Triterpenoid-Based Self-Healing Supramolecular Polymer Hydrogels Formed by Host-Guest Interactions.

Pentacyclic triterpenoids, a class of naturally bioactive products having multiple functional groups, unique chiral centers, rigid skeletons, and good biocompatibility, are ideal building blocks for fabricating versatile supramolecular structures. In this research, the natural pentacyclic triterpenoid glycyrrhetinic acid (GA) was used as a guest molecule for β-cyclodextrin (β-CD) to form a GA/β-CD (1:1) inclusion complex. By means of GA and β-CD pendant groups in N,N'-dimethylacrylamide copolymers, a supramolecular polymer hydrogel can be physically cross-linked by host-guest interactions between GA and β-CD moieties. Moreover, self-healing of this hydrogel was observed and confirmed by step-strain rheological measurements, whereby the maximum storage modulus occurred at a [GA]/[β-CD] molar ratio of 1:1. Additionally, these polymers displayed outstanding biocompatibility. The introduction of a natural pentacyclic triterpenoid into a hydrogel system not only provides a biocompatible guest-host complementary GA/β-CD pair, but also makes this hydrogel an attractive candidate for tissue engineering.

[1]  X. Zhu,et al.  Thermoresponsiveness of copolymers bearing cholic acid pendants induced by complexation with β-cyclodextrin. , 2014, Langmuir : the ACS journal of surfaces and colloids.

[2]  Wei Wang,et al.  A Mechanically Strong, Highly Stable, Thermoplastic, and Self‐Healable Supramolecular Polymer Hydrogel , 2015, Advanced materials.

[3]  B. G. Bag,et al.  Hierarchical Self-Assembly of a Renewable Nanosized Pentacyclic Dihydroxy-triterpenoid Betulin Yielding Flower-Like Architectures. , 2015, Langmuir : the ACS journal of surfaces and colloids.

[4]  Jun Hu,et al.  First preparation of a triterpenoid-based supramolecular hydrogel in physiological phosphate buffered saline, , 2015 .

[5]  Feihe Huang,et al.  A self-healing supramolecular polymer gel with stimuli-responsiveness constructed by crown ether based molecular recognition , 2013 .

[6]  Y. Ju,et al.  A new dual-responsive organogel based on uracil-appended glycyrrhetinic acid. , 2011, Organic letters.

[7]  K. Sasaki,et al.  Effects of triterpene compounds on cytotoxicity, apoptosis, and immune response in cultured cells , 2006, Journal of Natural Medicines.

[8]  S. Choi,et al.  Schaltbare Hydrogele durch supramolekulare Vernetzung adamantylhaltiger LCST‐Copolymere mit Cyclodextrin‐Dimeren , 2006 .

[9]  B. G. Bag,et al.  Self-assembly of a renewable nano-sized triterpenoid 18β-glycyrrhetinic acid , 2012 .

[10]  R. Supino,et al.  Selective cytotoxicity of betulinic acid on tumor cell lines, but not on normal cells. , 2002, Cancer letters.

[11]  Jianxun Ding,et al.  Self-Healing Supramolecular Self-Assembled Hydrogels Based on Poly(L-glutamic acid). , 2015, Biomacromolecules.

[12]  Justin R. Kumpfer,et al.  Optically healable supramolecular polymers , 2011, Nature.

[13]  R. Prud’homme,et al.  Host–guest chemistry of linked β-cyclodextrin trimers and adamantyl substituted poly(acrylate)s in aqueous solution , 2013 .

[14]  Y. Ju,et al.  Steroid/triterpenoid functional molecules based on "click chemistry". , 2011, Chemistry, an Asian journal.

[15]  L. Lyon,et al.  Autonomic self-healing of hydrogel thin films. , 2010, Angewandte Chemie.

[16]  N. Miura,et al.  Protective effects of triterpene compounds against the cytotoxicity of cadmium in HepG2 cells. , 1999, Molecular pharmacology.

[17]  Jun Hu,et al.  A simple oleanlic acid derivative as potent organogelator , 2009 .

[18]  Jun Hu,et al.  Water-induced gel formation of an oleanlic acid–adenine conjugate and the effects of uracil derivative on the gel stability , 2012 .

[19]  R. Mezzenga,et al.  Fibrillar networks of glycyrrhizic acid for hybrid nanomaterials with catalytic features. , 2015, Angewandte Chemie.

[20]  Jie Zheng,et al.  A Novel Design Strategy for Fully Physically Linked Double Network Hydrogels with Tough, Fatigue Resistant, and Self‐Healing Properties , 2015 .

[21]  Jie Hao,et al.  Solvent-Directed Assembly of a Pyridinium-Tailored Methyl Oleanolate Amphiphile: Stepwise Growth of Microrods and Nanofibers. , 2016, Langmuir : the ACS journal of surfaces and colloids.

[22]  Akira Harada,et al.  Switchable hydrogels obtained by supramolecular cross-linking of adamantyl-containing LCST copolymers with cyclodextrin dimers. , 2006, Angewandte Chemie.

[23]  M. Meneghetti,et al.  Self-healing at the nanoscale. , 2009, Nanoscale.

[24]  Akira Harada,et al.  Redox-responsive self-healing materials formed from host–guest polymers , 2011, Nature communications.

[25]  B. G. Bag,et al.  First self-assembly study of betulinic acid, a renewable nano-sized, 6-6-6-6-5 pentacyclic monohydroxy triterpenic acid. , 2011, Nanoscale.

[26]  Marita Hernández,et al.  Beneficial actions of oleanolic acid in an experimental model of multiple sclerosis: a potential therapeutic role. , 2010, Biochemical pharmacology.

[27]  P. Das,et al.  18β‐glycyrrhetinic acid induces apoptosis through modulation of Akt/FOXO3a/Bim pathway in human breast cancer MCF‐7 cells , 2012, Journal of cellular physiology.

[28]  M. Yin,et al.  Antioxidative and anti-inflammatory protection of oleanolic acid and ursolic acid in PC12 cells. , 2008, Journal of food science.

[29]  X. Zhu,et al.  Self-Healing Supramolecular Hydrogel Made of Polymers Bearing Cholic Acid and β-Cyclodextrin Pendants , 2015 .

[30]  S. Moochhala,et al.  Ultrashort peptide nanofibrous hydrogels for the acceleration of healing of burn wounds. , 2014, Biomaterials.

[31]  G. Maity,et al.  A Terpenoid-based Gelator: The First Arjunolic Acid-derived Organogelator for Alcohols and Mixed Solvents , 2005 .

[32]  Qiang Yan,et al.  Therapeutic-Ultrasound-Triggered Shape Memory of a Melamine-Enhanced Poly(vinyl alcohol) Physical Hydrogel. , 2015, ACS applied materials & interfaces.

[33]  B. G. Bag,et al.  Vesicular and Fibrillar Gels by Self‐Assembly of Nanosized Oleanolic Acid , 2012 .

[34]  Ye Shi,et al.  A Conductive Self-Healing Hybrid Gel Enabled by Metal-Ligand Supramolecule and Nanostructured Conductive Polymer. , 2015, Nano letters.

[35]  P. Dey,et al.  Self-assembly of esters of arjunolic acid into fibrous networks and the properties of their organogels. , 2009, Langmuir : the ACS journal of surfaces and colloids.

[36]  O. Okay,et al.  Self-Healing Poly(acrylic acid) Hydrogels with Shape Memory Behavior of High Mechanical Strength , 2014 .

[37]  Maurizio Prato,et al.  Nanocomposite Hydrogels: 3D Polymer-Nanoparticle Synergies for On-Demand Drug Delivery. , 2015, ACS nano.

[38]  Yu Liu,et al.  Thermodynamic origin of selective binding of β-cyclodextrin derivatives with chiral chromophoric substituents toward steroids. , 2010, The journal of physical chemistry. B.

[39]  Yoshihito Osada,et al.  Self-healing gels based on constitutional dynamic chemistry and their potential applications. , 2014, Chemical Society reviews.

[40]  A. Hashidzume,et al.  Interaction of cyclodextrins with side chains of water soluble polymers: A simple model for biological molecular recognition and its utilization for stimuli-responsive systems , 2006 .

[41]  D. Pioletti,et al.  Controlled release from a mechanically-stimulated thermosensitive self-heating composite hydrogel. , 2014, Biomaterials.

[42]  B. G. Bag,et al.  Vesicular self-assembly of a natural triterpenoid arjunolic acid in aqueous medium: study of entrapment properties and in situ generation of gel–gold nanoparticle hybrid material , 2014 .

[43]  K. Lee,et al.  Anti-AIDS agents. 30. Anti-HIV activity of oleanolic acid, pomolic acid, and structurally related triterpenoids. , 1998, Journal of natural products.

[44]  Jun Hu,et al.  Self-assembly of sodium glycyrrhetinate into a hydrogel: characterisation and properties† , 2013 .

[45]  Jun Hu,et al.  Supramolecular helical nanofibers assembled from a pyridinium-functionalized methyl glycyrrhetate amphiphile. , 2015, Nanoscale.

[46]  Akira Harada,et al.  Photoswitchable gel assembly based on molecular recognition , 2012, Nature Communications.

[47]  Jun Li,et al.  A thermoresponsive hydrogel formed from a star-star supramolecular architecture. , 2013, Angewandte Chemie.

[48]  Loes M. J. Kroon-Batenburg,et al.  Supramolecular hydrogels formed by β-cyclodextrin self-association and host–guest inclusion complexes , 2010 .

[49]  R. Kasi,et al.  Stimuli-responsive polymer gels. , 2008, Soft matter.

[50]  G. Jiang,et al.  Leading neuroblastoma cells to die by multiple premeditated attacks from a multifunctionalized nanoconstruct. , 2011, Journal of the American Chemical Society.

[51]  T. Yamaguchi,et al.  An Autonomous Phase Transition−Complexation/Decomplexation Polymer System with a Molecular Recognition Property , 2006 .

[52]  C. Highley,et al.  Direct 3D Printing of Shear‐Thinning Hydrogels into Self‐Healing Hydrogels , 2015, Advanced materials.

[53]  C. Klaassen,et al.  Oleanolic acid activates Nrf2 and protects from acetaminophen hepatotoxicity via Nrf2-dependent and Nrf2-independent processes. , 2009, Biochemical pharmacology.

[54]  B. Sébille,et al.  Association between amphiphilic poly(ethylene oxide) and β-cyclodextrin polymers: aggregation and phase separation , 1999 .

[55]  A. Eschenmoser,et al.  Revisited after 50 Years: The `Stereochemical Interpretation of the Biogenetic Isoprene Rule for the Triterpenes' , 2005 .