SPIO nanoparticle-stabilized PAA-F127 thermosensitive nanobubbles with MR/US dual-modality imaging and HIFU-triggered drug release for magnetically guided in vivo tumor therapy.

Nanobubbles can serve as promising, next-generation theranostic platforms for ultrasound (US) and magnetic resonance (MR) imaging, and combined magnetic targeting (MT) and high-intensity focused ultrasound (HIFU)-triggered drug release for tumor therapy. Nanobubble-based dual contrast enhancement agents encapsulated with perfluoropentane and stabilized with superparamagnetic iron oxide (SPIO) nanoparticles have been synthesized through a single-step emulsion process from thermosensitive F127 and polyacrylic acid (PAA). Both US and MR imaging contrast can be optimized by varying the shell thickness and SPIO-embedded concentration. The US contrast can be enhanced from a mean gray value of 62 to 115, and the MR r2 value can be enhanced from 164 to 208 (s(-1)mM (-1)Fe) by increasing the SPIO concentration from 14.1 to 28.2mg/mL, respectively. In vivo investigations of SPIO-embedded nanobubbles in excised tumors under external MT revealed that the US and MR signals change quantitatively compared to the same site without MT. This combined strategy enables the nanobubbles to enhance both passive targeting (increasing the permeability by HIFU) and physical MT of chemotherapeutic drugs to tumors. The integration of functionalities makes this nanobubble system a powerful and viable new tool to achieve simultaneous in vivo tumor imaging and efficacious cancer therapy.

[1]  Zhi-Feng Gan,et al.  Preparation and properties of a novel drug delivery system with both magnetic and biomolecular targeting , 2009, Journal of materials science. Materials in medicine.

[2]  S. Davis,et al.  The effect of surface coverage and conformation of poly(ethylene oxide) (PEO) chains of poloxamer 407 on the biological fate of model colloidal drug carriers. , 2001, Biochimica et biophysica acta.

[3]  Yuanyi Zheng,et al.  Perfluorohexane‐Encapsulated Mesoporous Silica Nanocapsules as Enhancement Agents for Highly Efficient High Intensity Focused Ultrasound (HIFU) , 2012, Advanced materials.

[4]  P. Carson,et al.  The role of inertial cavitation in acoustic droplet vaporization , 2008, IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control.

[5]  Yu Zhang,et al.  Superparamagnetic iron oxide nanoparticle-embedded encapsulated microbubbles as dual contrast agents of magnetic resonance and ultrasound imaging. , 2009, Biomaterials.

[6]  J. Wang-Rodriguez,et al.  Hard shell gas-filled contrast enhancement particles for colour Doppler ultrasound imaging of tumors. , 2010, MedChemComm.

[7]  Victor Frenkel,et al.  Ultrasound mediated delivery of drugs and genes to solid tumors. , 2008, Advanced drug delivery reviews.

[8]  S. D. De Smedt,et al.  Crucial factors and emerging concepts in ultrasound-triggered drug delivery. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[9]  Marina Temchenko,et al.  Solubilization and stabilization of camptothecin in micellar solutions of pluronic-g-poly(acrylic acid) copolymers. , 2004, Journal of controlled release : official journal of the Controlled Release Society.

[10]  Chih-Kuang Yeh,et al.  Paclitaxel-liposome-microbubble complexes as ultrasound-triggered therapeutic drug delivery carriers. , 2013, Journal of controlled release : official journal of the Controlled Release Society.

[11]  K. Hynynen,et al.  Ultrasound Enhanced Delivery of Molecular Imaging and Therapeutic Agents in Alzheimer's Disease Mouse Models , 2008, PloS one.

[12]  M. Gilbert,et al.  Treatment of Single Brain Metastasis with Resection, Intracavity Carmustine Polymer Wafers, and Radiation Therapy Is Safe and Provides Excellent Local Control , 2007, Clinical Cancer Research.

[13]  D. Cohn,et al.  Engineering thermoresponsive polymeric nanoshells. , 2009, Biomaterials.

[14]  Samuel A Wickline,et al.  Targeted ultrasonic contrast agents for molecular imaging and therapy. , 2001, Current problems in cardiology.

[15]  Victor Frenkel,et al.  Potential role of pulsed-high intensity focused ultrasound in gene therapy. , 2006, Future oncology.

[16]  Mu-Yi Hua,et al.  Novel magnetic/ultrasound focusing system enhances nanoparticle drug delivery for glioma treatment. , 2010, Neuro-oncology.

[17]  Faqi Li,et al.  Engineering Inorganic Nanoemulsions/Nanoliposomes by Fluoride‐Silica Chemistry for Efficient Delivery/Co‐Delivery of Hydrophobic Agents , 2012 .

[18]  J. Dobson.  Magnetic nanoparticles for drug delivery , 2006 .

[19]  Mu-Yi Hua,et al.  Magnetic resonance monitoring of focused ultrasound/magnetic nanoparticle targeting delivery of therapeutic agents to the brain , 2010, Proceedings of the National Academy of Sciences.

[20]  Michel Claudon,et al.  Ultrasound contrast agents: properties, principles of action, tolerance, and artifacts , 2001, European Radiology.

[21]  L. Curiel,et al.  Influence of the docetaxel administration period (neoadjuvant or concomitant) in relation to HIFU treatment on the growth of Dunning tumors: results of a preliminary study , 2008, Prostate Cancer and Prostatic Diseases.

[22]  R. Misra.  Core–shell magnetic nanoparticle carrier for targeted drug delivery: challenges and design , 2010 .

[23]  T. Groth,et al.  Characterization of PLGA nanospheres stabilized with amphiphilic polymers: hydrophobically modified hydroxyethyl starch vs pluronics. , 2009, Molecular pharmaceutics.

[24]  M. Wheatley,et al.  Development of a novel method for synthesis of a polymeric ultrasound contrast agent. , 2003, Journal of biomedical materials research. Part A.

[25]  Katherine W Ferrara,et al.  Driving delivery vehicles with ultrasound. , 2008, Advanced drug delivery reviews.

[26]  Tse-Ying Liu,et al.  A novel drug vehicle capable of ultrasound-triggered release with MRI functions. , 2011, Acta biomaterialia.

[27]  Hao Zeng,et al.  Monodisperse MFe2O4 (M = Fe, Co, Mn) nanoparticles. , 2004, Journal of the American Chemical Society.

[28]  P. Kulkarni,et al.  Monitoring of magnetic targeting to tumor vasculature through MRI and biodistribution. , 2010, Nanomedicine.

[29]  Ajit Raisinghani,et al.  Physical principles of microbubble ultrasound contrast agents. , 2002, The American journal of cardiology.

[30]  J. Xie,et al.  Pulsed high-intensity focused ultrasound enhances apoptosis and growth inhibition of squamous cell carcinoma xenografts with proteasome inhibitor bortezomib. , 2008, Radiology.

[31]  Sergio Uzzau,et al.  Development of polymeric microbubbles targeted to prostate-specific membrane antigen as prototype of novel ultrasound contrast agents. , 2011, Molecular pharmaceutics.

[32]  Yang Sun,et al.  Superparamagnetic PLGA-iron oxide microcapsules for dual-modality US/MR imaging and high intensity focused US breast cancer ablation. , 2012, Biomaterials.

[33]  Yang Sun,et al.  Manganese oxide-based multifunctionalized mesoporous silica nanoparticles for pH-responsive MRI, ultrasonography and circumvention of MDR in cancer cells. , 2012, Biomaterials.

[34]  Ping Wang,et al.  Nanobubbles for enhanced ultrasound imaging of tumors , 2012, International journal of nanomedicine.

[35]  Fabian Kiessling,et al.  Iron oxide nanoparticle-containing microbubble composites as contrast agents for MR and ultrasound dual-modality imaging. , 2011, Biomaterials.

[36]  Ralf Seip,et al.  Ultrasound-triggered release of materials entrapped in microbubble-liposome constructs: a tool for targeted drug delivery. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[37]  R. Eckersley,et al.  Ultrabubble: A Laminated Ultrasound Contrast Agent with Narrow Size Range , 2009 .

[38]  Y. Liu,et al.  Efficacy of contrast-enhanced US and magnetic microbubbles targeted to vascular cell adhesion molecule-1 for molecular imaging of atherosclerosis. , 2011, Radiology.

[39]  Sung-Min Choi,et al.  Thermally reversible pluronic/heparin nanocapsules exhibiting 1000-fold volume transition. , 2006, Langmuir : the ACS journal of surfaces and colloids.

[40]  K. Maruyama,et al.  Progress in the development of ultrasound-mediated gene delivery systems utilizing nano- and microbubbles. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[41]  Y. Chen,et al.  Self-assembling PVA-F127 thermosensitive nanocarriers with highly sensitive magnetically-triggered drug release for epilepsy therapy in vivo , 2012 .

[42]  H. Harn,et al.  Activation of Nonsteroidal Anti-Inflammatory Drug-Activated Gene-1 via Extracellular Signal-Regulated Kinase 1/2 Mitogen-Activated Protein Kinase Revealed a Isochaihulactone-Triggered Apoptotic Pathway in Human Lung Cancer A549 Cells , 2007, Journal of Pharmacology and Experimental Therapeutics.

[43]  Hao Zeng,et al.  Monodisperse MFe 2 O 4 ( M ) Fe , Co , Mn ) Nanoparticles , 2022 .