Supramolecular Drug Delivery System from Macrocycle-Based Self-Assembled Amphiphiles for Effective Tumor Therapy

Abstract

Intelligent drug delivery systems (DDSs) that can improve therapeutic outcomes of antitumor agents and decrease their side effects are urgently needed to satisfy special requirements of treatment of malignant tumors in clinics. Here, the fabrication of supramolecular self-assembled amphiphiles based on the host−guest recognition between a cationic water-soluble pillar[6]arene (WP6A) host and a sodium decanesulfonate guest (G) is reported. The chemotherapeutic agent doxorubicin hydrochloride (DOX) can be encapsulated into the formed vesicle (G/WP6A) to construct supramolecular DDS (DOX@G/WP6A). WP6A affords strong affinities to G to avoid undesirable off-target leakage during delivery. Nanoscaled DOX@G/WP6A is capable of preferentially accumulating in tumor tissue via enhanced permeability and retention (EPR) effect. After internalization by tumor cells, the abundant adenosine triphosphate (ATP) binds competitively with WP6A to trigger the disintegration of self-assembled vesicles with the ensuing release of DOX. In vitro and in vivo research confirmed that DOX@G/WP6A is not only able to promote antitumor efficacy but also reduce DOX-related systemic toxicity. The above favorable findings are ascribed to the formation of ternary selfassembly, which profits from the combination of the factors of the EPR effect and the ATP-triggered release.

Intelligent design of polymersomes for antibacterial and anticancer applications

“…In addition to the stimuli from microenvironment, we can also use external stimuli, such as light, ultrasound, and magnetic fields, to obtain stimuli responsiveness. According to the source of the stimuli and the mode of action, stimuli‐responsive polymersome‐based delivery systems can be divided into: (1) chemical stimuli, including pH (Du, Chen, et al, 2012b; Johnson et al, 2015; Wang, Yang, et al, 2016c), redox (Bej et al, 2020; Curcio et al, 2015; Hu et al, 2018; Karandish, Mamnoon, et al, 2018b; Laskar et al, 2019; Wang et al, 2014), reactive oxygen species (Zhou, Feng, et al, 2017b), potassium ion (You et al, 2017); (2) physical stimuli, such as temperature (Kozlovskaya et al, 2019; Liu, Kozlovskaya, et al, 2015a), light (Park et al, 2018), X‐ray (Zhou, Chan, et al, 2018b), magnetic field (Oliveira et al, 2013), ultrasound (Wang, Yin, et al, 2018c; Wei, Sun, et al, 2020a); (3) biological stimuli, such as enzyme (Pramod et al, 2015), adenosine triphosphate (ATP) (Chen et al, 2021). Among which, pH‐ and redox‐ responsive polymersomes were mostly reported.…”

“…(3) biological stimuli, such as enzyme (Pramod et al, 2015), adenosine triphosphate (ATP) (Chen et al, 2021). Among which, pH-and redox-responsive polymersomes were mostly reported.…”

“…Such polymersomes showed rapid release behavior under the acidic condition and esterase catalysis. Chen and co-workers reported novel polymersomes based on the hostÀguest recognition between a cationic water-soluble pillar[6]arene (WP6A) host and a sodium decanesulfonate guest (Chen et al, 2021). After internalization by tumor cells, the abundant ATP binds competed with WP6A to trigger the disintegration of self-assembled polymersomes, resulting in rapid drug release.…”

Synthesis of a new water-soluble hexacarboxylated tribenzotriquinacene derivative and its competitive host–guest interaction for drug delivery

“…In recent years, supramolecular chemotherapy has received considerable attention by utilizing a supramolecular strategy to decrease the cytotoxicity of anticancer drugs to normal cells while preserving their cytotoxicity against cancer cells [ 11 ]. Supramolecular systems derived from macrocycles [ 12 – 13 ], such as calix[ n ]arenes (CXs), cyclodextrins (CDs), cucurbiturils (CBs), and pillararenes, are of particular interest because they can act as vehicles for anticancer drugs by either self-assembling into nanocarriers [ 14 – 16 ] or forming host–guest complexes with anticancer drugs [ 17 – 20 ].…”

Complexation of specific residues by carboxylatopillar[6]arene for improving the zymolytic stability of arginine-containing peptides

“…Initially, the host–guest complexation of CP6A with 20 naturally occurring amino acids was investigated using an indicator displacement assay. 42–44 A competitive fluorescence titration was carried out to qualitatively determine their association constants ( K a ) in phosphate buffer solution (PBS) at pH 7.4. Previous work has reported that CP6A could effectively quench fluorescence of acridine orange (AO) with a suitable binding affinity.…”