A Cleavable Self-Inclusion Conjugate with Enhanced Biocompatibility and Antitumor Bioactivity

Open AccessCCS ChemistryCOMMUNICATIONS22 Dec 2022A Cleavable Self-Inclusion Conjugate with Enhanced Biocompatibility and Antitumor Bioactivity Han Wu, Tian Xia, Feilong Qi, Shan Mei, Yu Xia, Jiang-Fei Xu and Xi Zhang Han Wu Key Laboratory of Organic Optoelectronics and Molecular Engineering, Department of Chemistry, Tsinghua University, Beijing 100084 , Tian Xia MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Department of Chemistry, Tsinghua University, Beijing 100084 , Feilong Qi Key Laboratory of Organic Optoelectronics and Molecular Engineering, Department of Chemistry, Tsinghua University, Beijing 100084 , Shan Mei Key Laboratory of Organic Optoelectronics and Molecular Engineering, Department of Chemistry, Tsinghua University, Beijing 100084 , Yu Xia MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Department of Chemistry, Tsinghua University, Beijing 100084 , Jiang-Fei Xu *Corresponding author: E-mail Address: [email protected] Key Laboratory of Organic Optoelectronics and Molecular Engineering, Department of Chemistry, Tsinghua University, Beijing 100084 and Xi Zhang Key Laboratory of Organic Optoelectronics and Molecular Engineering, Department of Chemistry, Tsinghua University, Beijing 100084 https://doi.org/10.31635/ccschem.022.202202410 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail The effective encapsulation of antitumor drugs by dynamic host–guest interactions at the submicromolar level remains a challenge. Herein, we report a cleavable self-inclusion camptothecin-cucurbit[7]uril (CPT-CB[7]) conjugate. The binding affinity of CB[7] to CPT is greatly enhanced owing to the intramolecular self-inclusion, demonstrating a concentration-independent encapsulation efficiency of nearly 100%. The disulfide linker of CPT-CB[7] conjugate can be cleaved in the reductive tumor microenvironment, transforming the self-inclusion into a binary host–guest complexation pattern, thus releasing the CPT thoroughly. The enhanced biocompatibility and antitumor bioactivity of the cleavable self-inclusion conjugate have been confirmed by in vitro and in vivo experiments. This line of research will open new horizons for supramolecular drug delivery systems operating in diluted and competitive conditions. Download figure Download PowerPoint Introduction Supramolecular drug delivery systems based on host–guest interactions are of great interest owing to their optimized pharmacokinetic properties, precise structures and controlled drug release.1–11 The bioactivity of antitumor drugs can be disguised by host–guest complexation and then recovered upon dissociation.12–16 To date, many kinds of supramolecular drugs have been developed to show higher biocompatibility as well as better therapeutic effects,17–19 such as oxaliplatin-cucurbit[7]uril (CB[7]),12,20–23 melphalan-β-cyclodextrin,24 and chlorambucil-calix[5]arene complexes.25 Nevertheless, for a wide range of antitumor drugs, the half maximal inhibitory concentration (IC50) is as low as about 100 nM to several μM.26–31 Considering the concentration-dependent nature of host–guest complexation, it remains a challenge for these drugs to form stable supramolecular drugs under sub-μM concentrations with both high encapsulation efficiency and stimuli-triggered release properties. Self-inclusion refers to intramolecular complexation of a host–guest conjugate that enhances the binding affinity of the host to the linked guest on account of the reduced entropic penalty.32–37 We can find proteins with the self-inclusion structure in the nature. For example, gasdermin D, a key protein for cell pyroptosis, effectively inhibits its bioactivity through intramolecular association of the functional fragments. Once cleaving the linkage between the assembled fragments, its bioactivity is recovered by dissociating the functional fragments.38,39 Inspired by this entropy-driven association, as shown in Scheme 1a, we assumed that a host-drug conjugate could be designed to form a self-inclusion supramolecular drug that would work under highly diluted conditions. Scheme 1 | (a) A schematic diagram of supramolecular drugs on the basis of the binary host–guest complexation and the cleavable self-inclusion conjugate proposed in this work; (b) the chemical structure of the cleavable host-drug conjugate CPTSSCB, and a schematic illustration of the GSH triggered drug release. Download figure Download PowerPoint To this end, as shown in Scheme 1b, a camptothecin (CPT) was linked with a CB[7] via a linkage containing a disulfide bond to construct a cleavable host-drug conjugate named CPTSSCB. CPT is a plant-derived antitumor drug which can form a ternary complex with topoisomerase I and DNA to inhibit DNA replication and induce cell apoptosis.25,40 The IC50 of CPT is about 100 nM. For the host-drug conjugate CPTSSCB, on the one hand, the CPT fragment can effectively bind with CB[7] by self-inclusion to form a stable supramolecular drug even under 100 nM. On the other hand, the disulfide linkage can be cleaved in the reductive tumor microenvironment,13,41–43 transforming the self-inclusion supramolecular drug into a binary host–guest complexation pattern, thus thoroughly releasing the CPT on account of the concentration-dependent dissociation. Results and Discussion The host-drug conjugate CPTSSCB was synthesized via mild reactions and characterized by NMR spectroscopy and high-resolution electrospray ionization mass spectrometry (ESI-MS; see the synthesis and characterization part in Supporting Information Figures S1–S6). We wondered whether the CPTSSCB could self-include to form a supramolecular drug. 1H NMR experiments were employed to study the host–guest complexation of CPTSSCB. As shown in the 1H NMR spectrum of 150 μM CPTSSCB in D2O (Figure 1bi), the chemical shift values of aromatic protons of the CPT fragment are in the 7.0–9.0 ppm range. After addition of a competitive molecule p-Xylylenebis(trimethylammonium bromide) (PXTM), a strong guest that can bind CB[7] with a binding constant as high as 1010 M−1 (See the chemical structure of PXTM in Figure 1a. Its synthetic method is shown in the synthesis and characterization part in the Supporting Information, and the characterization of the binding constant between PXTM and CB[7] is shown in Supporting Information Figure S7.), the four peaks at 7.1–7.6 ppm shifted downfield to 7.7–8.2 ppm. This suggests that the terminal benzene unit of CPT moiety was encapsulated in the cavity of CB[7]. In addition, the legible and sharp peaks of CPTSSCB shown in Figure 1b suggest that CPTSSCB does not self-assemble into large aggregates. Meanwhile, the diffusion coefficient of the saturated CPTSSCB aqueous solution (around 350 μM) was determined to be 2.30 × 10−10 m2s−1 through diffusion-ordered NMR spectroscopy, which is close to that of the CB[7] (3.11 × 10−10 m2s−1).35 The above results indicate that CPTSSCB forms a single-molecule host–guest complex in aqueous solution. Figure 1 | (a) Chemical structures of PXTM and CPTSSCB; (b) partial 1H NMR spectra of 150 μM CPTSSCB (i), 150 μM CPTSSCB + 3.0 equiv PXTM (ii), the peaks marked red belong to the benzene unit of CPT moiety, and chemical structure of PXTM, 800 MHz, D2O, 298.1 K; (c) ion mobility spectra of CPTSSCB (m/z = 951.2) under 10 μM, 1.0 μM, and 100 nM; (d) ion mobility spectrum of the 1.0 μM CPTSSCB with 10 μM PXTM (m/z = 1061.8). K0 stands for reduced mobility. Download figure Download PowerPoint The self-inclusion structure of CPTSSCB was further confirmed by trapped ion mobility spectrometry-time-of-flight mass spectrometry.34,35,44,45 As shown in Figure 1c, the collision cross section (CCS) of CPTSSCB under 10 μM was determined to be 425 Å2, which is close to that of a host–guest complex of CB[7] and viologen (335 Å2), while far less than that of a di-CB[7] conjugate (730 Å2, Supporting Information Figure S13). In addition, through diluting the CPTSSCB solution to 1.0 μM and 100 nM, the CCS values remained unchanged, clearly indicating their concentration-independent complexation property. Furthermore, as shown in Figure 1d, after an addition of excess PXTM to dissociate the complex, the CCS value increased to 461 Å2, indicating the release of the CPT fragment from the self-inclusion complex. By combining these results, we can conclude that CPTSSCB indeed forms a self-inclusion supramolecular drug under sub-μM concentrations. To calculate the encapsulation efficiency of CPTSSCB, we employed isothermal titration calorimetry to study the binding constant of self-inclusion. As shown in Supporting Information Figure S8, through titrating PXTM into CPTSSCB, the competitive binding constant was determined to be 1.05 × 107 M−1. By comparing it with the binding constant of PXTM with CB[7] (2.43 × 1010 M−1), the binding constant of the self-inclusion of CPTSSCB was calculated to be 2.31 × 103. Such a high binding affinity of self-inclusion ensures the encapsulation efficiency of CPTSSCB as high as 99.96% while not being affected by concentration. In comparison, the encapsulation ratio of CPT by CB[7] through the binary host–guest complexation pattern was estimated to be only 0.28% under 1.0 μM.46 In addition, the solubility of CPTSSCB was about 350 μM in water, which is about 100-fold higher than that of the pristine CPT, indicating the significantly improved water solubility through effective self-inclusion.47 Furthermore, as shown in Supporting Information Figure S9, after incubation with human serum albumin (HSA) for 2 h, the free CPTSSCB remained about 29.5% as measured by fluorescence intensity while for CPT, only 0.4% remained. This result indicates that CPTSSCB is able to resist adsorption and hydrolysis in the presence of HSA owing to the strong binding affinity of self-inclusion. In other words, the self-inclusion supramolecular drug shows enhanced stability against HSA. The above results demonstrate that the encapsulation efficiency of self-inclusion is nearly 100%, and the formation of a self-inclusion supramolecular drug significantly enhances the solubility and stability of CPT. To test the drug release efficiency of CPT from CPTSSCB, high-performance liquid chromatography (HPLC) experiments were carried out. As shown in Figure 2a, the retention time of CPTSSCB (9.3 min) is shorter than that of CPT (12.1 min), which could be the benefit from its better water solubility. Due to the poor binding affinity (2800 M−1),48 most CPT in the binary host–guest complex of CPT and CB[7] are in the free form, leading to the same retention time of [email protected][7] and CPT. A small peak at 11.2 min can be ascribed to the host–guest complex of [email protected][7] in the binding form. As shown in Figure 2b, upon addition of 10 mM glutathione (GSH) to a 40 μM CPTSSCB solution, the peak that belongs to CPTSSCB gradually turns to that of CPT with the extension of reaction time, indicating the release of CPT. The release efficiency can be calculated based on the relative peak areas of HPLC curves, and the release efficiency is about 95.4% at 60 min ( Supporting Information Figure S11). This result demonstrates that the cleavage of disulfide linkage in CPTSSCB transforms the self-inclusion pattern into binary complexation pattern, thus releasing CPT by the dissociation of the binary complex under low concentrations. The ESI-MS was employed to analyze the intermediate product of this reduction reaction ( Supporting Information Figure S10). A proposed mechanism of this reaction process is shown in Figure 2c. Therefore, CPT can be thoroughly released from the self-inclusion supramolecular drug through the reduction of GSH. Figure 2 | (a) HPLC elution curves of CPT, [email protected][7], and CPTSSCB (10 μM); (b) HPLC elution curves of CPTSSCB (40 μM) reacted with 10 mM GSH at different reaction time; (c) proposed mechanism for releasing CPT from CPTSSCB by GSH. Download figure Download PowerPoint To investigate whether the cleavable self-inclusion conjugate can exhibit high antitumor bioactivity, the cytotoxicity of CPTSSCB against tumor cells was evaluated by CCK-8 assay after incubating them for 48 h. As shown in Figure 3a, the supramolecular drug CPTSSCB displayed a remarkable cytotoxicity against HCT116 cells, whose IC50 was calculated to be 224 nM. On the contrary, CPTSSCB showed the weaker antitumor bioactivity than the pristine CPT on health colorectal cells (NCM 460, as shown in Supporting Information Figure S14). In addition, the CPTSSCB also showed a high antitumor bioactivity against Hela cells with the IC50 of 179 nM ( Supporting Information Figure S12). Similar cytotoxicity of CPTSSCB and pristine CPT indicates that the CPT fragment in CPTSSCB can be effectively released to show its antitumor bioactivity. To confirm the release of CPT through the cleavage of the disulfide bond, a self-inclusion conjugate that cannot be cleaved, named CPTEGCB (Figure 3b), was used as a control. Due to the absence of the disulfide bond, the CPT fragment in CPTEGCB was stably encapsulated in the cavity of CB[7] by self-inclusion, thus demonstrating low cytotoxicity. As shown in Figure 3a, the cell viability of HCT116 was higher than 90% in the concentration range of 1.0 nM∼1.0 μM, and the IC50 of CPTEGCB is higher than 10 μM. Therefore, the cleavable self-inclusion conjugate exhibited high antitumor bioactivity on the basis of tumor microenvironment-triggered drug release. Figure 3 | (a) Cell viability of CPT, CPTSSCB, and CPTEGCB for HCT116 cells after incubating 48 h; (b) chemical structure of CPTEGCB. Download figure Download PowerPoint We wondered whether the high antitumor bioactivity of the cleavable self-inclusion conjugate could be exhibited in vivo. To answer this question, Hela tumor xenograft model experiments were conducted on nude mice, and the therapeutic effect of CPTSSCB was estimated according to their tumor size and body weight. As shown in Figure 4a, the tumor growth inhibition rate of CPTSSCB was as high as 76.2%, exhibiting significant treatment outcomes. While CPT shows a limited inhibition rate of tumor growth, this could be attributed to its instability in blood circulation and poor water solubility. The control compound CPTEGCB also did not exhibit remarkable inhibition for tumor growth, indicating that the introduction of a cleavable bond is necessary for drug release. In addition, as shown in Figure 4b, the negligible relative body weight loss of mice in the CPTSSCB group was observed, demonstrating its safety and good biocompatibility for mice. To further understand the higher tumor growth inhibition rate of CPTSSCB, the in vivo blood elimination kinetics of CPTSSCB and CPT have been studied on SD rats. As shown in Supporting Information Figure S15, the rats that intravenously administrated CPTSSCB demonstrated significantly higher CPT concentration in plasma than neat CPT group. The area under the curve in plasma was 3.94 μg/mL·h for CPTSSCB group, which was 5.25-fold higher than that of CPT group. Therefore, this could be a possible reason for the better anti-tumor activity of CPTSSCB than CPT in the animal experiments. The above results confirm that the cleavable self-inclusion conjugate not only ensures the safety of CPT, but it also remarkably improves the in vivo antitumor bioactivity. Figure 4 | (a) Relative tumor volume and (b) relative body weight of nude mice with Hela tumor xenografts during treatment with prescribed formulations (n = 3, tail vein injection, in terms of CPT concentration with 2.5 mg/kg, 7 times in 2 weeks). Download figure Download PowerPoint Conclusion We have constructed a cleavable self-inclusion host-drug conjugate CPTSSCB and successfully demonstrated its good biocompatibility as well as enhanced antitumor bioactivity. The significant advantages of CPTSSCB result from its nearly 100% encapsulation efficiency even under sub-μM, which improves the water solubility and stability of CPT. What is more, the cleavage of CPTSSCB under the reductive tumor microenvironment transforms the self-inclusion manner into binary host–guest complexation, triggering complete drug release owing to the concentration-dependent complexation. We envision that this self-inclusion supramolecular strategy can be applied to many other kinds of antitumor drugs as well as host molecules. It is highly anticipated that this line of research will open new horizons for supramolecular drug delivery systems operating under diluted and competitive conditions. Supporting Information Supporting Information is available and includes experimental details about synthetic methods and characterizations of PXTM, CPTSSCB, and CPTEGCB; the binding constant of self-inclusion; interaction between HSA and CPT, [email protected][7], and CPTSSCB; drug release by GSH; cytotoxicity of self-inclusion supramolecular drug to Hela cells and NCM460 cells; some diffusion coefficients and CCS of model molecules; and in vivo blood elimination kinetics of CPT and CPTSSCB. Disclosures Animal care and handling procedures were in agreement with the guidelines evaluated and approved by the Institutional Animal Care and Use Committee (IACUC) of the Laboratory Animal Research Center, Tsinghua University. Study protocols involving animals were approved by the IACUC of the Laboratory Animal Research Center, Tsinghua University (2022-299). Conflict of Interest There is no conflict of interest to report. Funding Information This work was financially supported by the Ministry of Science and Technology of China (grant no. 2018YFA0208900), the National Natural Science Foundation of China (grant no. 21821001), and the Strategic Priority Research Program of Chinese Academy of Sciences (grant no. XDB36000000). 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