Nanotechnology. 2017 Jul 7;28(27):275601.

Coordination polymer nanocapsules prepared using metal–organic framework templates for pH-responsive drug delivery

Lei Tang, Jiafu Shi, Xiaoli Wang, Shaohua Zhang, Hong Wu, Hongfan Sun, Zhongyi Jiang

From the School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, People’s Republic of China

Correspondence should be addressed to Hong Wu, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, People’s Republic of China, Email:



A facile, efficient, and versatile approach is presented to synthesize pH-responsive nanocapsules (∼120 nm) by combining the advantages of metal–organic frameworks (MOFs) and metal–organic thin films. ZIF-8 nanoparticles are used as templates on which a thin film coating of iron (III)–catechol complexes is derived from the coordination between dopamine-modified alginate (AlgDA) and iron(III) ions. After the template removal, nanocapsules with a pH-responsive wall are obtained. Doxorubicin (Dox), a typical anticancer drug, is first immobilized in ZIF-8 frameworks through coprecipitation and then encapsulated in nanocapsules after the removal of ZIF-8. The structure of the iron(III)–catechol complex varies with pH value, thus conferring the Dox@Nanocapsules with tailored release behavior in vitro. Cytotoxicity tests illustrate the highly effective cytotoxicity of Dox@Nanocapsules towards cancer cells. This study provides a new method for preparing smart nanocapsules and offers more opportunities for the controlled delivery of drugs.



Despite significant advances in diagnosis and therapy over the past 30 years, cancer remains one of the leading causes of death. Patients treated by conventional strategies commonly suffer from frequent relapses and severe side effects. The lowered extracellular pH is important signatures strongly associated with cancer invasion, progression, and metastasis.[1,2] In this regard, pH-responsive delivery system represents an effective strategy for cancer therapies because most cancer tissues have lower extracellular pH values (pH=5.7–7.8) than normal tissues and the bloodstream, and pH values drop further inside cells, especially, inside endosomal (pH=5.5–6.0) and lysosomal (pH=4.5-5.0) compartments.[3] To date, different types of drug carriers, including liposomes, polymeric micelles, carbon nanotubes,  mesoporous silica nanoparticles have been extensively studied for the construction of pH-responsive delivery system.

Nanocapsules are exceptionally promising materials with applications in areas as diverse as catalysis, imaging, drug delivery, and protection of sensitive agents such as enzymes and proteins. Especially in the drug delivery system, nanocapsules have gained tremendous attention due to their potential applications in encapsulation and controllable drug release. However, to be a promising drug delivery nanocarrier, nanocapsules should be biocompatible, readily synthesized, and able to control the release of a drug. However, despite considerable effort, developing nanocapsules that can meet all of these requirements is still a challenge. Our recent publication addresses this issue by combining the advantages of metal–organic frameworks and metal–organic thin films.

Metal–organic coordination chemistry has been widely explored due to its mild and controllable features, especially in the preparation of metal–organic frameworks (MOFs) and metal–organic thin films. [4,5,6] MOFs have emerged as one of the highest-potential drug delivery carriers due to their outstanding porosity features and facile synthesis procedures. Compared to conventional templates, MOFs can efficiently carry anticancer drugs and be completely removed under mild conditions, thus providing an advantageous and novel class of template material for nanocapsule preparation. Meanwhile, metal–organic thin films can also be formed based on metal–organic coordination chemistry through appropriate screening of organic ligands and metal ions. Metal–organic thin films exhibit potential applications due to their diverse properties, including hybrid physicochemical properties, stimuli responsiveness, and controlled functionality. It can be reasonably supposed that combining the advantages of porous MOF nanocrystal (as a sacrificial template/carrier for immobilization) and metal–organic thin film (as a pH-responsive wall for smart release) may offer a novel, feasible, and efficient approach to preparing stimuli-responsive nanocapsules for controlled anticancer drug delivery (Figure 1).

Recent studies indicated the new coordination polymer nanocapsules displayed obvious pH-responsive release performances (Figure 2a). At pH 7.4, a slow release of Dox was found, with less than 23% of Dox being released over 37 h. Incubation of Dox@Nanocapsules at pH 6.0 resulted in a slightly increased release of Dox to 25% within 37 h. When the incubation pH value was reduced to 5.0, a remarkable increase in Dox release was achieved with a high release percentage of 71% in 37 h. At alkaline pH condition (pH 8.2), the release behavior was notably depressed (only 14% after 37 h). To investigate the cytotoxic effects of the Dox@Nanocapsules, an MTT assay was used to examine the cell viabilities of HeLa cell lines. For the cell viability assays, free Dox, Fe–AlgDA nanocapsules without Dox, and Dox@ Nanocapsules were introduced into the culture media, respectively. As shown in figure 2b, the Fe –AlgDA nanocapsules without Dox had little cytotoxic effect on cells, whereas the Dox@Nanocapsules exhibited an effective cytotoxicity towards cancer cells. The free Dox showed higher cytotoxicity compared to Dox@Nanocapsules, which indicated that the nanocapsules provided an added advantage of controlled release.

Fluorescence microscopy images were used to study the intracellular release behavior of Dox@Nanocapsules. Red fluorescence imaging was performed to trace the released Dox. In the case of free Dox, the red fluorescence spread all over the cells in 2 h, primarily because the free Dox could easily diffuse into the cytosol. For the Dox@Nanocapsules (Figure 3), Dox was concentrated in the cytoplasm after 2 h’s incubation, and there was only very slight red fluorescence in the nuclei. The whole spreading of red fluorescence was observed after 8 h. This delayed spreading demonstrated that the release of Dox from nanocapsules was in a slow, controllable and sustainable way in the cytosol.

To further elucidate the mechanism of pH-responsive release of Dox from nanocapsules, the suspension of nanocapsules was monitored as the pH value changed. The color of the suspension changed progressively from colorless, blue/ green, pink, to red when the pH was gradually increased from 4.0 to 9.8(Figure 4a). UV–vis absorbance spectroscopy also confirmed that the coordination state between Fe and AlgDA was affected by pH values (Figure 4b). Raman spectroscopy was recorded to further demonstrate the interaction of Fe3+-catechol complexes in the polymer networks after metal-organic thin film coating (Figure 4c and 4d). The peak at 1230-1550 cm-1 was ascribed to the vibrations of the carbon bonds in the catechol ring. The three major characteristic peaks of metal-catechol interaction appeared in the range of 470-670 cm-1 and their intensity increased with the increase of pH value. The peaks at 592 and 640 cm-1 were assigned to the interaction between the C3 and C4 oxygens of the catechol, respectively. The peak at 538 cm-1, which origniated from the change of the bidentate chelate, became weaker when the pH value decreased from 8.2 to 7.4 and to 5.0.

In summary, a novel approach is developed for the synthesis of pH-responsive nanocapsules via metal-organic coordination chemistry, where metal-organic frameworks (MOFs) serve as the sacrificial core and metal-organic thin films serve as the pH-responsive wall. The nanocapsules can effectively carry anticancer drugs by ZIF-8-mediated drug loading and exhibit pH-responsive fashion for controlled drug delivery.



Figure 1. Illustration of the preparation procedure of Dox@Na- nocapsules and the pH-responsive release behavior of Dox.



Figure 2. (a) In vitro Dox release profiles of the Dox@Nanocapsules at different pH values. (b) Cell viability of HeLa cells incubated with free Dox, nanocapsules, and Dox@Nanocapsules for 24 h.



Figure 3. Fluorescence microscopy image analysis of HeLa cells incubated with Dox@Nanocapsules for 2 and 8 h.



Figure 4. (a) Set of photographs of nanocapsules in different pH environments. (b) UV absorbance spectra of solution of nanocapsules at different pH values (4.0, 5.0, 6.0, 7.4, and 8.2). (c) Metal–organic coordination films 3 forming on the surface of plate glass at pH 5.0, 7.4, and 8.2 (prepared for resonance Raman spectroscopy). (d) Resonance Raman spectroscopy of Fe –catechol complexation at different pH.



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