Supramolecular polymeric materials based on macrocyclic hosts for cancer therapy

All over the world, cancer has become the leading cause of human death and a major obstacle to improving life expectancy [1]. Although the survival rate of cancer has been improved significantly thanks to the continued efforts of researchers, there is still a long way to go before cancer is completely cured [2, 3]. Surgery, radiotherapy, and chemotherapy are still the mainstays of cancer therapy [4, 5]. However, limitations and side effects mean that these methods do not meet the current clinical need for cancer therapy [6–8]. For example, (i) surgery has a high risk, low success rate, and various complications; (ii) as a topical treatment, radiotherapy requires to be highly sensitive to tumors and damages healthy tissue; (iii) chemotherapy leads to a sharp reduction in the number of immune cells and the damage of visceral function [9–11]. Therefore, it is urgent to develop new treatment strategies to solve these problems, improving the therapeutic effect of cancer [12]. Supramolecular chemistry is a frontier science proposed by J.M. Lehn, a Nobel laureate chemist in 1987, which intersected with biology, physics, materials science, information science, and environmental science [13–19]. The main research directions of supramolecular chemistry can be divided into host–guest chemistry and supramolecular assembly chemistry [20–25]. Among them, supramolecular polymers based on macrocyclic hosts (such as cyclodextrins, calixarenes, cucurbiturils, and pillararenes) are a new type of polymers that combines the advantages of supramolecules and polymers (Figure 1) [26–36]. Compared with traditional polymers, macrocyclic hosts-based supramolecular polymers are mainly formed by connecting multiple repeating units through host–guest interactions [37–42]. The reversibility and dynamics of host–guest interactions give supramolecular polymeric materials unparalleled advantages, such as sensitive stimuli-responsiveness, good biocompatibility, and high biodegradability [43–47]. Based on these advantages, macrocyclic hosts-based supramolecular polymeric materials provide a new strategy for cancer therapy [48–52]. At present, macrocyclic hosts-based supramolecular polymeric materials have been widely used in cancer therapy [53–59]. For example, Huang and co-workers developed an amphiphilic supramolecular diblock polymer based on the host–guest interaction between pillar[5]arene and viologen derivative (Figure 2a) [60]. The polymer was further self-assembled into polymeric vesicles in water to deliver doxorubicin (DOX), which improved the therapeutic effect of DOX and reduced the side effects on healthy tissues. Additionally, Zhang and co-workers constructed a cucurbit[7]uril-based supramolecular polymer to load oxaliplatin (OxPt) and mitochondrial targeting peptide (N-Ph-KLAK) effectively (Figure 2b) [61]. In the tumor microenvironment, OxPt and N-Ph-KLAK were competitively released to destroy the nucleus and mitochondria, respectively, successfully inhibiting the viability of cancer cells. Moreover, Yu and co-workers reported a supramolecular polymer based on the host–guest interaction between cyclodextrin and camptothecin (Figure 2c) [62]. The nanoparticles were self-assembled by the supramolecular polymer could be efficiently internalized by tumor cells for synergistic chemotherapy and chemodynamic therapy. Furthermore, Guo, Cai, and co-workers exploited a hypoxia/glutathione dual-responsive calix[4]arene-based supramolecular polymer to self-assemble into nanoparticles (Figure 2d) [63]. In tumor cells, the loaded anticancer drugs were efficiently released in response to the tumor microenvironment, successfully inhibiting tumor growth.