Construction of drug–drug conjugate supramolecular nanocarriers based on water-soluble pillar[6]arene for combination chemotherapy

Abstract

The synergistic effect of two anticancer drugs can significantly overcome the multidrug resistance of tumor cells and improve the drug bioavailability. Herein, two different anticancer drugs, camptothecin and chlorambucil, are successfully connected together by a disulfide linkage to get a novel drug-drug conjugated prodrug (G). Using water-soluble pillar[6]arene (WP6) as a host molecule, a supramolecular host-guest complex WP6⊃G is formed, which can further self-assemble into supramolecular vesicles in aqueous solution. In the specific microenvironment of cancer cells, the disulfide linkage is destroyed and the two anticancer drugs can be released efficiently to achieve a better synergistic effect than a single anticancer drug. Notably, these prodrug nanocarriers can not only effectively kill the cancer cells but also obviously reduce the undesirable side effects on normal cells.

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

“…The water solubility of amphiphilic pillar [6]arene (WP6) was achieved by linking carboxyl groups to both ends of WP6. 43 There are many paradigms of amphiphilic pillar [5]arenes based on carboxyl modification. Hu, Wang and co-workers synthesized a water-soluble pillar [5]arene from carboxyl modified pillar [n]arenes in 2015, and successfully developed an amphiphilic inclusion complex based on it and the lysine derivative.…”

“…In this study, two anticancer drugs, chlorambucil and camptothecin were linked by disulfide bonds, and new conjugated prodrugs were generated through the recognition of a host and guest using WP6. 43 This complex could self-assemble into vesicles in an aqueous medium. The disulfide bond had GSH responsive and could be destroyed in tumor cells, causing the simultaneous release of the two drugs and achieving synergistic treatment against cancer cells (Figure 17).…”

“…When introducing examples, we discuss not only the synthesis of these amphiphilic pillar [n]arenes but also the construction of the supramolecular vesicles based on amphiphilic pillar[n]arenes, including their application in the targeted and stimuli-responsive drug delivery in SDDs. [41][42][43][44] Moreover, the current challenges of and future prospects for multifunctional amphiphilic pillar [n] arenes are also illustrated.…”

Supramolecular peptide constructed by molecular Lego allowing programmable self-assembly for photodynamic therapy

“…Pillararene-based supra-amphiphiles, which bridge the gap between controllable self-assembly and simple synthesis by non-covalent interactions, are being actively investigated 21–23 . Compared with other macrocycles, facile functionalization, reliable host−guest recognition and multiple stimuli-responsivenesses of pillararenes endow the supra-amphiphiles with various morphologies and properties such as vesicles for controlled release and NPs for cell imaging 24–30 .…”

A mitochondria-targeted delivery system of doxorubicin and evodiamine for the treatment of metastatic breast cancer

“…2,3 Small molecule chemotherapeutic drugs do not have tumor targeting function, leading to serious toxicity and side effects on normal tissues, and their effect on tumor treatment is not ideal. [4][5][6] The accurate delivery of drugs to the targeted tumor site is key to improving traditional chemotherapy, which can be achieved by nanocarrier-based drug delivery systems. The nanocarrierbased drug delivery system has unique advantages, including improving the solubility of hydrophobic drugs, [7][8][9] prolonging blood circulation of drugs, and increasing drug accumulation in the tumor tissue in solid tumors through the enhanced permeation and retention (EPR) effect, which can greatly help to reduce the side effects of chemotherapeutic drugs and enhance their pharmacological effects.…”