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Marie-Christine Onuta

Contact Information
Office: MEYR 405A
Phone: 410-455-5601
Daniel-Onuta CV
Lab Website

Associate Professor

Ph.D. University of Bordeaux 1 (France) 2003; Post-Doctoral Tokyo University (Japan) 2004; Post-Doctoral Indiana University (IN) 2004

Professional Interests

Need of better delivery systems

Several challenges need to be overcome in chemotherapy to markedly increase its efficacy and potency. Chief among them, multiple side effects and the occurrence of drug resistance severely compromise the efficacy of chemotherapy. Whereas several drug delivery systems exist and intense research is done on combined therapy and on tumor targeting, the simultaneous targeting of different therapeutic entities to the cancer cells is still an area of research to be developed.

Nanovectors: new types of drug delivery systems

 
Preparation of nanovectors

Nanovectors represent a valid approach to fulfil this need due to their inherent high multivalency and versatility. Indeed, nanovectors are in general composed of at least three main parts: – a nanometer sized core (hollow or solid) – a therapeutic and/or imaging load and some tumor cell recognition component.

The nanoscale of the nanovectors endows them with unique properties. Among them, their potential for a large cargo of similar and/or different functions and their reduced clearance time confer on them superiority over traditional drug carriers. Indeed, their dimensions make them big enough to avoid elimination by renal filtration while enabling them to bear multiple functionalities. Also, they can integrate means to bypass biological barriers. For instance, it is now well established that the use of PEG is a very good option to avoid recognition by the immune system. Nanovectors are still small enough (< 100 nm) such that the uptake by macrophages of the RES,leading to body clearance, remains minimal.

Advantages of gold nanoparticles and dendrimers

Gold nanoparticles (GNPs) and dendrimers have already shown great potential for therapeutic use. GNPs are biocompatible and inert. Their synthesis is easy and cheap. Their size and coating can be modulated as desired (2 to 100 nm in size). Dendrimers are synthetic polymeric molecules composed of multiple perfectly branched monomers that emanate radially from a central core, leading to a spherical shape. Due to their size (nanometer scale), their low polydispersity and their multifunctionality, dendrimers have found use as drug carriers conferring low cytotoxicity, membrane permeability and targeting capabilities.

Dendrons can be described as fragments of dendrimers, being hyper-branched organic molecules with a terminal focal point allowing for attachment to a central core. In this project, the focal point is used as the site of binding to the surface of the GNPs.

Strategy

The strategy here is as follows. By using a central anchoring GNP, and attaching dendron units with distinct functionalities, it will be possible to generate a potent drug delivery vehicle for different tumor therapies. These functionalities are chemotherapeutic drugs, targeting ligands and imaging enhancers. This strategy will be applied to three types of cancer: pancreatic, breast and prostate cancers.

Selected Publications

  1. (Pan, H.; Grow, M. E.;) Wilson, O. M. and Daniel, M.-C.* “A New PPI Dendron as Potential Convenient Building-block in Construction of Multifunctional Systems” Tetrahedron, 2013, 2799-2806.
  2. Zabetakis, K.*; Ghann, W. E.*; Kumar, S.; Daniel, M.-C. “Effect of high gold salt concentrations on the size and polydispersity of gold nanoparticles prepared by an extended Turkevich-Frens method” Gold Bulletin, 2012, 45(4), 203-211.
  3. Ghann, W. E.; Aras, O.; Fleiter, T.; Daniel M.-C. “Syntheses and Characterization of Lisinopril-Coated Gold Nanoparticles as Highly Stable Targeted CT Contrast Agents in Cardiovascular Diseases” Langmuir, 2012, 28(28), 10398-10408.
  4. Ghann, W. E.; Aras, O.; Fleiter, T.; Daniel, M.-C. “Synthesis and biological studies of highly concentrated lisinopril-capped gold nanoparticles for CT tracking of angiotensin converting enzyme (ACE)” Proc. SPIE 2011, 8025, 80250H.
  5. Pan, H.; Daniel, M.-C. “Studies of MRI relaxivities of gadolinium-labeled dendrons” Proc. SPIE 2011, 8025, 80250F.
  6. Pan, H.; Daniel, M.-C. “Gadolinium-labeled dendronized gold nanoparticles as new targeted MRI contrast agent” Proc. SPIE 2010, Vol. 7674(Smart Biomedical and Physiological Sensor Technology VII), 767404/1-767404/10.
  7. Daniel, M.-C.; Aras, O.; Smith, M. F.; Nan, A.; Fleiter, T.; “Targeted in-vivo computed tomography (CT) imaging of tissue ACE using concentrated lisinopril-capped gold nanoparticle solutions” Proc. SPIE 2010, Vol. 7674(Smart Biomedical and Physiological Sensor Technology VII), 76740J/1-76740J/9.
  8. Daniel, M.-C.; Tsvetkova, I. B.; Quinkert, Z.T.; Murali, A.; De, M.; Rotello, V. M.; Kao, C. C.; Dragnea, B. ‘Role of Surface Charge Density in Nanoparticle-Templated Assembly of Bromovirus Protein Cages.’ ACS Nano 2010, 4(7), 3853-3860.
  9. Li, Y.; Baeta, C.; Aras, O.; Daniel, M.-C. “Preparation of lisinopril-capped gold nanoparticles for molecular imaging of angiotensin-converting enzyme” Proc. SPIE 2009, Vol. 7313, 731304.
  10. Sun, J.; Dufort, C.; Daniel, M.-C.;, Murali A.; Chen, C.; Gopinath, K.; Stein, B.; De, M.; Rotello, V. M.; Holzenburg, A.; Kao, C. C.; Dragnea, B. ‘Core-controlled Polymorphism in Virus-like-Particles.’ Proceedings of the National Academy of Science of the United States of America 2006, 104(4), 1354-1359.
  11. Dixit, S. K.; Goicochea, N. L.; Daniel, M.-C.; Murali, A.; Bronstein, L.; De, M.; Stein, B.; Rotello, V. M.; Kao, C. C.; Dragnea, B. ‘Quantum Dot Encapsulation in Viral Capsids.’ Nano Letters 2006, 6, 1993-1999.
  12. Chen, C.; Daniel, M.-C.; Quinkert, Z. T.; De, M.; Stein, B.; Bowman, V. D.; Chipman, P. R.; Rotello, V. M.; Kao, C. C.; Dragnea, B. ‘Nanoparticle-Templated Assembly of Viral Protein Cages.’ Nano Letters 2006, 6, 611-616.

Funding

Comparative Studies of the Intracellular Trafficking of Several Classes of Dendronized Drug Nanocarriers
$65,000
UMB-UMBC Research and Innovation Partnership Seed Grant Program
August 1, 2013 -July 31, 2014
Other PI: Peter Swaan
Reporter Compounds for Quantitative Imaging of Biomolecular Interactions using Coherent x-ray Scattering
$128,106 / $43,524 to Daniel Lab
NSF/FDA SIR
06/15/2012 – 05/31/2013
PI: Maricel Kann
Co-PI: Elsa Garcin
Multifunctional Nanovectors for Pancreatic Cancer Therapy
$100,000
American Association for Cancer Research-Pancreatic Cancer Action Network (AACR-PanCAN)
07/01/08 – 06/30/10
The objective of this research proposal is to use gold nanoparticlescoated with dendrons containing gemcitabine, anti-RON antibodiesand transferrin, allowing targeting of pancreatic cancer cells by means of enhanced transferrin-mediated endocytosis.
“Multifunctional Gold Nanoparticles as New Nanovectors for Targeted Combination Therapy of Prostate Cancer”
$317,923
DoD (CDMRP)
09/21/09 – 09/20/12

Courses Taught

  • CHEM 490: Special Topics in Chemistry - Nanoparticles and their multiple applications. After a brief explanation of the particularity of NANOparticles in general, the course will cover the different existing types of semiconductor and metallic nanoparticles by describing their synthesis, characterization, properties and applications. The specific techniques of characterization for nanoparticles will be emphasized as well as their biological applications.
  • CHEM 405: Inorganic Chemistry
  • CHEM 405L: Advanced Inorganic Chemistry Lab

Research Description

Multifunctional Nanocarriers

Short description of the research in the group:

Preparation and characterization of multifunctional nanovectors primarily based on gold nanoparticles and dendrons for the optimization of drug efficiency, especially in cancer and gene therapy.

Research interests of the group:

Several challenges need to be overcome in chemotherapy to markedly increase its efficacy and potency. Chief among them, multiple side effects and the occurrence of drug resistance severely compromise the efficacy of chemotherapy. Whereas several drug delivery systems exist and intense research is done on combined therapy and on tumor targeting, the simultaneous targeting of different therapeutic entities to the cancer cells is still an area of research to be developed.
Nanovectors represent a valid approach to fulfill this need due to their inherent high multivalency and versatility. Indeed, nanovectors are in general composed of at least three main parts: – a nanometer sized core (hollow or solid) – a therapeutic and/or imaging load and some tumor cell recognition component.
The nanoscale of the nanovectors endows them with unique properties. Among them, their potential for a large cargo of similar and/or different functions and their reduced clearance time confer on them superiority over traditional drug carriers. Indeed, their dimensions make them big enough to avoid elimination by renal filtration whileenabling them to bear multiple functionalities. Also, they can integrate means to bypass biological barriers. For instance, it is now well established that the use of PEG is a very good option to avoid recognition by the immune system. Nanovectors are still small enough (< 100 nm) such that the uptake by macrophages of the RES,leading to body clearance, remains minimal.
Gold nanoparticles (GNPs) and dendrimers have already shown great potential for therapeutic use. GNPs are biocompatible and inert. Their synthesis is easy and cheap. Their size and coating can be modulated as desired (2 to 100 nm in size). Dendrimers are synthetic polymeric molecules composed of multiple perfectly branched monomers that emanate radially from a central core, leading to a spherical shape. Due to their size (nanometer scale), their low polydispersity and their multifunctionality, dendrimers have found use as drug carriers conferring low cytotoxicity, membrane permeability and targeting capabilities.
Dendrons can be described as fragments of dendrimers, being hyper-branched organic molecules with a terminal focal point allowing for attachment to a central core. In this project, the focal point is used as the site of binding to the surface of the GNPs.
The strategy here is as follows. By using a central anchoring GNP, and attaching dendron units with distinct functionalities, it will be possible to generate a potent drug delivery vehicle for different tumor therapies. These functionalities are chemotherapeutic drugs, targeting ligands and imaging enhancers. This strategy will be applied to three types of cancer: pancreatic, breast and prostate cancers.

Projects

Multifunctional Nanovectors for Chemotherapy

Gold Nanoparticle-cored PPI dendrimers as platform for multifunctional drug delivery systems.
Gold Nanoparticle-cored PPI dendrimers as platform for multifunctional drug delivery systems.

The objective of this project is the preparation and testing of a multifunctional drug delivery system based on gold nanoparticles and functionalized dendrons (Scheme ), for use in  cancer chemotherapy. The functionalized dendrons to be constructed will contain the therapeutic agents  (dendrons D and E), a targeting moiety (dendron T) for preferential uptake by tumor cells. At the moment, the group is focusing on pancreatic and prostate cancer.

The in vitro testing will be conducted in collaboration with the Greenebaum Cancer Center Translational Laboratory at the University of Maryland School of Medicine (UMSOM). The targeting properties of the nanovectors will be fisrt evaluated. Antiproliferative activity/cytotoxicity of the nanovectors will be assessed by using the methyltetrazolium (MTT) proliferation assay. Inhibitory concentrations 50 and 100% will be determined.

Lisinopril-Capped Gold Nanoparticles for Targeted CT Imaging of Tissue ACE

Lisinopril-Capped Gold Nanoparticles for Targeted CT Imaging of Tissue ACE

The development of cardiac and pulmonary fibrosis have been associated with overexpression ofangiotensin-converting enzyme (ACE). Thus, targeted imaging of the ACE is of crucial importance for monitoring of the tissue ACE activity as well as the treatment efficacy in heart failure.  In this respect, lisinopril-capped goldnanoparticles were prepared to provide a new type of probe for targeted molecular imaging of ACE by tuned K-edge computed tomography (CT) imaging.  Concentrated solutions of these modified gold nanoparticles, with a diameter of around 16 nm, show high contrast in CT imaging and have been used for in vivo testing on rats.