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. 2020 May 18;11(6):1191–1195. doi: 10.1021/acsmedchemlett.0c00040

Polysaccharide-Based Nanoparticles for Two-Step Responsive Release of Antitumor Drug

Hong-Guang Fu 1, Yong Chen 1, Qilin Yu 1, Yu Liu 1,*
PMCID: PMC7294702  PMID: 32551000

Abstract

graphic file with name ml0c00040_0006.jpg

A novel two-step in situ method for targeted antitumor drug release by supramolecular assembly (Fc-CPT@HACD) was constructed using camptothecin prodrug (Fc-CPT) and β-cyclodextrin (β-CD)-modified hyaluronic acid (HACD). Benefiting from the overexpressed H2O2 and glutathione (GSH) in tumor cells, Fc-CPT@HACD can be disassembled by oxidation of ferrocene (Fc) to Fc+, leading to an efficient release of the anticancer drug camptothecin (CPT) to induce tumor cell apoptosis without affecting normal cells. The in vivo experiment results also demonstrated that Fc-CPT@HACD possessed higher anticancer efficiency than free CPT, accompanied by negligible side effects.

Keywords: Supramolecular assembly, cyclodextrin, HACD, multistimuli-responsive, tumor targeting

The construction of novel targeting stimuli-responsive supramolecular drug systems (SDSs) by simple non-covalent interactions has attracted considerable attention to overcome several drawbacks (severe side effects, nonspecific distribution, systemic instability, rapid blood clearance, etc.)1,2 of conventional chemotherapeutic agents by achieving controlled drug release. These stimuli include internal features (redox potential,3 hypoxic microenvironment,4 glucose level,5 enzymatic activity,6 reduced pH,7 ATP level,8 etc.) and external triggers (temperature,9 light,10ultrasound,11 magnetic field,12 etc.). As most non-covalent interactions are easily destroyed in the internal environment before they reach the nidus, possibly causing side effects, the resultant SDSs need to be protected thoughtfully. Hydrophobic-interaction-based macrocyclic host–guest stimuli-responsive supramolecular assemblies have been developed and opened the prospect of cancer therapy both in vitro and in vivo.13,14 One particular macrocycle, β-cyclodextrin (β-CD), composed by seven d-glucopyranose units, is distinguished by the significant controlled capture and release behavior of β-CD and ferrocene in aqueous solution.15 Moreover, most of the cyclodextrin derivatives show good water solubility, negligible toxicity in animals, and excellent biocompatibility, further promoting their biomedical applications.16 On the other hand, by trapping free radicals, abnormal glutathione (GSH) serves as an antioxidant to control the oxidative stress in redox homeostasis. As the concentration of GSH in tumor cells (∼10 mM)17 is hundreds of times higher than that in normal cells, the disulfide bonds that are cleavable by GSH have been greatly studied as redox-responsive linkers in supramolecular assemblies with specific drug release inside cells.

However, despite the great efforts that have been made, most of the existing supramolecular assemblies are not specifically loaded for tumor cells. Recently, introducing malignant-tumor-targeting ligands (e.g., folic acid,18 biotin,19 transferrin,20 and sugars21) on assemblies to enhance the drug accumulation in cancer tissues accompanying insignificant toxicity to normal tissues has become a popular strategy to overcome this problem. Besides the above-mentioned targeting ligands, hyaluronic acid (HA), a biocompatible, biodegradable, and water-soluble polysaccharide, has also been used extensively.22−24

In the present work, taking advantage of the host–guest binding affinity between β-CD and ferrocene,25 we used a ferrocene (Fc)-appended camptothecin prodrug (Fc-CPT) and β-CD-appended HA (HACD) to construct the supramolecular assembly Fc-CPT@HACD having a hydrophilic HA shell that may protect the CPT prodrug from hydrolysis against water (Scheme 1). To our delight, the supramolecular assembly shows excellent targeting ability toward tumor cells and tissues, negligible cytotoxicity toward normal tissues, and effective drug release both in vitro and in vivo. After Fc-CPT@HACD gets into tumor cells, the intrinsically higher H2O2 in the cytoplasm oxidizes Fc to Fc+ and destroys the binding between Fc and β-CD. Without the protection of the HA shell, the exposed disulfide bonds linking CPT and Fc are cut,26 resulting in fast release of CPT. This makes Fc-CPT@HACD a promising candidate for selective inhibition of tumor growth.

Scheme 1. Construction of the Supramolecular Assembly Fc-CPT@HACD and Its Application for H2O2- and GSH-Triggered Release of CPT through Intravenous Injection.

Scheme 1

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With the excellent host and guest in hand, the binding properties were studied. As the β-CDs in HACD provide many binding sites, native β-CD (99% purity) was employed as a model host to investigate the supramolecular interactions between Fc-CPT and β-CD by UV–vis titration in PBS (0.01 M) containing 5% DMSO (99.8% purity). As shown in Figure 1a, the Job’s plot indicated a 1:1 stoichiometry between β-CD and Fc-CPT, as the minimum in the plot appeared at 0.5. With the gradual addition of β-CD, the characteristic UV absorbance of Fc-CPT decreased dramatically in the range from 245 to 404 nm (Figure 1b) accompanied by a slight red shift, suggesting a conversion from free Fc-CPT to the host–guest species Fc-CPT@β-CD. Fortunately, 2D rotating-frame Overhauser effect spectroscopy (ROESY) showed obvious nuclear Overhauser effect (NOE), which was in accordance with UV titration result (Figure S2). Moreover, the binding constant between Fc-CPT and β-CD was determined to be (1.5 ± 0.5) × 103 M–1 by a nonlinear least-squares fit of the UV titration data at 261 nm (Figure S3), which is comparable to the reported K value for binding between Fc-CPT and β-CD.21

Figure 1.

Figure 1

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(a) Job’s plot for Fc-CPT upon complexation with β-CD in pH 7.2 PBS containing 5% DMSO. (b) UV–vis spectra of Fc-CPT (1.0 × 10–5 M) upon addition of native β-CD in pH 7.2 PBS containing 5% DMSO.

Dynamic light scattering (DLS), scanning electron microscopy (SEM), high-resolution transmission electron microscopy (HR-TEM), Tyndall effect, and zeta potential experiments were used to investigate the size, morphology, and surface charge of Fc-CPT@HACD ([Fc-CPT] = 0.01 mM). The critical aggregation concentration (CAC) of Fc-CPT@HACD was investigated by monitoring the dependence of the optical transmittance at 260 nm on the concentration of Fc-CPT (Figure S4) and measured to be 2.97 × 10–3 mM. The host molecule HACD could form fiberlike aggregates with a length of several micrometers (Figure S5). Upon addition of Fc-CPT, the fiberlike aggregates converted to spherical particles. This implied that the Fc-CPT@HACD system existed in the form of aggregates, which was also certificated by the Tyndall effect (Figure 2d). TEM images showed the morphology of Fc-CPT@HACD as discrete nanoparticles with an average diameter of 50–76 nm (Figure 2a) based on counting of about 100 particles. Moreover, the hydrodynamic diameter (Dh) of Fc-CPT@HACD was measured to be ca. 63 nm by DLS with a narrow distribution (Figure 2b), which was consistent with the diameter obtained by TEM. The zeta potentials of HACD and Fc-CPT@HACD were measured to be ca. −60.1 and −58.1 mV (Figures 2c and S6). In addition, the UV–vis spectrum of Fc-CPT@HACD was nearly unchanged in fetal bovine serum over 7 h (Figure S7), indicating that the structure of Fc-CPT@HACD was largely maintained. The Fc-CPT loading efficiency (weight of loaded Fc-CPT/weight of feeding drug) and Fc-CPT encapsulation ratio were calculated to be 94.7% and 6.5%, respectively (the detailed calculation process is presented in Figure S8).

Figure 2.

Figure 2

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(a) TEM image, (b) DLS curve, and (c) zeta potential of obtained Fc-CPT@HACD. In (c) the Y axis represents the normalized current intensity. (d) Tyndall effect of Fc-CPT in the absence (right) and presence (left) of HACD in PBS (pH 7.2, I = 0.01 M, [Fc-CPT] = 0.01 mM; PBS was made up from Na2HPO4 and KH2PO4).

Next, the multistimuli responsiveness of Fc-CPT@HACD was investigated. It is well-known that Fc can be oxidized to Fc+ by H2O2. In the absence of H2O2 and GSH, Fc-CPT showed stronger absorption intensity than Fc-CPT@HACD with a slight blue shift. Upon addition of H2O2 (AR, 30 wt % in H2O) or GSH (98% purity), these two UV–vis spectra became similar to each other (Figures S9 and S10) at the end, which could be explained by the transition from Fc-CPT to Fc+-CPT (Figure S9) or the release of CPT (Figure S10), which further resulted in the disassembly of the nanoparticles. Moreover, cyclic voltammetry (CV) was used to characterize the electrochemical behaviors of Fc-CPT@HACD and Fc-CPT@HACD + H2O2. Fc-CPT@HACD showed only a reversible oxidation process, but Fc-CPT@HACD + H2O2 showed irreversible oxidation and reduction processes (Figure S11). The different oxidation potentials of Fc-CPT@HACD and Fc-CPT@HACD + H2O2 could be attributed to the transition from Fc-CPT@HACD to Fc+-CPT and HACD. Compared with Figure S7, it was found that Fc-CPT could be released from the Fc-CPT@HACD system in the presence of H2O2 in 10 h (Figure S12). Interestingly, the fluorescence of Fc-CPT@HACD was activated by addition of GSH. Upon excitation at 250 nm, the fluorescence of Fc-CPT@HACD + GSH at 450 nm showed a 10-fold enhancement, which was similar to single CPT (Figure S13). High-performance liquid chromatography (HPLC) was also performed to verify the cleavage of CPT from Fc-CPT@HACD upon addition of GSH. As shown in Figure S14, a peak at 3.5 min (retention time) corresponding to CPT was detected after the supramolecular assembly was incubated with GSH.

The in vitro anticancer efficacies of CPT (98% purity), Fc-CPT, CPT + HACD, and the Fc-CPT@HACD supramolecular assembly were examined in human lung adenocarcinoma (A549) cells and human normal embryonic kidney (293T) cells (both obtained from the Cell Center of Peking Union Medical College) by MTT assays. Figure 3 and Table S1 demonstrate that all four groups exhibited dose-dependent antitumor activity toward tumor cells and low cytotoxicity toward normal cells. Fc-CPT@HACD even at a high concentration of 108.8 μM had no obvious toxicity toward 293T cells after incubation for 48 h, indicating the good biocompatibility of the supramolecular assembly. To our delight, even at the concentration of 108.8 μM, CPT alone, Fc-CPT alone, and the mixture of CPT and HACD exhibited no obvious toxicity toward A549 cells. The tumor cell mortality was less than 50%, showing a low toxicity to tumor cells due to their low solubility and weak host–guest binding ability in PBS. In contrast, the Fc-CPT@HACD supramolecular assembly showed more intense cytotoxicity. Relative cellular apoptosis rates of 80% and 95% were observed at 54.4 and 108.8 μM, respectively. Moreover, the tumor cellular uptake of the supramolecular assembly was investigated by fluorescence confocal microscopy. As shown in Figure S15, A549 cells displayed the bright blue fluorescence of Fc-CPT in the cytoplasm. We may conclude that the HA moiety of Fc-CPT@HACD specifically recognizes A549 cells by strongly binding to HA receptors on the cell surface and then enters the tumor cells through receptor-mediated endocytosis, which further encouraged us to investigate its efficiency for in vivo anticancer therapy on A549 tumor implanted mice.

Figure 3.

Figure 3

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Cellular viability of (a) 293T normal cells and (b) A549 tumor cells after the treatment with the CPT, Fc-CPT, CPT + HACD, and the Fc-CPT@HACD supramolecular assembly at various concentrations after incubation for 24 h.

As can be seen in Figure S16a, there was no significant fluctuation in body weight, suggesting negligible side effects of Fc-CPT@HACD for cancer therapy. Tumor volumes in the mice of the PBS groups were twice as large as they used to be, indicating no inhibition of tumor growth. Positive control groups with free CPT displayed moderate inhibition efficiency because the drug could hardly reach the tumor tissues. For the mice injected with Fc-CPT@HACD from tail vein, 50% tumor reduction was observed, resulting from the higher antitumor efficacy of the supramolecular assembly (Figure S16b). Compared with the control group with PBS and the positive control group with CPT, the tumor growth was inhibited in the treatment group by about 8.5-fold and 5.4-fold, respectively, indicating the promise of the Fc-CPT@HACD complex as an anticancer drug. The promising results may attributed to an accumulation of Fc-CPT@HACD in tumor tissues through the enhanced permeability and retention (EPR) effect and the slow drug release performance. Finally, hematoxylin and eosin (H&E) analysis of tumor issues and other major organs (spleen, liver, kidney, and lung) was conducted to assess the antitumor activity of Fc-CPT@HACD at the cellular level (Figure 4). Clearly, there was no noticeable injury in other organs of the mice. Tumor cells in the PBS group showed the densest and most regular morphology, indicating the least necrosis. The other control group and the Fc-CPT@HACD group showed moderate necrosis and the most necrosis, respectively. On the basis of these results, we may draw the conclusion that the targeting Fc-CPT@HACD exhibited enhanced antitumor efficiency with slighter side effects than commercially available CPT and was more effective than systems lacking targeting groups,27,28 systems lacking stimulus responsiveness,29or simple loading of antitumor drugs through π stacking.30,31

Figure 4.

Figure 4

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H&E staining of major organs (spleen, liver, kidney, and lung) and tumor sections in different treatment groups and healthy mice as a control. Scale bars are 80 μm.

In summary, we developed a stimuli-responsive tumor-targeting supramolecular assembly with Fc-CPT and HACD. Benefiting from the overexpressed HA receptor in malignant tumor, the obtained Fc-CPT@HACD could anchor to tumor issues specifically. We further demonstrated that the assembly could respond to H2O2 and GSH but exhibited significant stability in fetal bovine serum. The overexpressed H2O2 in tumor cells could oxidize Fc to Fc+, causing disruption of the assembly. Then the S–S bonds could be cut by abundant GSH, resulting in the generation of CPT. In vitro and in vivo experiments demonstrated that Fc-CPT@HACD possessed higher antitumor efficiency with negligible side affects compared with PBS and CPT. Thus, we believe that this study will provide a reference to develop a new kind of targeting-efficient in situ antitumor drug for use in the clinic.

Glossary

Abbreviations

GSH

glutathione

CPT

camptothecin

β-CD

β-cyclodextrin

Fc

ferrocene

Fc+

ferrocenium ion

HA

hyaluronic acid

A549 cells

human lung adenocarcinoma cells

293T cells

human normal embryonic kidney cells

EPR effect

enhanced permeability and retention effect

DMSO

dimethyl sulfoxide

CV

cyclic voltammetry

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.0c00040.

  • Experimental methods and procedures, additional spectra, and original data (PDF)

We thank the National Natural Science Foundation of China (21672113, 21772099, 21971127, and 21861132001) for financial support.

The authors declare no competing financial interest.

Supplementary Material

ml0c00040_si_001.pdf (908.7KB, pdf)

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Associated Data

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Supplementary Materials

ml0c00040_si_001.pdf (908.7KB, pdf)

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