Supramolecular nanotheranostics based on pillarenes

Abstract

With the rapid development of supramolecular chemistry and nanomaterials, supramolecular nanotheranostics has attracted remarkable attention owing to the advantages compared with conventional medicine. Supramolecular architectures relying on non-covalent interactions possess reversible and stimuli-responsive features; endowing supramolecular nanotheranostics based on supramolecular assemblies great potentials for the fabrication of integrated novel nanomedicines and controlled drug delivery systems. In particular, pillarenes, as a relatively new class of synthetic macrocycles, are important candidates in the construction of supramolecular therapeutic systems due to their excellent features such as rigid and symmetric structures, facile substitution, and unique host-guest properties. This review summarizes the development of pillarene-based supramolecular nanotheranostics for applications in biological mimicking, virus inhibition, cancer therapy, and diagnosis, which contains the following two major parts: (a) pillarene-based hybrid supramolecular nanotheranostics upon hybridizing with porous materials such as mesoporous silica nanoparticles, metal-organic frameworks, metal nanoparticles, and other inorganic materials; (b) pillarene-based organic supramolecular therapeutic systems that include supramolecular amphiphilic systems, artificial channels, and prodrugs based on host-guest complexes. Finally, perspectives on how pillarene-based supramolecular nanotheranostics will advance the field of pharmaceuticals and therapeutics are given.

Keywords: Drug delivery; hybrid materials; macrocyclic arenes; nanotheranostics; supramolecular chemistry.

Figure 1

Schematic illustration of the classification of pillarene-based supramolecular nanotheranostics. Pillarenes have been hybridized with mesoporous silica nanoparticles (MSNs), metal-organic frameworks (MOFs), metal nanoparticles, graphene oxide, etc. The pillarene-based supramolecular therapeutic systems are mainly constructed from their synthetic modifications, host-guest complexes, and the supramolecular assembly architectures.

Figure 2

(A) Illustration of pillar[5]arene-based supramolecular nanovalve on MSNs, regulating the release of cargos in response to pH changes and competitive agents; (B) Illustration of cargo release from MSN-based nanocarriers in response to acetylcholine. (C) Chemical structures of pillarene derivatives. Reproduced with permission from and , copyright 2013, 2014, respectively, WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Figure 3

Schematic illustrations of (A) pillar[6]arene-based triple-responsive drug delivery system constructed from MSNs; Reproduced with permission from , copyright 2014 American Chemical Society, (B) CP[5]A-based bistable [2]pseudorotaxane-modified MSNs for triple-responsive controlled release; Reproduced with permission from , copyright 2016 Royal Society of Chemistry, (C) near-infrared (NIR) light responsive hybrid nanocontainers embedded with Au nanorods for drug controlled release; Reproduced with permission from , copyright 2017 American Chemical Society, (D) pH-responsive drug delivery systems based on hollow MSNs and pillar[5]arene. Reproduced with permission from , copyright 2019 Royal Society of Chemistry.

Figure 4

Schematic illustration of the construction of pillarene-magnetic nanoparticles-gated hollow MSNs (HMSNs) for magnetic operated, multi-stimuli responsive hormone release to promote the growth of plants. Reproduced with permission from , copyright 2019 Royal Society of Chemistry.

Figure 5

(A) Schematic illustration of stimuli-responsive nanocarriers based on mechanized nanoMOFs with surface-installed, positively-charged stalks encircled by pillarenes. The mechanized UMCM-1-NH₂ nanocarriers can be operated either by pH changes or by competitive binding to regulate the release of cargos such as DOX; (B) Release curves represent the controlled drug delivery performance of MOF-based nanocarriers; Reproduced with permission from , copyright 2015 Royal Society of Chemistry. (C) Illustration of stimuli-responsive mechanized Zr-MOFs, operated by pH changes, Ca²⁺ concentration changes, and heating to regulate the release of 5-Fu. Reproduced with permission from , copyright 2016 Royal Society of Chemistry.

Figure 6

Schematic representation of (A) the fabrication process and operation of CP[6]A-based Fe₃O₄@UiO-66 theranostic nanoplatform and the structures of the representative building blocks; Reproduced with permission from , copyright 2018, WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim, and (B) UiO-66 MOFs serving as nanoplatform for dual targeted chemophotothermal therapy of cervical cancer. Reproduced with permission from , copyright 2018 American Chemical Society.

Figure 7

Schematic illustration of the self-assembly of WP6-stabilized AuNPs and a guest into various hybrid nanostructures in water and the NIR-triggered vesicle-to-micelle transition, resulting in the release of encapsulated calcein. Reproduced with permission from , copyright 2014 Royal Society of Chemistry.

Figure 8

Schematic representation of (A) the construction of upconversion nanoparticle-based nanosystem and its application in drug release and cell imaging; Reproduced with permission from , copyright 2018 American Chemical Society, and (B) the assembly of galactose derivative (G) with CP[5]A on CuS@CP NPs for DOX loading and release. Reproduced with permission from , copyright 2018 American Chemical Society.

Figure 9

(A) Partial X-ray crystal structure of bridged pillar[5]arene, indicating that water molecules (CPK model) were induced to form linear water wires in organic nanotubes (stick model). Reproduced with permission from , copyright 2011, WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. (B) Schematic representation of the increase in vesicle size caused by outside-to-inside water transport. Reproduced with permission from , copyright 2012 American Chemical Society. (C) The structure of artificial channels for amino acids transmission. Reproduced with permission from , copyright 2013 American Chemical Society. (D) Schematic presentation for the voltage-driven channel inserting into and leaving of lipid bilayer. Reproduced with permission from , copyright 2014, WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Figure 10

Schematic diagram of the design of a biomimetic mercury ion-gated nanochannel. Reproduced with permission from , copyright 2014 Royal Society of Chemistry.

Figure 11

Schematic illustration of (A) the inhibition of human papillomavirus 16 L1 pentamer formation by CP[5]A, (B) the stages of biofilm formation, (C) the structures of the two forms of CP6A and SA and their host-guest binding behavior, and (D) the antimicrobial (S. aureus) assay of SA, 1:1 molar ratio of SA and CP6A, and control of 10 eq. CP6A. Reproduced with permission from and , copyright 2014 and 2017 Royal Society of Chemistry. Reproduced with permission from , copyright 2016 American Chemical Society.

Figure 12

Schematic illustration of (A) the fabrication of supramolecular micelles and vesicles self-assembled from amphiphilic modification of pillarenes; (B) Supramolecular micelles and vesicles assembled from host-guest complexation with respective modification. Reproduced with permission from and , copyright 2014 Royal Society of Chemistry. Reproduced with permission from , copyright 2013 American Chemical Society.

Figure 13

Schematic illustration of supramolecular vesicles serving as drug delivery systems to release drug molecules upon activation by (A) magnetic field, (B) redox, and (C) pH, respectively. Reproduced with permission from , copyright 2018 American Chemical Society. Reproduced with permission from , copyright 2017 Royal Society of Chemistry. Reproduced with permission from , copyright 2015, WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Figure 14

Schematic representation of controllable construction of supramolecular prodrug vesicles and micelles with tumor-targeting features and their applications for tumor-targeting drug delivery upon lowing pH. Reproduced with permission from , copyright 2018, WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.