicate that the SAMNs developed in this study possess great potential for application in image-guided cancer chemotherapy.
authors.affiliation: Department of Molecular Science and Technology, Ajou University, 5 Woncheon, Yeongtong, Suwon 443-749, Republic of Korea.
authors.forename: Dai Hai
authors.initials: DH
authors.lastname: Nguyen
authors.affiliation: Biomedical Engineering, Yale University, CT 06511, USA.
authors.forename: Jung Seok
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Department of Molecular Science and Technology, Ajou University, 5 Woncheon, Yeongtong, Suwon 443-749, Republic of Korea.
authors.forename: Jong Hoon
authors.initials: JH
authors.lastname: Choi
authors.affiliation: Division of Bioengineering, College of Life Sciences and Bioengineering, Incheon National University, Incheon 22012, Republic of Korea.
authors.forename: Kyung Min
authors.initials: KM
authors.lastname: Park
authors.affiliation: Department of Molecular Science and Technology, Ajou University, 5 Woncheon, Yeongtong, Suwon 443-749, Republic of Korea.
authors.forename: Yunki
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Department of Molecular Science and Technology, Ajou University, 5 Woncheon, Yeongtong, Suwon 443-749, Republic of Korea. Electronic address: kdp@ajou.ac.kr.
authors.forename: Ki Dong
authors.initials: KD
authors.lastname: Park
mesh_terms: D016923:Cell Death / Q000187:drug effects; D003692:Delayed-Action Preparations; D016503:Drug Delivery Systems; D004705:Endocytosis / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D060328:Magnetic Phenomena; D008279:Magnetic Resonance Imaging; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D017239:Paclitaxel / Q000494:pharmacology; D010316:Particle Size; D000068936:Theranostic Nanomedicine / Q000379:methods*; D013818:Thermogravimetry
chemical_list: D003692:Delayed-Action Preparations; D017239:Paclitaxel
keywords: Controlled drug delivery; Cyclodextrin; MRI; Paclitaxel; Poly(ethylene glycol); Self-assembled magnetic nanoclusters; Superparamagnetic iron oxide; Theranostics