Systematic Surface Engineering of Magnetic Nanoworms for In vivo Tumor Targeting

Abstract

In the design of nanoparticles that can target disease tissue in vivo, parameters such as targeting ligand density, type of target receptor, and nanoparticle shape can play an important role in determining the extent of accumulation. Herein, a systematic study of these parameters for the targeting of mouse xenograft tumors is performed using superparamagnetic iron oxide as a model nanoparticle system. The type of targeting peptide (recognizing cell surface versus extracellular matrix), the surface coverage of the peptide, its attachment chemistry, and the shape of the nanomaterial [elongated (nanoworm, NW) versus spherical (nanosphere, NS)] are varied. Nanoparticle circulation times and in vivo tumor-targeting efficiencies are quantified in two xenograft models of human tumors (MDA-MB-435 human carcinoma and HT1080 human fibrosarcoma). It is found that the in vivo tumor-targeting ability of the NW is superior to that of the NS, that the smaller, neutral CREKA targeting group is more effective than the larger, positively charged F3 molecule, that a maximum in tumor-targeting efficiency and blood half-life is observed with ≈60 CREKA peptides per NW for either the HT1080 or theMDA-MB-435 tumor types, and that incorporation of a 5-kDa polyethylene glycol linker improves targeting to both tumor types relative to a short linker. It is concluded that the blood half-life of a targeting molecule–nanomaterial ensemble is a key consideration when selecting the appropriate ligand and nanoparticle chemistry for tumor targeting.

Point-of-care diagnostics for noncommunicable diseases using synthetic urinary biomarkers and paper microfluidics

“…To develop synthetic biomarkers for thrombosis and cancer, we first sought to design NPs for sensing the activity of the proteases thrombin and matrix metalloproteinase 9 (MMP9). We functionalized poly(ethylene glycol)-coated iron oxide nanoworms (NWs)-a long-circulating NP formulation previously characterized by collaborators and our laboratory (19,20)-with fluorescein-labeled derivatives of thrombin-and MMP9-cleavable substrates [PLGLRSW and PLGVRGK, respectively (8)] at a surface valency of 20-30 peptides per NW to induce intermolecular quenching (Fig. 1A).…”

“…Furthermore, we expect our formulation to be well tolerated by patients, as our NPs are synthesized from Food and Drug Administration-approved materials including polypeptides (e.g., bivalirudin, enfuvirtide), ligands (e.g., fluorescein), and iron oxide NPs which are already in use in humans at gram-scale doses to treat iron deficiency anemia (30-32) (e.g., Feridex, Lumirem). Additionally, these iron oxide nanoparticles have been characterized extensively, exhibiting long circulation half-life (19,20) and an inability to cross the glomerular basement membrane due to a hydrodynamic radius of ∼60 nm (8,33). The development of additional NP formulations or methods of administration such as transdermal (34) or inhalation (35) delivery may also provide an alternative to i.v.…”

“…S2F). NWs (∼60 nm) were synthesized from the reaction of iron(III) chloride hexahydrate and iron(II) chloride tetrahydrate with dextran (15-25 kDa) as previously described (19,20). Aminated NWs were derivatized with N-succinimidyl iodoacetate and reacted with sulfhydrylterminated protease-sensitive reporters.…”

Cooperative nanomaterial system to sensitize, target, and treat tumors

“…An optimized formulation of NWs was prepared as previously described (24,25), and coated with LyP-1 peptides via PEG linkers (∼40 peptides per nanoworm). Significant quantities of the LyP-1 peptide-conjugated NWs (LyP1NWs) were internalized Samples were incubated for 20 min at 37°C (−) or 45°C (þ) and then held at 37°C for an additional 2 h. Cell nuclei and p32 stained with 4 0 -6-diamidino-2-phenylindole (DAPI, Blue), and anti-p32 antibody followed by Alexa Fluor® 594 goat antirabbit IgG antibody (Red), respectively.…”

Targeting of drugs and nanoparticles to tumors

“…A tumor-targeting nanosystem that possesses both superparamagnetic and fluorescent quantum dot domains offers the possibility to provide a low resolution anatomical reference to guide the surgical procedure (by magnetic resonance imaging) and a high resolution mapping that can be visualized during surgery to identify surgical margins (by fluorescence imaging of quantum dots; Wang et al, 2004;Kim et al, 2005;Sathe et al, 2006;Kim and Taton, 2007;Song et al, 2007;Park et al, 2008;Ye et al, 2008). Recently, we have also designed iron oxide nanoparticles (nanoworms; Park et al, 2009b) with improved properties and nontoxic silicon-based quantum dots (Park et al, 2009a) for such purposes.…”