From Supramolecular Vesicles to Micelles: Controllable Construction of Tumor‐Targeting Nanocarriers Based on Host–Guest Interaction between a Pillar[5]arene‐Based Prodrug and a RGD‐Sulfonate Guest

Abstract

The targeting ability, drug‐loading capacity, and size of the drug nanocarriers are crucial for enhancing the therapeutic index for cancer therapy. Herein, the morphology and size‐controllable fabrication of supramolecular tumor‐targeting nanocarriers based on host–guest recognition between a novel pillar[5]arene‐based prodrug WP5‐DOX and a Arg‐Gly‐Asp (RGD)‐modified sulfonate guest RGD‐SG is reported. The amphiphilic WP5‐DOX⊃RGD‐SG complex with a molar ratio of 5:1 self‐assembles into vesicles, whereas smaller‐sized micelles can be obtained by changing the molar ratio to 1:3. This represents a novel strategy of controllable construction of supramolecular nanovehicles with different sizes and morphologies based on the same host−guest interactions by using different host−guest ratios. Furthermore, in vitro and in vivo studies reveal that both these prodrug nanocarriers could selectively deliver doxorubicin to RGD receptor‐overexpressing cancer cells, leading to longer blood retention time, enhanced antitumor efficacy, and reduced systematic toxicity in murine tumor model, suggesting their potential application for targeted drug delivery.

Stimuli-Responsive Drug-Delivery Systems Based on Supramolecular Nanovalves

“…7,8 As an essential player in supramolecular chemistry, reversible non-covalent interactions-which include electrostatic interactions, p-p stacking interactions, hydrophobic effects, van der Waals interactions, and hydrogen-bonding interactions-could effectively organize matching pieces together by molecular recognition to produce ordered supramolecular nanoarchitectures with tailorable size, morphology, and functions, such as micelles, nanoparticles (NPs), vesicles, and hydrogels. [9][10][11][12][13] The environment-operable properties that could respond to external changes are realized via dynamic association and dissociation of component parts in such supramolecular assemblies. [14][15][16] Depending on the flexible modular strategy, supramolecular therapeutics directed by synthetic knowledge has been proposed, especially in the fabrication of…”

Host-Guest Chemistry in Supramolecular Theranostics

“…Another part of supramolecular amphiphiles were also prepared by the scientists by using anticancer drugs as the hydrophobic parts, such as DOX and CPT 230-234. The solubility of the drugs was effectively enhanced and the cellular internalization was adjusted.…”

<p>Supramolecular Vesicles Based on Amphiphilic Pillar[n]arenes for Smart Nano-Drug Delivery</p>

“…86 In a recent study, Hu et al successfully synthesized a cationic amphiphilic WP5, the ends of which were modified with quaternary ammonium salt, a pillar [5]arene prodrug, WP5-DOX; and an Arg-Gly-Asp (RGD) modified sulfonate guest, RGD-SG; these components formed a stimuli-responsive tumor-targeted drug delivery system actualized by host-guest recognition. 87 In addition, Pei's group successfully constructed a cation amphiphilic pillar [5]arene (FCAP) with a terminal ferrocene, which self-assembled in aqueous solution to form a novel cationic vesicle with GSH-triggering and siRNA co-delivery capacity. 88 Subsequently, in 2016, a Trp-modified pillar [5] arene (TP5) was reported, to be a novel water-soluble amphiphilic macrocyclic molecule.…”

“…In 2018, Hu and colleagues reported stimuli-responsive targeted drug delivery systems formed by host-guest recognition between the novel pillar [5]arene prodrug WP5-DOX and sulfonate guest RGD-SG, a modified by Arg-Gly-Asp (RGD). 87 The morphology and size of this nanocarrier, which targets supramolecular tumors, could be controlled by using different ratios of hosts to guests.…”