Design of peptide-conjugated glycol chitosan nanoparticles for near infrared fluorescent (NIRF) in vivo imaging of bladder tumors

Enhanced permeability and retention (EPR) effects for tumor treatment have been utilized as a representative strategy to accumulate untargeted nanoparticles in the blood vessels around tumors. However, the EPR effect itself was not sufficient for the nanoparticles to penetrate into cancer cells. For the improvement of diagnosis and treatment of cancer using nanoparticles, many more nanoparticles need to specifically enter cancer cells. Otherwise, can leave the tumor area and not contribute to treatment. In order to enhance the internalization process, specific ligands on nanoparticles can help their specific internalization in cancer cells by receptor-mediated endocytosis. We previously developed glycol chitosan based nanoparticles that suggested a promising possibility for in vivo tumor imaging using the EPR effect. The glycol chitosan nanoparticles showed a long circulation time beyond 1 day and they were accumulated predominantly in tumor. In this study, we evaluated two peptides for specific targeting and better internalization into urinary bladder cancer cells. We conjugated the peptides on to the glycol chitosan nanoparticles; the peptide-conjugated nanoparticles were also labeling with near infrared fluorescent (NIRF) dye, Cy5.5, to visualize them by optical imaging in vivo. Importantly real-time NIRF imaging can also be used for fluorescence (NIRF)-guided surgery of tumors beyond normal optical penetration depths. The peptide conjugated glycol chitosan nanoparticles were characterized with respect to size, stability and zeta-potential and compared with previous nanoparticles without ligands in terms of their internalization into bladder cancer cells. This study demonstrated the possibility of our nanoparticles for tumor imaging and emphasized the importance of specific targeting peptides.

[1]  Vladimir Torchilin,et al.  Tumor delivery of macromolecular drugs based on the EPR effect. , 2011, Advanced drug delivery reviews.

[2]  V. Torchilin,et al.  Drug targeting. , 2000, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[3]  Ick Chan Kwon,et al.  Tumor-homing multifunctional nanoparticles for cancer theragnosis: Simultaneous diagnosis, drug delivery, and therapeutic monitoring. , 2010, Journal of Controlled Release.

[4]  Ick Chan Kwon,et al.  Hydrophobically modified glycol chitosan nanoparticles-encapsulated camptothecin enhance the drug stability and tumor targeting in cancer therapy. , 2008, Journal of controlled release : official journal of the Controlled Release Society.

[5]  D. Dhawan,et al.  Canine invasive transitional cell carcinoma cell lines: in vitro tools to complement a relevant animal model of invasive urinary bladder cancer. , 2009, Urologic oncology.

[6]  Ick Chan Kwon,et al.  Physicochemical Characteristics of Self-Assembled Nanoparticles Based on Glycol Chitosan Bearing 5β-Cholanic Acid , 2003 .

[7]  Sung Ho Ryu,et al.  A Nucleolin-Targeted Multimodal Nanoparticle Imaging Probe for Tracking Cancer Cells Using an Aptamer , 2010, Journal of Nuclear Medicine.

[8]  C. Rodriguez,et al.  Targeting canine bladder transitional cell carcinoma with a human bladder cancer-specific ligand , 2011, Molecular Cancer.

[9]  Ralph Weissleder,et al.  Magnetic nanoparticles for MR imaging: agents, techniques and cardiovascular applications , 2008, Basic Research in Cardiology.

[10]  Ick Chan Kwon,et al.  Dark quenched matrix metalloproteinase fluorogenic probe for imaging osteoarthritis development in vivo. , 2008, Bioconjugate chemistry.

[11]  P. Choyke,et al.  Clearance properties of nano-sized particles and molecules as imaging agents: considerations and caveats. , 2008, Nanomedicine.

[12]  Ick Chan Kwon,et al.  Real-time and non-invasive optical imaging of tumor-targeting glycol chitosan nanoparticles in various tumor models. , 2011, Biomaterials.

[13]  P. Low,et al.  Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-α targeting: first in-human results , 2011, Nature Medicine.

[14]  R. Tsien,et al.  Activatable cell penetrating peptides linked to nanoparticles as dual probes for in vivo fluorescence and MR imaging of proteases , 2010, Proceedings of the National Academy of Sciences.

[15]  K. Lam,et al.  Identification of a bladder cancer-specific ligand using a combinatorial chemistry approach. , 2012, Urologic oncology.

[16]  Ick Chan Kwon,et al.  Polymeric nanomedicine for cancer therapy , 2008 .

[17]  Erkki Ruoslahti,et al.  Targeting Bladder Tumor Cells In vivo and in the Urine with a Peptide Identified by Phage Display , 2007, Molecular Cancer Research.

[18]  Hiroshi Maeda,et al.  Tumor-selective delivery of macromolecular drugs via the EPR effect: background and future prospects. , 2010, Bioconjugate chemistry.

[19]  G. Liu,et al.  Targeted Herceptin–dextran iron oxide nanoparticles for noninvasive imaging of HER2/neu receptors using MRI , 2009, JBIC Journal of Biological Inorganic Chemistry.

[20]  F. Kiessling,et al.  Integrin Targeting for Tumor Optical Imaging , 2011, Theranostics.

[21]  Ick Chan Kwon,et al.  Self-assembled nanoparticles based on glycol chitosan bearing hydrophobic moieties as carriers for doxorubicin: in vivo biodistribution and anti-tumor activity. , 2006, Biomaterials.

[22]  Seulki Lee,et al.  Peptide-based probes for targeted molecular imaging. , 2010, Biochemistry.

[23]  Ralph Weissleder,et al.  Multifunctional magnetic nanoparticles for targeted imaging and therapy. , 2008, Advanced drug delivery reviews.

[24]  Xianrui Zhao,et al.  Mechanism-based tumor-targeting drug delivery system. Validation of efficient vitamin receptor-mediated endocytosis and drug release. , 2010, Bioconjugate chemistry.