1.Self-assembly in cellular milieu for supramolecular medicine.
Our main research centers on fundamental mechanistic studies and technologies related to self-assembly of small molecules that can improve human health. Specifically, we explore the molecular mechanism of self-assembly of small molecules in cellular environment for the development of novel therapeutics. We design and synthesize small molecules for self-assembling in cellular milieu, identify the cellular locations and protein targets of the self-assembly, evaluate molecular/cellular mechanism of the biological functions of the self-assembly for selectively inhibiting cancer cell proliferation.
Wang, H. M.; Feng, Z. Q. Q.; Wang, Y. Z.; Zhou, R.; Yang, Z. M.; Xu, B.* “Integrating Enzymatic Self-Assembly and Mitochondria Targeting for Selectively Killing Cancer Cells without Acquired Drug Resistance” J. Am. Chem. Soc., 2016, 138, 16046−16055
Zhou, J.; Du, X. W.; Xu, B.* “Regulating the Rate of Molecular Self-Assembly for Targeting Cancer Cells” Angew. Chem. Int. Ed., 2016, 55, 5770-5775.Zhou, J.; Du, X. W.; Yamagata, N.; Xu, B.* “Enzyme-Instructed Self-Assembly of Small D-Peptides as a Multiple-Step Process for Selectively Killing Cancer Cells” J. Am. Chem. Soc. 2016, 138, 3813-3823.
Li, J.; Kuang, Y.; Shi, J. F.; Zhou, J.; Medina, J. E.; Zhou, R.; Yuan, D.; Yang, C. H.; Wang, H. M.; Yang, Z. M.; Liu, J. F.; Dinulescu, D. M.* and Xu, B.* “Enzyme-Instructed Intracellular Molecular Self-assembly to Boost Activity of Cisplatin against Drug-Resistant Ovarian Cancer Cells” Angew. Chem. Intl. Ed., 2015, 54, 13307-13311
Shi, J. F.; Du, X. W.; Huang, Y. B.; Zhou, J.; Yuan, D.; Wu, D. D.; Zhang, Y.; Haburcak, R.; Epstein, I. R.*; Xu, B.* “Ligand-Receptor Interaction Catalyzes the Aggregation of Small Molecules to Induce Cell Necroptosis” J. Am. Chem. Soc. 2015, 137, 26-29
Kuang, Y.; Shi, J. F.; Li, J.; Yuan, D.; Alberti, K. A.; Xu, Q. B.; Xu, B.* “Pericellular Hydrogel/Nanonets Inhibit Cancer Cells” Angew. Chem. Intl. Ed., 2014, 53, 8104-8107.
Kuang, Y.; Xu, B.* “Nanofibers of Small Hydrophobic Molecules Disrupt Dynamics of Microtubles and Selectively Inhibit Gliobalstoma Cells” Angew. Chem. Int. Ed. 2013, 52, 6944-6948.
Gao, Y.; Shi, J. F.; Yuan, D.; Xu, B.* “Imaging enzyme-triggered self-assembly of small molecules inside live cells”Nat. Commun. 2012, 3, 1033 (DOI: 10.1038/ncomms2040).
Du, X. W.; Zhou, J.; Shi, J. F.; Xu, B.* “Supramolecular Hydrogelators and Hydrogels: From Soft Matter to Molecular Biomaterials” Chem. Rev., 2015, 115, 13165-13307.
Yang, Z. M.; Gu, H. W.; Fu, D. G.; Gao, P.; Lam, K. J. K.; Xu, B.* “Enzymatic Formation of Supramolecular Hydrogels” Adv. Mater. 2004, 16, 1440-1444.
2. Self-delivering drugs.
Conventional drug delivery largely is based on biodegradable polymers. Despite its tremendous success in dosage control, polymer-based carriers still have several limitations, such as low drug loading capacity and efficiency and the inability to reduce inherent adverse drug reactions (ADR). We introduced a new kind of biomaterials—molecular hydrogels of therapeutic agents for self-delivery of drugs. Based on the molecular self-assembly in water, it is possible to transform therapeutic agents into analogues that form hydrogels without compromising their pharmacological efficacy. This transformation allows the therapeutic agents to become “self-delivery” in the form of hydrogels. Besides increasing the drug loading, we demonstrated that the self-assembly of hydrogelators of drugs can increase the efficacy of drugs (e.g., enabling vancomycin to inhibit vancomycin resistant bacteria) and reduce ADR (e.g., boost selectivity of NSAID). Our reports on the molecular hydrogels made from clinical used drugs also have stimulated others to use the same approach to develop new systems for self-delivery drugs.
Li, J. Y.; Gao, Y.; Kuang, Y.; Shi, J. F.; Du, X. W.; Zhou, J.; Wang, H. M.; Yang, Z. M.; Xu, B.* “Dephosphorylation of D-Peptide Derivatives to Form Biofunctional, Supramolecular Nanofibers/Hydrogels and Their Potential Applications for Intracellular Imaging and Intratumoral Chemotherapy” J. Am. Chem. Soc., 2013, 135, 9907-9914.
Li, J. Y.; Kuang, Y.; Gao, Y.; Du, X. W.; Shi, J. F.; Xu, B.* “D-Amino Acids Boost the Selectivity and Confer Supramolecular Hydrogels of a Non-steroidal Anti-inflammatory Drug (NSAID)" J. Am. Chem. Soc., 2013, 135, 542-545.
Li, X. M.; Li, J. Y.; Gao, Y.; Kuang, Y.; Shi, J. F.; Xu, B.* “Molecular Nanofibers of Olsalazine Confer Supramolecular Hydrogels for Reductive Release of An Anti-inflammatory Agent “ J. Am. Chem. Soc. 2010, 132, 17707-17709.
Gao, Y.; Kuang, Y.; Guo, Z.-F.; Guo, Z. H.; Krauss, I. J.; Xu, B.* “Enzyme-Instructed Molecular Self-assembly Confers Nanofibers and A Supramolecular Hydrogel of Taxol Derivative” J. Am. Chem. Soc., 2009, 131, 13576-13577.
Zhao, F.; Ma, M. L.; Xu, B.* “Molecular Hydrogels of Therapeutic Agents” Chem. Soc. Rev. 2009, 38, 883-891.
3.Self-assembly of de novo glycoconjugates as functional mimic of glycans.
Carbohydrates or glycans play pivotal roles in cell biology: every living cell is covered with a complex array of glycans (i.e., glycocalyx); almost half of ECM proteins are either glycoproteins or proteoglycans; most secreted proteins of eukaryotes carry large amounts of covalently attached glycans. Despite the prevalence of glycans in the cellular environment, the development of glycobiomaterials for biomedical applications is rather limited because of the challenges in glycobiology and glycochemistry. Therefore, no general methods are available for the preparation of complex glycans. These factors greatly impede the development and application of glycobiomaterials for biomedicine. We pioneered the use of molecular self-assembly to sidestep the laborious synthesis of complex glycans for wound healing, promoting the proliferation of murine embryonic stem (mES) cells, and immune suppression. We are developing the supramolecular assemblies of a novel conjugate of nucleobase, amino acids, and saccharide, as a de novo glycoconjugate, for functional mimicking glycoproteins.
Yuan, D.; Shi, J. F.; Du, X. W.; Zhou, N.; Xu, B.* “Supramolecular Glycosylation Accelerates Proteolytic Degradation of Peptide Nanofibrils” J. Am. Chem. Soc., 2015, 137, 10092-10095.
Li, X. M.; Kuang, Y.; Shi, J. F.; Gao, Y.; Lin, H.C.; Xu, B.* “Multifunctional, Biocompatible Supramolecular Hydrogelators Consist Only of Nucleobase, Amino Acid, and Glycoside”, J. Am. Chem. Soc., 2011, 133, 17513-17518.
4. Multifunctional magnetic nanoparticles.
We have been exploring multifunctional magnetic nanoparticles (MNPs) as bionanomaterials. We demonstrated the first use of biofunctionalized MNPs to capture bacteria at ultralow concentration and separate proteins with high selectivity. Subsequently, we developed a robust anchor for attaching various molecules on iron oxide MNPs, and unexpectedly found a simple process for producing the first multifunctional MNP that is both fluorescent and magnetic. We demonstrated the use of MNPs for both MRI imaging and cancer cell inhibition. These findings illustrated the concept, the procedure, and the promises of the integration of molecular interactions with MNPs for biomedical applications, thus sparked the development of multifunctional MNPs for wide ranges of applications in biomedicine, such as bacteria detection, protein manipulation, medical imaging, toxin decorporation, and cancer therapy.
Long, M. J. C.; Pan, Y.; Lin, H.-C.; Hedstrom, L.; Xu, B.* “Cell Compatible Trimethoprim (TMP)-Decorated Iron Oxide Nanoparticles Bind Dihydrofolate Reductase (DHFR) for Magnetically Modulating Focal Adhesion of Mammalian Cells” J. Am. Chem. Soc., 2011, 133, 10006-10009.
Gao, J. H.; Gu, H. W.; Xu, B.* “Multifunctional Magnetic Nanoparticles: Design, Synthesis, and Biomedical Applications” Acc. Chem. Res. 2009, 42, 1097-1107.
Gao, J. H.; Zhang, W.; Huang, P. B.; Zhang, B.; Zhang, X. X.; Xu, B.* “Intracellular Spatial Control of Fluorescent Magnetic Nanoparticles” J. Am. Chem. Soc. 2008, 130, 3710-3711.
Gao, J. H.; Zhang, B.; Gao, Y.; Pan, Y.; Zhang, X. X.; Xu, B.* “Fluorescent Magnetic Nanocrystals by Sequential Addition of Reagents in a One-Pot Reaction: A Simple Preparation for Multifunctional Nanostructures” J. Am. Chem. Soc. 2007, 129, 11928-11935.
Gao, J. H.; Liang, G. L.; Zhang, B.; Kuang, Y.; Zhang, X. X.; Xu, B.* “FePt@CoS2 Yolk-shell Nanocrystals as A Potent Agent to Kill HeLa Cells” J. Am. Chem. Soc. 2007, 129, 1428-1433.
Wang, L.; Yang, Z. M.; Gao, J. H.; Xu, K. M.; Gu, H. W.; Zhang, B.; Zhang, X. X.; Xu, B.* “A Biocompatible Method of Decorporation: Bisphosphonate Modified Magnetite Nanoparticles to Remove Uranyl Ions from Blood” J. Am. Chem. Soc. 2006, 128, 13358-13359.
Gu, H. W.; Yang, Z. M.; Gao, J. H.; Chang, C. K.; Xu, B.* “Heterodimers of Nanoparticles: Formation at a Liquid-Liquid Interface and Particle-Specific Surface Modification by Functional Molecules” J. Am. Chem. Soc. 2005, 127, 34-35.
Gu, H. W.; Zheng, R. K; Zhang, X. X.; Xu, B.* “Facile One-Pot Synthesis of Bifunctional Heterodimers of Nanoparticles: A Conjugate of Quantum Dot and Magnetic Nanoparticles” J. Am. Chem. Soc. 2004, 126, 5664-5665.
5. Active gels.
While most of cross-linkers in synthetic networks are less active, cross-linkers in biopolymer networks are active. For example, the cytoskeleton of muscle cells has myosin motors as the active cross-linkers to crosslink actin filaments. Marveled by this amazing machinery evolution of converting chemical energy to mechanical motion, we have been developing an active cross-linker for construction of novel polymeric hydrogels. The aim of this research is to create an unprecedented molecular architecture for developing active gels as chemomechanical soft materials.
Zhang, Y.; Zhou, N.; Shi, J. F.; Pochapsky, S. S.; Pochapsky, S. S.; Zhang, B.; Zhang, X. X.; Xu, B.* “Unfolding a molecular trefoil derived from a zwitterionic metallopeptide to form self-assembled nanostructures” Nat. Commun. 2015, 6, 6165.
Zhang, Y.; Zhou, N.; Li, N.; Sun, M.; Kim, D.; Fraden, S. *; Epstein, I. E. *; Xu, B.* “Giant Volume Change of Active Gels under Continuous Flow” J. Am. Chem. Soc., 2014, 136, 7341-7346.
Zhang, Y.; Zhou, N.; Akella, S.; Kuang, Y.; Kim, D.; Schwartz, A.; Bezpalko, M.; Foxman, B. M.; Fraden, S.; Epstein, I. R.*;Xu, B.* “Active Cross-linkers that Lead to Active Gels” Angew. Chem. Int. Ed. 2013, 52, 11494-11498.
6. Artificial enzymes.
While the mimic of enzyme aims to preserve the essence of enzymes in a simpler system than proteins, industrial biotransformation demands high activity and stability of enzymes. Recent researches suggest that small peptide-based nanofibers in the form of molecular hydrogels can provide a general platform to achieve both important goals. Our research activities on small peptide-based nanomaterials for catalysis hope to provide practical applications of enzymes and enzyme mimic for addressing important societal problems in energy, environment, and health.
Gao, Y.;Zhao, F.; Wang, L.; Zhang, Y.; Xu, B.* “Small Peptide Nanofibers as the Matrices of Molecular Hydrogels for Mimicking Enzymes and Enhancing the Activity of Enzymes”, Chem. Soc. Rev. 2010, 39, 3425-3433.
Wang, Q. G.; Li, L. H.; Xu, B.* “Bioinspired Supramolecular Confinement of Luminol and Heme Proteins to Enhance Chemiluminescent Quantum Yield” Chem. Eur. J., 2009, 15, 3168-3172.
Wang, Q. G.; Yang, Z. M.; Ma, M. L.; Chang, C. K.*; Xu, B.* “High Catalytic Activities of Artificial Peroxidase Based on Supramolecular Hydrogel Containing Heme Models” Chem. Eur. J., 2008, 14, 5073-5078.
Wang, Q.G.; Yang, Z. M.; Zhang, X. Q.; Xiao, X. D.; Chang, C. K.*; Xu, B.* “A Supramolecular Hydrogel-Encapsulated Hemin as an Artificial Enzyme to Mimic Peroxidase” Angew. Chem. Int. Ed., 2007, 46, 4285-4289
Metallogels are a growing class of soft matters that consist of coordination bonds as the key driving force for maintaining the three-demension networks of the gels. We coined the term of "metallogel" and demonstrated the first catalytic metallogels.
Zhang, Y.; Zhang, B.; Kuang, Y.; Gao, Y.; Shi, J.; Zhang, X. X.; Xu, B.* “A Redox Responsive, Fluorescent Supramolecular Metallohydrogel Consists of Nanofibers with Single-Molecule Width” J. Am. Chem. Soc., 2013, 135, 5008-5011
Xing, B. G.; Choi, M.-F.; Xu, B.* “Spontaneous Enrichment of Organic Molecules from Aqueous and Gas Phases Into A Stable Metallogel” Langmuir, 2002, 18, 9654-9658.
Xing, B. G.; Choi, M.-F.; Xu, B.* “Design of Coordination Polymer Gels as Stable Catalytic Systems” Chem. Eur. J. 2002, 8, 5028-5032.
Xing, B. G.; Choi, M.-F.; Xu, B.* “A Stable Metal Coordination Polymer Gel Based on A Calixarene and Its ‘Uptake’ of Nonionic Organic Molecules from the Aqueous Phase” Chem. Commun., 2002, 362.