Evaluation of the stability of cucurbit[8]uril-based ternary host−guest complexation in physiological environment and the fabrication of a supramolecular theranostic nanomedicine

Abstract

Background Supramolecular theranostics have exhibited promising potentials in disease diagnosis and therapy by taking advantages of the dynamic and reversible nature of non-covalent interactions. It is extremely important to figure out the stability of the driving forces in physiological environment for the preparation of theranostic systems. Methods The host−guest complexation between cucurbit[8]uril (CB[8]), 4,4′-bipyridinium, and napththyl guest was fully studied using various characterizations, including nuclear magnetic resonance spectroscopy, ultraviolet–visible (UV–vis) spectroscopy, isothermal titration calorimetry (ITC). The association constants of this ternary complex were determined using isothermal titration calorimetry. The stability of the non-covalent interactions and self-assemblies form from this molecular recognition was confirmed by UV–vis spectroscopy and dynamic light scattering (DLS). A supramolecular nanomedicine was constructed on the basis of this 1:1:1 ternary recognition, and its in vitro and in vivo anticancer efficacy were thoroughly evaluated. Positron emission tomography (PET) imaging was used to monitor the delivery and biodistribution of the supramolecular nanomedicine. Results Various experiments confirmed that the ternary complexation between 4,4′-bipyridinium, and napththyl derivative and CB[8] was stable in physiological environment, including phosphate buffered solution and cell culture medium. Supramolecular nanomedicine (SNM@DOX) encapsulating a neutral anticancer drug (doxrubincin, DOX) was prepared based on this molecular recognition that linked the hydrophobic poly(ε-caprolactone) chain and hydrophilic polyethylene glycol segment. The non-covalent interactions guaranteed the stability of SNM@DOX during blood circulation and promoted its tumor accumulation by taking advantage of the enhanced permeability and retention effect, thus greatly improving the anti-tumor efficacy as compared with the free drug. Conclusion Arising from the host-enhanced charge-transfer interactions, the CB[8]-based ternary recognition was stable enough in physiological environment, which was suitable for the fabrication of supramolecular nanotheranostics showing promising potentials in precise cancer diagnosis and therapy. Graphic Abstract

PSMA-Targeted Supramolecular Nanoparticles Prepared From Cucurbit[8]uril-Based Ternary Host–Guest Recognition for Prostate Cancer Therapy

“…In order to further confirm the interactions in the ternary complex, 2D nuclear Overhauser effect spectroscopy (NOESY) NMR was performed in D 2 O The UV-vis absorption spectrum further proved the generation of charge transfer (CT) interactions in the cavity of CB [8] (Figure 1F). Different from the mixture of Nap and MV in aqueous solution, upon adding the addition of CB [8] to the solution containing Nap and MV, a broad absorption band from 400 to 500 nm was observed, which was in accord with the representative CT band (Wu H. et al, 2021) Because the concentration of MV,Nap,and CB [8] used in preparation of SNPs@DOX was low, the absorption related to the CT band was not so apparent (Figure 1H). Moreover, the color of the solution immediately turned to light yellow upon addition of CB [8] into the solution containing Nap and MV (molar ratio = 1:1:1), which directly proved the formation of CT complex (Figure 1F).…”

“…Millipore ultrapure water was obtained on a Milli-Q purification system. MV-PCL and Nap-PEG synthesis method referenced published literature ( Wu H. et al, 2021 ), with the same characterization parameters.…”

“…Furthermore, nanomedicines designed by host–guest chemistry holds stimuli-responsive capability, in which the non-covalent linkages are sensitive to specific tumor microenvironment, facilitating drug accumulation and release at the sites of action ( Appel et al, 2012 ; Busseron et al, 2013 ; Webber et al, 2016 ; Han et al, 2018 ; Yu and Chen, 2019 ). The host–guest molecular recognition based on cucurbit[8]uril (CB [8]) is very promising because CB [8] can accommodate parallel π–π stacking geometry of electron-sufficient donors and electron-deficient acceptors in its large cavity (479 Å 3 ), which means CB [8] is able to form a 1:1:1 ternary host–guest complex serving as a noncovalent linker ( Barrow et al, 2015 ; Pazos et al, 2019 ; Sun et al, 2021 ; Wu H. et al, 2021 ). In the development of supramolecular nanomedicines, CB [8] holds the ability to integrate targeted molecules into the system through non-covalent interactions ( Wu et al, 2017 ).…”

“…In the development of supramolecular nanomedicines, CB [8] holds the ability to integrate targeted molecules into the system through non-covalent interactions ( Wu et al, 2017 ). Furthermore, the stability and biosafety of molecular recognition based on CB [8] have been proven in vivo ( Wu H. et al, 2021 ). All those excellent nature makes CB [8] stand out from other supramolecular materials in the field of supramolecular nanomedicine.…”

Hydrophilic Tetraphenylethene-Based Tetracationic Cyclophanes: NADPH Recognition and Cell Imaging With Fluorescent Switch

“…For example, tetracationic cyclophanes which are constructed on the basis of π -electron-deficient 4,4’-bipyridinium units, can selectively complex with π -electron-rich guests to form 1:1 or 1:2 complexes ( Bühner et al, 1988 ; Philp et al, 1991 ; Trabolsi et al, 2010b ). Recently, tetraphenylethene (TPE) derivatives which are a classic aggregation-induced emission (AIE) luminophores ( Zhou et al, 2018 ; Ding et al, 2021 ; Wu H et al, 2021 ), have been utilized as building blocks to construct macrocyclic compounds ( Mei et al, 2015 ). Attributing to the AIE effect and propeller structure, the TPE-based cyclophanes not only display excellent photophysical properties but also possess flexible and diversified cavity structures which can be explored to capture biomolecules ( Luo et al, 2012 ; Zhao et al, 2012 ; Kwok et al, 2015 ).…”