Combined multimodal optical imaging and targeted gene silencing using stimuli-transforming nanotheragnostics.

Combined diagnosis and therapy for cancer has been of great interest in medicine. Small interference RNA (siRNA)-encapsulating polyplexes were covalently coated with small gold nanoparticles (Au NPs) via acid-cleavable linkages in order to explore the possibility of achieving combined stimuli-responsive multimodal optical imaging and stimuli-enhanced gene silencing. In a mildly acidic tumor environment, Au NPs are dissociated from the siRNA-carrying polyplexes, generating various optical signal changes such as diminished scattering intensity, increased variance of Doppler frequency, and blue-shifted UV absorbance (stimuli-responsive imaging). Simultaneously, Au NP dissociation exposes the siRNA-carrying polyplex with elevated surface charge and results in enhanced cellular uptake and transfection (stimuli-enhanced therapy). In this study, the feasibility of achieving combined diagnosis and therapy for cancer (theragnostics) is demonstrated by (1) microscopic and spectrophotometric confirmation of acid-transformation of the nanoparticles, (2) reduced scattering intensity and increased variance of Doppler frequency in an acidic pH upon the nanoparticle's transformation, and (3) simultaneous optical signal changes and gene silencing in vitro under a tumor pH-mimicking condition. This novel type of stimuli-responsive nanotheragnostics will provide a new paradigm for pinpointed, multimodal, and combined imaging and therapy for cancer.

[1]  Michele Follen,et al.  Real-time vital optical imaging of precancer using anti-epidermal growth factor receptor antibodies conjugated to gold nanoparticles. , 2003, Cancer research.

[2]  H Akita,et al.  Development of a novel systemic gene delivery system for cancer therapy with a tumor-specific cleavable PEG-lipid , 2007, Gene Therapy.

[3]  Naomi J Halas,et al.  Nanoshell-enabled photothermal cancer therapy: impending clinical impact. , 2008, Accounts of chemical research.

[4]  R. Stafford,et al.  Nanoshell-mediated near-infrared thermal therapy of tumors under magnetic resonance guidance , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[5]  S. Link,et al.  Probing a century old prediction one plasmonic particle at a time. , 2010, Nano letters.

[6]  Evaluation of a multimode fiber optic low coherence interferometer for path length resolved Doppler measurements of diffuse light. , 2007, The Review of scientific instruments.

[7]  Leon Hirsch,et al.  Nanoshell-Enabled Photonics-Based Imaging and Therapy of Cancer , 2004, Technology in cancer research & treatment.

[8]  S. Basu,et al.  Controlled interparticle spacing for surface-modified gold nanoparticle aggregates. , 2008, Langmuir : the ACS journal of surfaces and colloids.

[9]  D. Leeper,et al.  Extracellular pH distribution in human tumours. , 1995, International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group.

[10]  W. Drexler.  Ultrahigh-resolution optical coherence tomography. , 2004, Journal of biomedical optics.

[11]  Stephen U. S. Choi,et al.  Role of Brownian motion in the enhanced thermal conductivity of nanofluids , 2004 .

[12]  Xiaohua Huang,et al.  Cancer cell imaging and photothermal therapy in the near-infrared region by using gold nanorods. , 2006, Journal of the American Chemical Society.

[13]  Zhihua Ding,et al.  High-resolution optical coherence tomography over a large depth range with an axicon lens. , 2002, Optics letters.

[14]  Elazer R. Edelman,et al.  Adv. Drug Delivery Rev. , 1997 .

[15]  Zhongping Chen,et al.  In vivo Imaging of Oral Mucositis in an Animal Model Using Optical Coherence Tomography and Optical Doppler Tomography , 2007, Clinical Cancer Research.

[16]  Lei Wang,et al.  Frequency domain phase-resolved optical Doppler and Doppler variance tomography , 2004 .

[17]  Valery V. Tuchin,et al.  Optical amplification of photothermal therapy with gold nanoparticles and nanoclusters , 2006 .

[18]  R. Narain,et al.  Monodisperse Protein Stabilized Gold Nanoparticles via a Simple Photochemical Process , 2008 .

[19]  A. Yu,et al.  Investigation on the interaction between colloidal gold and human complement factor 4 at different pH by spectral methods. , 2006, Colloids and surfaces. B, Biointerfaces.

[20]  Mathias Brust,et al.  A multidentate peptide for stabilization and facile bioconjugation of gold nanoparticles. , 2009, Bioconjugate chemistry.

[21]  Naomi J Halas,et al.  Nanosphere arrays with controlled sub-10-nm gaps as surface-enhanced raman spectroscopy substrates. , 2005, Journal of the American Chemical Society.

[22]  David R. Smith,et al.  Interparticle Coupling Effects on Plasmon Resonances of Nanogold Particles , 2003 .

[23]  J. Storhoff,et al.  Strategies for Organizing Nanoparticles into Aggregate Structures and Functional Materials , 1997 .

[24]  Carsten Sönnichsen,et al.  A molecular ruler based on plasmon coupling of single gold and silver nanoparticles , 2005, Nature Biotechnology.

[25]  Kazunori Kataoka,et al.  PEGylated Nanoparticles for Biological and Pharmaceutical Applications , 2003 .

[26]  K. Suslick,et al.  Engineered microsphere contrast agents for optical coherence tomography. , 2003, Optics letters.

[27]  J. Griffiths,et al.  Causes and consequences of acidic pH in tumors: a magnetic resonance study. , 1999, Advances in enzyme regulation.

[28]  Zhongping Chen,et al.  Enhanced detection of early-stage oral cancer in vivo by optical coherence tomography using multimodal delivery of gold nanoparticles. , 2009, Journal of biomedical optics.

[29]  J. West,et al.  Immunotargeted nanoshells for integrated cancer imaging and therapy. , 2005, Nano letters.

[30]  D. Fernig,et al.  Determination of size and concentration of gold nanoparticles from UV-vis spectra. , 2007, Analytical chemistry.

[31]  Zhongping Chen,et al.  Imaging and quantifying transverse flow velocity with the Doppler bandwidth in a phase-resolved functional optical coherence tomography. , 2002, Optics letters.

[32]  Woonggyu Jung,et al.  Optical sectioning for microfluidics: secondary flow and mixing in a meandering microchannel. , 2008, Lab on a chip.

[33]  Young Jik Kwon,et al.  Acid-responsive linear polyethylenimine for efficient, specific, and biocompatible siRNA delivery. , 2009, Bioconjugate chemistry.

[34]  W. Kreutz,et al.  Acidic pH inhibits non-MHC-restricted killer cell functions. , 2000, Clinical immunology.

[35]  J. West,et al.  Near-infrared resonant nanoshells for combined optical imaging and photothermal cancer therapy. , 2007, Nano letters.

[36]  G. Frens.  Controlled Nucleation for the Regulation of the Particle Size in Monodisperse Gold Suspensions , 1973 .

[37]  Christopher M. Overall,et al.  Validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy , 2006, Nature Reviews Cancer.

[38]  Y. Kwon,et al.  Enhanced retroviral transduction of 293 cells cultured on liquid-liquid interfaces. , 2001, Biotechnology and bioengineering.