An Activatable Host–Guest Conjugate as a Nanocarrier for Effective Drug Release through Self-Inclusion

Abstract

There is a challenge in supramolecular chemotherapy for constructing a system equipped with both sufficient protection and high-efficiency release of drugs. To this end, a new strategy of an activatable host–guest conjugate with self-inclusion property is proposed. Based on the binding affinity gain of intramolecular host–guest self-inclusion, an activatable host–guest conjugate was designed, bearing cucurbit[7]­uril as the host, an alkyl ammonium moiety as the guest, and the redox-responsive disulfide linkage. Oxaliplatin, a clinical antitumor drug, could be firmly encapsulated by the activatable host–guest conjugate to form the supramolecular drug with high stability. Moreover, oxaliplatin loaded in the activatable host–guest conjugate could be almost completely released by self-inclusion triggered by glutathione in a tumor microenvironment, thus exhibiting comparable antitumor bioactivity with naked oxaliplatin through in vitro cell experiments. It is highly anticipated that this line of research may open new horizons for programmable and on-demand supramolecular chemotherapy with high antitumor efficiency.

Supramolecular Biopharmaceutical Carriers Based on Host–Guest Interactions

“…Wu and co-workers used disulfide bonds to link two CB [7] spacer alkylammonium conjugates to form an activatable host−guest conjugate named DCBSS. 86 This system can encapsulate the drug oxaliplatin molecule through host−guest interaction, and due to the nature of the disulfide bond in the system that is reducible to thiol, it can trigger the self-inclusion of CB [7] and alkylammonium, resulting in the effective release of oxaliplatin. In another way, Yue and coworkers developed CB [7] covalently modified Fe 3 O 4 NPs, which later enabled CB [7] to bind to amantadine via host− guest interactions, ultimately enabling targeted drug delivery and specific drug release.…”

“…The other enables drug release through a functional bond between two CB­[ n ]­s groups. Wu and co-workers used disulfide bonds to link two CB[7] spacer alkylammonium conjugates to form an activatable host–guest conjugate named DCBSS . This system can encapsulate the drug oxaliplatin molecule through host–guest interaction, and due to the nature of the disulfide bond in the system that is reducible to thiol, it can trigger the self-inclusion of CB[7] and alkylammonium, resulting in the effective release of oxaliplatin.…”

Mitochondria-Targeted Self-Assembly of Peptide-Based Nanomaterials

“…However, this covalent approach suffers from the long reaction time (e.g., 2 days) and the competitive reactions from the thiol and amine groups. To construct a fast and simple method for systemic delivery of peptide pharmaceuticals, Wang et al based on the concept of non-covalent supramolecular chemotherapy (Chen et al, 2017;Chen et al, 2018a;Wu et al, 2021), proposed a strategy of supramolecular peptide therapeutics . Owning to the strong host-guest interaction between the cucurbit[7]uril (CB[7]) and N-terminal phenylalanine (N-Phe) residue in the peptide (binding constant ∼2 × 10 6 M −1 ), the N-Phe-containing KLAK peptides were carried by the CB[7]-PEG copolymers in a simple (mixing in the aqueous solution) and fast (several minutes) manner with a high peptide encapsulation efficiency (>97%) under the peptide concentration of 0.5 mM.…”

Understanding of supramolecular solution polymerization and interfacial polymerization via forming multiple hydrogen bonds: a computer simulation study

“…Supramolecular polymers refer to chain-like aggregates of monomers linked by non-covalent bonds, which are held together by highly directional secondary and reversible interactions and possess polymeric properties in solution and in bulk. 1,2 The non-covalent bonds can be multiple hydrogen bonds, [3][4][5][6][7][8] p-p interactions, [9][10][11][12][13][14] host-guest interactions [15][16][17][18][19][20] and metal coordination interactions. [21][22][23][24][25] Supramolecular polymers have self-healing, degradable, and regenerative properties, which are often used to design responsive, self-healing, and environmentally friendly materials.…”