My research is focused on rational design and synthesis of novel polymers that may have applications in biomaterials, biotechnology and pharmaceuticals as well as other applications. Currently, two research directions are ongoing.
1. Biodelivery: Polymer Nanocarriers for Targeted Drug Delivery and Gene Delivery to Cancer
Cancer has dethroned heart disease as the top killer among Americans under the age of 85. Most patients, although initially responsive, eventually develop and succumb to drug-resistant metastases. For example, the success of typical postsurgical regimens for ovarian cancer is limited by primary tumors being intrinsically or becoming refractory to treatment. First-line treatment yields about 30% complete pathologic remission and an overall response rate of 75%, but the disease usually recurs within 2 years of the initial treatment. Thus, drug resistance is a major obstacle to the successful cancer chemotherapy, particularly at advanced stages.
Cancer cells have many intrinsic and acquired drug resistance mechanisms to mitigate the cytotoxic effects of anti-cancer drugs (Figure 1). These mechanisms include the loss of surface receptors or transporters to slow drug influx, cell-membrane-associated multidrug resistance to remove drugs, specific drug metabolism or detoxification, intracellular drug sequestration, overexpression of Src tyrosine kinase and splicing factor SPF45, increased DNA-repair activity, altered expression of oncogenes and regulatory proteins and increased expression of antiapoptotic genes and mutations to resist apoptosis, and etc.
Figure 1. Illustration of some drug resistance mechanisms of cancer cells
Our research in this area is focused on using active nanocarriers to deliver drugs to the specific subcellular targets to overcome cancer drug resistance for high therapeutic efficacy. Generally, we start from design and synthesis of new stimulus-responsive multifunctional polymers and fabrication of programmed or active nanocarriers. These nanocarriers are then tested in vitro and in vivo.
The fist system is cancer-targeted lysosomal triggered fast release nanoparticles (Figure 2). In vitro and in vivo evaluation shows that drugs in these nanoparticles have higher anticancer activity than free and conventional nanoparticle-encapsulated drugs. This work is highly recognized as one of the four “most intriguing” work of 2006-2Q selected by CAS from over 200,000 documents per quarter.
Figure 2.The numbers of tumors on intestine/ mesentery (per cm2) of the nude mice. Cisplatin dose was 10 mg/kg/treatment. Mice were treated twice at fourth and the fifth weeks after inoculation of SKOV-3 cells. Data represent mean value ± S.E.
The second system is nuclear localization nanoparticles for nuclear drug delivery (Figure 3). The central hypothesis is that delivery of drugs to the immediate vicinity of the anticancer drug targets¾the nuclear DNA¾ can circumvent both of the cell-membrane associated multidrug resistance and the intracellular drug resistance mechanisms. The big challenge is how to activate the nuclear localization agents only inside cancer cells. We developed a charge-reversal technique and successfully solved the problem (Angewandte Chemie International Edition, 2007, 46, 4999-5002).
Figure 3. Nuclear localization of the PEI-based charge-reversal nanoparticles observed by confocal scanning laser microscopy after cultured with SKOV-3 cells for 24 h at 37 ۫C. The nuclei were stained with DRAQ5 (blue). The nanoparticles loaded with PKH26 were assigned to red. Pink spots were nanoparticles colocalized in the nuclei.
In polymer-mediated gene delivery, cationic polymers generally complex plasmids to compact them into nanoparticles and to shield their negative charges for effective cellular internalization. Tight packing is also needed for DNA trafficking to the nucleus and protection from degradation by enzymes. However, this tight complexation has been found as one of the major barriers to efficient DNA transcription because in the nucleus the complexed DNA is inaccessible for the transcription machine. Facilitated dissociation of the complexes using short,reversibly crosslinked, degradable, or low positively-charged cationic polymers or charge-reversible amphiphiles has been shown to significantly enhance transgenic efficiency.
Our research in this area is rational design of polymers that can deliver loosely packed or even free DNA (Scheme 1 and Figure 4) into the nucleus for high transfection efficiency. Our ultimate goal is to develop polymer gene therapy for cancer or other diseases.
Scheme 1. Virion-mimicking nanocapsule formation via a pH-controlled hierarchical self-assembly of the PCL/PDEA/PEG terpolymer brush and DNA. The PDEA chains were positively charged by protonation at pH 5 (a); They complexed with DNA and formed a hydrophilic core; the hydrophobic PCL chains collapsed on the core, forming a membrane surrounding the core; the hydrophilic PEG chains were incompatible with the hydrophobic PCL layer and thus were extended in the aqueous solution, forming the hydrophilic outer layer (b); After the solution pH was raised to pH 7.2, the PDEA chains were deprotonated, became neutral and insoluble, and thus dissociated from the DNA, leaving free DNA in the core (c) (Angewandte Chemie International Edition, 2008, early view online).
Figure 4. The artificial virus: free DNA in polymer nanocapsules
· Y. Shen,* H. Tang, and M. Radosz, “pH-responsive nanoparticles for drug delivery” Invited chapter in Drug Delivery Systems- Methods in Molecular Medicine, Kewal Jain (ed), Humana Press, to be published in 2007.
· P. Xu, E. A. Van Kirk, Y. Zhan, W. J. Murdoch, M. Radosz, Y. Shen,* “Targeted charge-reversal nanoparticles for nuclear drug delivery”, Angewandte Chemie International Edition
, 46, 4999-5002. Highlighted http://www.nanowerk.com/spotlight/spotid=2113.php
· P. Xu, S.-Y. Li, Q. Li, E. A. Van Kirk, J. Ren,* Z. Zhang, W. J. Murdoch, Y. Shen,* Virion-mimicking nanocapsules from pH-controlled-hierarchical self-assembly for gene delivery, Angewandte Chemie International Edition, 2008, early view online.
· Y Shen,*Y. Zhan, E. A. Van Kirk, W. Murdoch, M. Radosz, “Multifunctioning pH-responsive nanoparticles from hierarchical self-assembly of polymer brush for cancer chemotherapy’, Submitted to AIChE Journal.
· N. Wang, A. Dong, M. Radosz, Y Shen,* “Degradable thermoresponsive polyethylene glycol analogs”, Journal of Biomedical Materials Research A, in press.
· N. Wang, A. Dong, E. A. Van Kirk, H. Tang, W. Murdoch, M. Radosz, Y Shen,* “Degradable polyethylene glycol analogs as versatile drug delivery carriers”, Macromolecular Bioscience, in press.
· W. Jin, Y. Zhan, E. A. Van Kirk, L. Liu, P. Xu, W. Murdoch, M. Radosz, Y. Shen,* “Degradable cisplatin-releasing core-shell nanogels from zwitterionic poly(beta-aminoester)-graft-PEG for cancer chemotherapy, Drug Delivery 2007, 14, 279-286.
· P. Xu, S. Li, J. Ren, W. J. Murdoch, M. Radosz, Y. Shen*, “Biodegradable cationic polyester as an efficient carrier for gene delivery to neonatal cardiomyocytes”, Biotechnology and Bioengineering, 2006, 95, 893-903.
· P. Xu, E. A. Van Kirk, W. J. Murdoch, Y. Zhan, D. D. Isaak, M. Radosz, Y. Shen*, “Anticancer efficacies of cisplatin-releasing nanoparticles”, Biomacromolecules, 2006, 7, 829-835.
Selected as one of the four “the Most Intriguing work” by CAS scientists for 2Q of 2006 from over 200,000 documents per quarter, including articles from nearly 9,500 journals, and patents from 50 active patent-issuing authorities from around the world.
· P. Xu, E. A. Van Kirk, S. Li, J. Ren, W. J. Murdoch, M. Radosz, Y. Shen*, “Highly stable core-surface crosslinked nanoparticles as cisplatin carriers”, Colloids and Surfaces B: Biointerfaces, 2006, 48, 50-57.
· P. Xu, H. Tang, S. Li, J. Ren, E. A. Van Kirk, W. J. Murdoch, M. Radosz, Y. Shen,* “Enhanced stability of core-surface crosslinked micelles fabricated from amphiphilic brush copolymers”, Biomacromolecules, 2004, 5, 1736-1744.
2. Advanced Polymeric Materials and Catalysts for Atom Transfer Radical Polymerization
Association of polymer chains with uncontrolled distribution of hydrogen bonding sites leads to random clusters and three-dimensional networks through a process of random intra- and intermolecular bonding which leads to self- and cross-association or both. By contrast, uniform polymer chains with a well-defined distribution of hydrogen-bonding sites can self assemble with their complementary chains, that is, they can form highly aligned chain duplexes with well-defined bond sequences. Such polymer self-assembly, reminiscent of DNA self-assembly, can lead to valuable biotic and abiotic advanced materials. The challenge is how to synthesize such self-assembling polymers. Our current research is using living polymerization techniques, particularly atom transfer radical polymerization (ATRP), to synthesize such self-assembling polymers. The AFM image shows the V-shape of a self-assembling block copolymer synthesized via a two-step ATRP method (Figure 5). In addition, highly active and supported ATRP catalysts have also been developed.
Figure 5. AFM image of block copolymer on mica surface of in DMSO/DMF solution
· H. Tang, N. Arulsamy, M. Radosz, Y. Shen*, N. V. Tsarevsky, W. A. Braunecker, W. Tang, K. Matyjaszewski*, “Highly active catalyst for atom transfer radical polymerization”, Journal of American Chemical Society 2006, 128, 16277-16285. Highlighted in Chemical & Engineering News, 84(44), October 30, 2006, 40-41.
· H. Tang, M. Radosz, Y. Shen,* “Synthesis and self-assembly of thymine- and adenine-containing homopolymers and diblock copolymers” Journal of Polymer Science Part A: Polymer Chemistry, 2006, 44, 5995-6006.
· H. Tang, M. Radosz, Y. Shen,* “Template-atom transfer radical polymerization of diaminopyrimidine derivatized monomer in the presence of uracil-containing polymer” Journal of Polymer Science Part A: Polymer Chemistry, 2006, 44, 6607-6615.
· S. Ding, M. Radosz, Y. Shen*, “Magnetic nanoparticle supported catalyst for atom transfer radical polymerization”, Macromolecules, 2006, 39, 6399-6405.One of the Most-Accessed Articles in Macromolecules: July-September, 2006
· H. Tang, M. Radosz, Y. Shen*, “CuBr2/N,N,N’,N’-tetra[(2-pyridal)-methyl]ethylenediamine –tertiaryamine as highly active and versatile catalyst for atom transfer radical polymerization via activator generated by electron transfer”, Macromolecular Rapid Communication, 2006, 27, 1127-1131.
· S. Ding, M. Radosz, Y. Shen*, “Magnetic supported catalyst for ATRP”. Chapter in Progress in Controlled/Living Polymerization: From Synthesis to Materials, ACS Symposium. Series 2006, 944, 71-84.
· S. Ding, M. Radosz, Y. Shen*, “Ionic liquid supported catalyst for atom transfer radical polymerization”, Macromolecules 2005, 38, 5921-5928.
· S. Ding, H. Tang, M. Radosz, Y. Shen*, “Atom transfer radical polymerization of ionic liquid 2-(1-butylimidazolium-3-yl)ethyl methacrylate tetrafluoroborate”, Journal of Polymer Science, Part A: Polymer Chemistry 2004, 42, 5794-5801.
· Y. Shen,* H. D. Tang, and S. Ding, “Catalyst separation in atom transfer radical polymerization”, Progress in Polymer Science, 2004, 29, 1053-1078 (Ranked top 19 of the most download papers in the journal in 2005).
· S. Ding, M. Radosz, Y. Shen*, “A new tetradentate ligand for atom transfer radical polymerization” Journal of Polymer Science Part A: Polymer Chemistry, 2004, 42, 3553-3562.
· S. Ding, M. Radosz, Y. Shen*, “Atom transfer radical polymerization of N,N-dimethylacrylamide”, Macromolecular Rapid Communication, 2004, 25, 632-636.
· J. Yang, S. Ding, M. Radosz, Y. Shen*, “Reversible catalyst supporting via hydrogen bonding-mediated self assembly for atom transfer radical polymerization of MMA”, Macromolecules, 2004, 37, 1728-1734.
· S. Ding, J. Yang, M. Radosz, Y. Shen*, “Atom transfer radical polymerization of methyl methacrylate by reversibly supported catalysts on silica gel via self assembly”, Journal of Polymer Science Part A: Polymer Chemistry 2004, 1, 22-30.