Hydrophobic pharmaceuticals mediated self-assembly of β-cyclodextrin containing hydrophilic copolymers: Novel chemical responsive nano-vehicles for drug delivery

A poly(ethylene glycol)‐b‐poly(L‐lysine) diblock copolymer (PEG‐b‐PLL) was synthesized. Micellization of this hydrophilic copolymer due to the block‐specific threading of α‐cyclodextrin (α‐CD) molecules onto the polyethylene glycol (PEG) block yielded supramolecular‐structured nanoparticles, which undergoes pH‐inducible gelation in aqueous media. The pH‐inducible gelation of supramolecular micelle in water appeared to be completely reversible upon pH changes. The synergetic effect of selective complexation between PEG block and α‐CD and the pH‐inducible hydrophobic interaction between PLL blocks at pH 10 was believed to be the driving force for the formation of the supramolecular hydrogel. 1H NMR and wide angle X‐ray diffraction (WAXD) were employed to confirm the inclusion complexation between α‐CD and PEG block. Meanwhile, the morphology of the micellized nanoparticles was investigated by transmission electron microscopy (TEM). The thermal stability of inclusion complexes (ICs) was investigated and the rheologic experiment was conducted to reveal the micelle‐gel transition. Such pH‐induced reversible micelle‐gel transition of the supramolecular aggregates may find applications in several fields, for example as advanced biomedical material possessing stimulus‐responsiveness. © 2008 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 46: 782–790, 2008

CONSPECTUS: Cyclodextrins (CDs) have many attractive functions, including molecular recognition, hydrolysis, catalysis, and polymerization. One of the most important uses of CDs is for the molecular recognition of hydrophobic organic guest molecules in aqueous solutions. CDs are desirable host molecules because they are environmentally benign and offer diverse functions. This Account demonstrates some of the great advances in the development of supramolecular materials through host-guest interactions within the last 10 years. In 1990, we developed topological supramolecular complexes with CDs, polyrotaxane, and CD tubes, and these preparation methods take advantage of self-organization between the CDs and the polymers. The combination of polyrotaxane with αCD forms a hydrogel through the interaction of αCDs with the OH groups on poly(ethylene glycol). We categorized these polyrotaxane chemistries within main chain type complexes. At the same time, we studied the interactions of side chain type supramolecular complexes with CDs. In these systems the guest molecules modified the polymers and selectively formed inclusion complexes with CDs. The systems that used low molecular weight compounds did not show such selectivity with CDs. The multivalency available within the complex cooperatively enhances the selective binding of CD with guest molecules via the polymer side chains, a phenomenon that is analogous to binding patterns observed in antigen-antibody complexes. To incorporate the molecular recognition properties of CDs within the polymer side chains, we first prepared stimuli-responsive sol-gel switching materials through host-guest interactions. We chose azobenzene derivatives for their response to light and ferrocene derivatives for their response to redox conditions. The supramolecular materials were both redox-responsive and self-healing, and these properties resulted from host-guest interactions. These sol-gels with built in switches gave us insight for creating materials that were self-healing or could serve as artificial muscle. Furthermore, we developed another self-healing material with CD inclusion complexes that showed selective self-healing properties after its surface was cut. These CD self-healing materials do not include chemical cross-linkers; instead the inclusion complex of CDs with guest molecules stabilized the material's strength. However, by introducing chemical cross-linkers into the hydrogels, we produced materials that could expand and contract. The chemical cross-linked hydrogels with responsive groups bent in response to external stimuli, and the cross-linkers controlled the ratio of inclusion complexes. Furthermore, we used the molecular recognition of CDs to achieve macroscopic self-assemblies, and this chemistry can direct these macroscopic objects into even larger aggregated structures. As we have demonstrated, reversible host-guest interactions have tremendous potential for the creation of a wide variety of functional materials.

Injectable amphiphilic hydrogel systems from the self-assembly of partially alkylated poly(2-dimethyl aminoethyl) methacrylate with inherent antimicrobial property and sustained release behaviour

A novel cyclodextrin-containing star polymer was synthesized by atom transfer radical polymerization using the arm-first approach. Copolymerization of a mixture of mono- and multi-methacrylate substituted cyclodextrin and 2-(dimethylamino) ethyl methacrylate initiated by poly(ethylene glycol) macroinitiator produced a core cross-linked star polymer. The star polymer could self-assemble into nanostructures via host–guest interactions between the cyclodextrin polymer and hydrophobic guest molecules. The morphologies of these nanostructures showed regular transitions by altering the type of guest molecule, the ratio of star polymer to guest, and the pH of the solution. Furthermore, doxorubicin (DOX) was entrapped into the star polymer for the purpose of drug delivery. In vitro experiments demonstrated that the DOX-loaded nanoparticles could release their payload in response to the endosomal-pH after being internalized by HeLa cell via endocytosis. At high DOX concentration, DOX-loaded nanoparticles showed significantly higher cell cytotoxicity compared to the free drug. The results indicate that the star polymer has great promise for potential anticancer treatment.

Poly(ethylene glycol)-b-poly(2-(diethylamino)ethyl methacrylate-co-2-cinnamoyloxyethyl acrylate) (PEG-b-P(DEAEMA/CEA)) was prepared by reversible addition-fragmentation chain transfer (RAFT)-controlled radical polymerization. As solution pH is increased from an acidic pH, the hydrodynamic radius (R(h)) increases abruptly near pH 7, indicative of the micelle formation at pH > 7. The micelle formation at pH > 7 was supported by (1)H NMR and light scattering data. Upon irradiation of light, polymer chains in the core of the polymer micelle are cross-linked as a result of the photodimerization of the cinnamoyl groups, yielding a nanogel. The nanogel was characterized by gel-permeation chromatography (GPC), light scattering, small-angle X-ray scattering (SAXS), transmission electron microscopy (TEM), and fluorescence techniques. The nanogel displayed an ability to solubilize N-phenyl-1-naphthylamine (PNA) and 1-pyrenemethanol (hydrophobic guest molecules) into the hydrophobic core at pH > 7. It was confirmed with PNA that the solubilization of a guest molecule occurred at polymer concentrations (C(p)) lower than the critical micelle concentration (cmc) for PEG-b-P(DEAEMA/CEA) because the nanogel retains its micellar structure at C(p) < cmc. 1-Pyrenemethanol is strongly captured by the nanogel at pH 10, whereas it is easily released from the nanogel when pH is reduced to 3. This indicates that the hydrophobicity of the core of the nanogel can be modulated by a change in the degree of protonation of the DEAEMA units in the core, and thus the capture of a guest molecule and its release can be controlled by a change in solution pH.

Pagoda[5]arene (P5), which is composed of five 2,6-dimethoxylanthracene (2,6-DMA) subunits bridged by methylene groups at 1,5 positions, was conveniently synthesized in 43% by trifluoroacetic acid ...

A series of well‐defined double hydrophilic graft copolymers containing poly[poly(ethylene glycol) methyl ether acrylate] (PPEGMEA) backbone and poly[poly(ethylene glycol) ethyl ether methacrylate] (PPEGEEMA) side chains were synthesized by the combination of single electron transfer‐living radical polymerization (SET‐LRP) and atom transfer radical polymerization (ATRP). The backbone was first prepared by SET‐LRP of poly(ethylene glycol) methyl ether acrylate macromonomer using CuBr/tris(2‐(dimethylamino)ethyl)amine as catalytic system. The obtained comb copolymer was treated with lithium diisopropylamide and 2‐bromoisobutyryl bromide to give PPEGMEA‐Br macroinitiator. Finally, PPEGMEA‐g‐PPEGEEMA graft copolymers were synthesized by ATRP of poly(ethylene glycol) ethyl ether methacrylate macromonomer using PPEGMEA‐Br macroinitiator via the grafting‐from route. The molecular weights of both the backbone and the side chains were controllable and the molecular weight distributions kept narrow (Mw/Mn ≤ 1.20). This kind of double hydrophilic copolymer was found to be stimuli‐responsive to both temperature and ion (0.3 M Cl− and SO). © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 647–655, 2010

Simultaneous quantitative recognition of all purines including N6-methyladenine via the host-guest interactions on a Mn-MOF

Event Abstract Back to Event Glyco-nanoparticles toward nanobiological applications: Synthesis and controlled self-assembly of poly-/oligosaccharide containing block copolymers Issei Otsuka1*, Sami Halila1* and Redouane Borsali1* 1 CERMAV-CNRS, Grenoble Alpes University, Physico-chemistry and self-assembly of glycopolymers, France Introduction: Self-assembly of amphiphilic block copolymers (BCPs) that consist of biomacromolecules as one of their building blocks has attracted growing interest in nanobiological applications. Poly-/oligosaccharides are one of the most abundant biomacromolecules which can be obtained from biomass. Thus, our research group has reported various oligosaccharide containing BCPs and their self-assembly in solution and film states. In this presentation, we focus on controlled self-assembly of the oligosaccharide containing BCPs into glyco-nanoparticles in aqueous media for therapeutic molecular delivery application. Materials and Methods: The oligosaccharide containing BCPs were synthesized through copper-catalyzed azide-alkyne cycloaddition of propargyl-functionalized oligosaccharides (maltoheptaose (MH), xyloglucan oligosaccharides (XGO), and beta-cyclodextrin (CD)) with azido end-functionalized polymers (PS, PMMA, PCL and PNIPAM). Self-assembly of the oligosaccharide containing BCPs were performed mainly by nanoprecipitation and thermal aggregation methods. The details were reported in our related publications[1]-[6]. Results: The oligosaccharide containing BCPs such as MH-b-PS and MH-b-PMMA were self-assembled into micellar nanoparticles that consist of hydrophilic oligosaccharide shells and hydrophobic polymer cores in aqueous media. The BCPs composed of oligosaccharides and PNIPAM were self-assembled into micellar and vesicular nanoparticles in water by slowly increasing the temperature above the lower critical solution temperature (LCST) of the PNIPAM block. Hydrophobic active guest molecules such as dyes, drugs, and gold nanoparticles were successfully encapsulated into those nanoparticles through self-assembly process. These results were demonstrated by light scattering and imaging techniques including transmission electron microscopy. Discussion: Oligosaccharide containing amphiphilic BCPs can self-assemble into nanoparticles that consist of shells of hydrophilic oligosaccharides and cores of hydrophobic polymers in aqueous media due to energetic repulsion effects between the hydrophobic polymers and water. The hydrophobic guest molecules can be stabilized in the hydrophobic core of the nanoparticles due to hydrophobic effect. Thermo-responsive solubility variation (from hydrophilic to hydrophobic) of the PNIPAM blocks about the LCST induced the self-assembly of the BCPs such as MH-b-PNIPAM. The hydrodynamic radii of those nanoparticles were controlled from tens to hundreds nanometers by this means. Conclusion: The glyco-nanoparticles that can encapsulate active guest molecules were successfully prepared by controlled self-assembly of the oligosaccharide-containing BCPs. The radii of these glyco-nanoparticles were controlled within the size necessary for targeting tumor cells (10-200 nm) by enhanced permeability and retention (EPR) effect. The thermo-responsive formation and dissolution of the glyco-nanoparticles is very important and significant for controlled therapeutic molecular delivery. The authors acknowledge financial support from CNRS, the PolyNat Carnot Institute, and Labex ARCANE (ANR-11-LABX-0003-01).

We report the synthesis of a hydrophilic copolymer with one polyethylene glycol (PEG) block and one β-cyclodextrin (β-CD) containing block by a "click" reaction between azido-substituted β-CD and propargyl flanking copolymer. (1)H NMR study suggested a highly efficient conjugation of β-CD units by this approach. The obtained copolymer was used as a host macromolecule to construct assemblies in the presence of hydrophobic guests. For assemblies containing a hydrophobic polymer, their size can be simply adjusted by simply changing the content of hydrophobic component. By serving as a guest molecule, hydrophobic drugs can also be loaded accompanying the formation of nanoparticles, and the drug payload is releasable. Therefore, the copolymer synthesized herein can be employed as a carrier for drug delivery.

Inter-particle secondary crosslinks allow microporous annealed particle (MAP) hydrogels to be formed. Methods to introduce secondary crosslinking networksin MAP hydrogels include particle jamming, annealing with covalent bonds, and reversible noncovalent interactions. Here, we investigate the effect of two different approaches to secondary crosslinking of polyethylene glycol (PEG) microgels via reversible guest-host interactions. We generated a dual-particle MAP-PEG hydrogel using two species of PEG microgels, one functionalized with the guest molecule, adamantane, and the other with the host molecule, β-cyclodextrin (Inter-MAP-PEG). In a different approach, a mono-particle MAP-PEG hydrogel was generated using one species of microgel functionalized with both guest and host molecules (Intra-MAP-PEG). The Intra-MAP-PEG formed a homogenous distribution due to the single type of microgels used. We then compared the mechanical properties of these two types of MAP-PEG hydrogels and found that Intra-MAP-PEG resulted in significantly softer gels with lower yield stress. We investigated the effect of intra-particle guest-host interactions through titrated weight percentage and the concentration of functional groups added to the hydrogel. We found that there was an ideal concentration of guest-host molecules that enables intra- and inter-particle guest-host interactions with sufficient covalent crosslinking. Based on these studies, Intra-MAP-PEG provides a homogeneous guest-host hydrogel that is shear-thinning with reversible secondary crosslinking.

Combination therapy has been a norm in clinical practice to effectively treat cancer. Besides polytherapy, nowadays, smart and nanobased drug carriers are extensively being explored to deliver drugs according to pathophysiological environment of diseases. In this regard, herein we designed intelligent mesoporous architecture, incorporating both combinational therapy with smart nanotechnology, to simultaneously deliver two highly hydrophobic chemotherapeutic drugs in response to extracellular and/or intracellular acidic environ of tumor. Novelty of the system lies in the employment of acid responsive ZnO QDs to clog not only the nanochannels of mesoporous silica, encapsulating one hydrophobic drug, but also exploitation of chelate forming propensity of another hydrophobic drug (curcumin) to load a significant quantity onto the surface of ZnO nanolids. Cell viability results revealed an extraordinarily high cytotoxic efficiency of that lethal drug cocktail even at a concentration as low as 3 μg/mL nanocarrier. We envision that this sophisticated nanocarrier, which utilizes both interior pore and exterior surface of nanolids for loading different hydrophobic guest molecules and their subsequent acid responsive release, will undoubtedly, illustrates its remarkable potential in targeted chemotherapy.

Cucurbit[7]uril (CB[7]), a representative member of the host family cucurbit[n]uril, can host-guest interact with many guest molecules such as adamantane, viologen and naphthalene derivatives. This host-guest interaction provides an easy strategy in gene vector assembling. Furthermore, CB[7] can self-assemble on gold nanospheres (AuNSs). Herein, the combination of CB[7] and AuNSs provides both advantages of host-guest interaction and photo-thermal effect of AuNSs. In this study, polyethyleneimine (PEI) and polyethylene glycol (PEG) were separately interacted with CB[7] via host-guest interaction. Then by assembling on AuNSs, PEI and PEG were combined together to condense DNA into polyplexes as well as enhance circulation stability of the polyplexes. These gene vectors were found to have high cellular uptake efficiency and low cytotoxicity. Furthermore, the well distributed AuNSs in the polyplexes could transform light into heat under light exposure because of the photo-thermal effect. This was found to effectively promote the entry of gene into cytoplasm and highly enhanced gene transfection efficiency.

We present an extensive analysis of one- and two-photon absorption processes in some organic host-guest (H-G) complexes using linear and quadratic response theory within the framework of time-dependent density functional theory. For this purpose, we have considered all possible 20 host-guest complexes constructed from 4 host and 5 guest molecules. We have analysed how the one- and two-photon activity of the host and guest molecules are transferred to the respective host-guest complexes and how the electron donating and electron accepting ability of host-guest complexes affect their two-photon activity. Based on an analysis using the concept of channel interference, we have performed an in-depth analysis of the two-photon absorption processes in all these systems and provided a microscopic explanation for their variation among different complexes.

Loading and controlled release of sufficient hydrophobic drugs to tumor cells has been the bottleneck in chemotherapy for decades. Herein we report the development of a fluorescent and mesoporous carbon nanoshell (FMP-CNS) that exhibits a loading capacity for the hydrophobic drug paclitaxel (PTX) as high as ∼80 wt% and releases the drug in a controllable fashion under NIR irradiation (825 nm) at an intensity of 1.5 W cm-2. The high drug loading is primarily attributed to its mesoporous structure and to the supramolecular π-stacking between FMP-CNSs and PTX molecules. The FMP-CNS also exhibits wavelength-tunable and upconverted fluorescence properties and thus can serve as an optical marker for confocal, two-photon, and near infrared (NIR) fluorescence imaging. Furthermore, our in vitro results indicate that FMP-CNSs demonstrate high therapeutic efficacy through the synergistic effect of combined chemo-photothermal treatment. In vivo studies demonstrate marked suppression of tumor growth in mice bearing rat C6 glioblastoma after administration with a single intratumoral injection of PTX-loaded FMP-CNS.