Influence of supramolecular encapsulation of camptothecin by cucurbit[7]uril: reduced toxicity and preserved anti-cancer activity

Abstract

a Camptothecin (CPT), a natural antineoplastic agent that was originally isolated from the bark and stem of Camptotheca acuminata, targets a wide range of cancers by inhibition of topoisomerase I during DNA replication. In this study, we investigated the use of cucurbit [7]uril (CB [7]) for molecular encapsulation of CPT and the associated benefits of such encapsulation of CPT on its anti-cancer activity, and side effects have been systemically evaluated both in vitro and in vivo. The cytotoxicity of the free CPT and complexed CPT (CPT@CB [7]) was examined by MTT assay using both a healthy liver cell line (L02) and a liver cancer cell line (Bel-7402). Interestingly, both the free CPT and CPT@CB [7] demonstrated comparable anti-cancer efficacy in vitro on the cancer cell line Bel-7402, whereas CPT@CB [7] showed obviously lower toxicity on the healthy liver cell line L02, in comparison with the free CPT. The anti-cancer/anti-angiogenic activity and non-specific toxicity of both free CPT and CPT@CB [7] were further investigated in vivo with both transgenic and wild-type zebrafish models, showing again that CPT@CB [7] exhibited reduced non-specific toxicities with well-preserved anti-angiogenic activities, when compared with the free CPT. These results demonstrate that CB [7] may work as a functional excipient for alleviation of undesired side-effects of selected organic drugs.

Applications of Cucurbit[n]urils (n=7 or 8) in Pharmaceutical Sciences and Complexation of Biomolecules

“…[25] In addition, we have continued to study the influence of CB [7]'s complexations on the biological activities of CPT both in vitro and in vivo. [10] Upon encapsulation, CPT@CB [7] complexes exhibited a reduced systemic toxicity profile ( Figure 4) and preserved the anti-cancer activity of CPT at the same time. [10] Similarly, we studied supramolecular complexation of CB [7] with another natural alkaloid, nitidine chloride (NC) that was iniitally extracted from the root of Zanthoxylum nitidum showing promising anticancer activity together with nonspecific toxicity.…”

“…[10] Upon encapsulation, CPT@CB [7] complexes exhibited a reduced systemic toxicity profile ( Figure 4) and preserved the anti-cancer activity of CPT at the same time. [10] Similarly, we studied supramolecular complexation of CB [7] with another natural alkaloid, nitidine chloride (NC) that was iniitally extracted from the root of Zanthoxylum nitidum showing promising anticancer activity together with nonspecific toxicity. [9] In the presence of CB [7], the hepatotoxicity of NC tested on L02, a liver cell line, was significantly alleviated (IC 50 : reduced from 3.48 AE 0.49 mM to 6.87 AE 0.80 mM) and the anticancer activity tested on MCF-7, a breast cancer cell line, was improved (IC 50 : increased from 7.28 AE 0.36 mM to 2.94 AE 0.15 mM) at the same time.…”

“…[4] These properties have attracted much attention from scientists. [10] On the other hand, due to its modest water-solubility and a larger cavity that can often accommodate two small molecules simultaneously, [3] CB [8] has been widely used in polymer/material sciences [11] and biomedical sciences. [5] Upon encapsulation by CB [7], a variety of drug molecules have exhibited enhanced bioavailability, [7] improved water solubility, [8] modulated efficacy [9] and reduced toxicity.…”

Molecular Encapsulation of Histamine H2-Receptor Antagonists by Cucurbit[7]Uril: An Experimental and Computational Study

“…Of biomedical relevance, we have demonstrated that CB [7] encapsulation of a neurotoxin MPTP in vivo may lessen the neurotoxicity of the guest molecule [18]. Additionally, we observed that encapsulation of anti-cancer drug camptothecin and anti-tuberculosis drug clofazimine by CB [7] has reduced these drug's inherent toxicities and maintained their therapeutic efficacy, as demonstrated by both in vitro and in vivo evidence [21,22].…”

“…Along this line, our research group has investigated CB [7]'s encapsulations of a variety of biomedically important molecules during the past years, including imidazolium-and thiazolium-based model drugs [10,11], the photosensitizer norharmane [12], the anti-peptic ulcer drug ranitidine [13], the anticoagulant coumarin and the associated model drug coumarin-6 [14], vitamin B 12 and its coenzyme [15], vitamin B 1 [16], vitamin B 6 [17], the neurotoxin MPTP/MPP + [18], anesthetic agents such as tricaine [19], benzocaine and its metabolite para-aminobenzoic acid [20], as well as the anti-cancer drug camptothecin [21] and the anti-tuberculosis drug clofazimine [22]. It has been generally demonstrated by us and other researchers that drugs encapsulated within CB [7] may lead to one or more of several benefits including improved solubility, chemical stability, and therapeutic efficacy as well as reduced side-effects [14,18,19,[21][22][23][24]. For instance, a molecular capsule of coumarin-6@CB [7] was shown to have significantly increased bio-uptake both in vitro and in vivo, in comparison with the free coumarin-6 [14].…”