Cyclodextrin-Mediated Hierarchical Self-Assembly and Its Potential in Drug Delivery Applications  Iurii Antoniuk, Catherine Amiel  Journal of Pharmaceutical Sciences  Volume 105, Issue 9, Pages 2570-2588 (September 2016) DOI: 10.1016/j.xphs.2016.05.010 Copyright © 2016 American Pharmacists Association® Terms and Conditions

Figure 1 Levels of hierarchical self-assembly of collagen. Reproduced from Elemans et al.3 Journal of Pharmaceutical Sciences 2016 105, 2570-2588DOI: (10.1016/j.xphs.2016.05.010) Copyright © 2016 American Pharmacists Association® Terms and Conditions

Figure 2 Components and formulation principle of the siRNA targeted delivery system CALAA-01. The supramolecular host-guest complexes are first formed between linear βCDP and bifunctionalized Tf-PEG-Ada in the Vial 2; upon mixing with the siRNA (Vial), they hierarchically self-assemble into sterically stabilized targeted nanoparticles. Adapted from Davis.47 Journal of Pharmaceutical Sciences 2016 105, 2570-2588DOI: (10.1016/j.xphs.2016.05.010) Copyright © 2016 American Pharmacists Association® Terms and Conditions

Figure 3 (a) Formulation of CD-PEI nanoparticles by condensation between plasmid DNA and positively charged βCD-grafted PEI; (b) Immobilization of the resulting polyCDplexes onto Ada modifies surface via multivalent inclusion interactions. Adapted from Park et al.59 Journal of Pharmaceutical Sciences 2016 105, 2570-2588DOI: (10.1016/j.xphs.2016.05.010) Copyright © 2016 American Pharmacists Association® Terms and Conditions

Figure 4 (a) Schematic illustration of the polyCDplexe hierarchical self-assembly among pβCD, cationic connector, and DNA; (b) chemical structures of various Ada-connectors; (c) Transmission electron microscopy images illustrating the evolution of plasmid DNA compaction degree as a function of the amount of cationic connector Ada5 associated with prior polyCDplexe formation (pβCD/Ada5/DNA = 20/X/1). The first image (X = 0) represents free pDNA in water. Adapted from Wintgens et al.62 Journal of Pharmaceutical Sciences 2016 105, 2570-2588DOI: (10.1016/j.xphs.2016.05.010) Copyright © 2016 American Pharmacists Association® Terms and Conditions

Figure 5 Formulation of supramolecular gene vectors: (a) rotaxanation of the PCL block of the brPEI-PCL-PEG ternary copolymer by inclusion complexation with α-cyclodextrin; (b) formation of polyplexes via electrostatic association with DNA. Adapted from Shuai et al.66 Journal of Pharmaceutical Sciences 2016 105, 2570-2588DOI: (10.1016/j.xphs.2016.05.010) Copyright © 2016 American Pharmacists Association® Terms and Conditions

Figure 6 (a) Chemical structures of used guest (PPEGMA-co-PHEMA-AD) and host (PHPMAco-PPMA-DOX-CD) polymers with pH-sensitive AD-benzoic imine (cleaved at pH 6.5) and DOX-hydrazone (cleaved at pH 5) links respectively; (b) schematic illustration of the formation of host-guest self-assemblies and their dual pH-responsive rearrangement endolysosomal internalization and drug release. Adapted from Zan et al.77 Journal of Pharmaceutical Sciences 2016 105, 2570-2588DOI: (10.1016/j.xphs.2016.05.010) Copyright © 2016 American Pharmacists Association® Terms and Conditions

Figure 7 Formation of hierarchical core-shell nanoparticles for delivery of doxorubicin with switchable tumor cell triggered targeting and release. Reproduced from Quan et al.80 Journal of Pharmaceutical Sciences 2016 105, 2570-2588DOI: (10.1016/j.xphs.2016.05.010) Copyright © 2016 American Pharmacists Association® Terms and Conditions

Figure 8 Schematic representation of the formation and redox-triggered disassembly of the TPPC6-SS-Ada/PEG-βCD hierarchical micelles for photodynamic therapy. Adapted from Liu et al.83 Journal of Pharmaceutical Sciences 2016 105, 2570-2588DOI: (10.1016/j.xphs.2016.05.010) Copyright © 2016 American Pharmacists Association® Terms and Conditions

Figure 9 Schematic illustration of the proposed mechanism of the hydrophobic self-assembly and competitor-induced disassembly of the βCD/tyrosine-based hierarchical vesicles. Reproduced from Ma et al.84 Journal of Pharmaceutical Sciences 2016 105, 2570-2588DOI: (10.1016/j.xphs.2016.05.010) Copyright © 2016 American Pharmacists Association® Terms and Conditions

Figure 10 Doxorubicin and apoptosis-inducing pDNA co-delivery system obtained via 2-step host-guest mediated hierarchical self-assembly. Adapted from Fan et al.85 Journal of Pharmaceutical Sciences 2016 105, 2570-2588DOI: (10.1016/j.xphs.2016.05.010) Copyright © 2016 American Pharmacists Association® Terms and Conditions

Figure 11 Host-guest mediated bricks and mortar approach for the preparation of size-controlled Au-SNPs. Reproduced from Wang et al.87 Journal of Pharmaceutical Sciences 2016 105, 2570-2588DOI: (10.1016/j.xphs.2016.05.010) Copyright © 2016 American Pharmacists Association® Terms and Conditions

Figure 12 Schematic illustration of the βCD-P-coated nanoMOF host-guest PEGylation strategy. Adapted from Agostoni et al.95 Journal of Pharmaceutical Sciences 2016 105, 2570-2588DOI: (10.1016/j.xphs.2016.05.010) Copyright © 2016 American Pharmacists Association® Terms and Conditions

Figure 13 Schematic illustration of the 2-step hierarchical CD-PPRTX gel formation mechanism: (a) hydrophobically driven inclusion of high molecular weight PEG chains into αCD; (b) hydrogen bonding between the threaded αCD microcrystalline domains leading to gelation. Adapted from Liu et al.107 Journal of Pharmaceutical Sciences 2016 105, 2570-2588DOI: (10.1016/j.xphs.2016.05.010) Copyright © 2016 American Pharmacists Association® Terms and Conditions

Figure 14 Schematic illustration of the inclusion-driven formation of αCD/PEG-PHB-PEG polypseudorotaxane (a) and αCD/PEG-PHB-PEG-based doubly cross-linked hydrogel (b). Adapted from Li et al.109 Journal of Pharmaceutical Sciences 2016 105, 2570-2588DOI: (10.1016/j.xphs.2016.05.010) Copyright © 2016 American Pharmacists Association® Terms and Conditions

Figure 15 Schematic illustration of the preparation of αCD/PEG PPRTX hierarchical hydrogels containing pDNA polyplexes for gene transfection and sustained release. Reproduced from Li et al.116 Journal of Pharmaceutical Sciences 2016 105, 2570-2588DOI: (10.1016/j.xphs.2016.05.010) Copyright © 2016 American Pharmacists Association® Terms and Conditions

Figure 16 Illustration of the star-star supramolecular complex formation via βCD/Ada inclusion complexation, followed by its temperature-triggered hierarchical hydrogelation. Reproduced from Zhang et al.123 Journal of Pharmaceutical Sciences 2016 105, 2570-2588DOI: (10.1016/j.xphs.2016.05.010) Copyright © 2016 American Pharmacists Association® Terms and Conditions

Figure 17 Schematic illustration of the formation and temperature- or competitor-triggered dissociation of QD-containing hierarchical hydrogels made of HIC. Reproduced from Liu et al.99 Journal of Pharmaceutical Sciences 2016 105, 2570-2588DOI: (10.1016/j.xphs.2016.05.010) Copyright © 2016 American Pharmacists Association® Terms and Conditions

Figure 18 Schematic illustration of the UV/Vis irradiation and competitor binding responsiveness of the bacteriophage M13-βCD/HA-Azo hierarchical hydrogel. Reproduced from Chen et al.128 Journal of Pharmaceutical Sciences 2016 105, 2570-2588DOI: (10.1016/j.xphs.2016.05.010) Copyright © 2016 American Pharmacists Association® Terms and Conditions

Figure 19 Schematic illustration of the formation of hierarchical chemically responsive hydrogels containing amphiphilic βCD supramolecular vesicles as cross-linking points. Adapted from Himmelein et al.101 Journal of Pharmaceutical Sciences 2016 105, 2570-2588DOI: (10.1016/j.xphs.2016.05.010) Copyright © 2016 American Pharmacists Association® Terms and Conditions