Rational Design of Polyphenol-Poloxamer Nanovesicles for Targeting

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Rational Design of Polyphenol-Poloxamer Nanovesicles for Targeting Inflammatory Bowel Disease Therapy Xinyu Wang, Jun-Jie Yan, Lizhen Wang, Donghui Pan, Runlin Yang, YuPing Xu, Jie Sheng, Qianhuan Huang, Huimin Zhao, and Min Yang Chem. Mater., Just Accepted Manuscript • Publication Date (Web): 02 Jun 2018 Downloaded from http://pubs.acs.org on June 2, 2018

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Chemistry of Materials

Rational Design of Polyphenol-Poloxamer Nanovesicles for Targeting Inflammatory Bowel Disease Therapy Xinyu Wang†*, Jun-Jie Yan†, Lizhen Wang, Donghui Pan, Runlin Yang, YuPing Xu, Jie Sheng, Qianhuan Huang, Huimin Zhao, Min Yang* Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, China ABSTRACT: Currently, there is no curative treatment for inflammatory bowel disease (IBD), which has an increased risk of colitis-associated cancer. Corticosteroids are the main clinical IBD therapeutics but have significant side effects. Even heavy corticosteroid use can result in the failure of IBD treatment which may lead to resective surgery. In this study, we designed one type of new drug delivery system (DDS) delivering dexamethasone (DEX), an anti-inflammation corticosteroid, for IBD therapy. This DDS was screened by hydrogen bonding-induced facile self-assembly of natural and safe polyphenols and polymers. The nanoparticles fabricated from tannic acid and Pluronic F-68 have a uniform spherical shape. With approximately 10% DEX loaded, PPNP-DEX showed responsive release behavior in the presence of esterase. Moreover, PPNP-DEX exhibited great potential in radical scavenging at inflammation sites. Drug retention rates can also be enhanced in mice with colitis compared with healthy controls because of this inflammation targeting ability. Owing to all these advantages, PPNP-DEX achieved remarkable treatment efficacy in colitis mice compared to PPNP or free DEX. This study demonstrates PPNP as a promising drug delivery platform for IBD therapy. More importantly, it provides a new design strategy of therapeutics for various inflammatory diseases.

INTRODUCTION Inflammatory bowel disease (IBD), which has two major types, ulcerative colitis and Crohn’s disease, has a prevalence of 150-250 per 100000 people.1 Additionally, IBD predisposed patients have a 20% incidence of developing of colitisassociated cancer, a type of high-mortality colon cancer.2 However, a large number of patients receiving treatments currently cannot adequately control their symptoms, thus adversely affecting their quality of life.3,4 Reactive oxygen species (ROS), such as superoxide (O2−), singlet oxygen (O21), hydrogen peroxide (H2O2), hydroxyl radical (•OH), hypochlorite (ClO−), and peroxynitrite (ONOO−) are involved in many important biochemical processes.5 It was found that ROS play an important role in the initiation and progression of human IBD, which has made them a target for therapy.6 ROS-responsive thioketal nanoparticles have achieved excellent treatment efficacy in dextran sulfate sodium (DSS)-induced colitis.7 It has been reported that IBD therapy also benefits from ROS defence.8,9 Thus, we hypothesized that combination delivery of ROS scavengers and anti-inflammation drugs might achieve a better therapeutic effect. Multifunctional nanoparticles have many biomedical application including drug delivery, cancer therapy, diagnosis, and immuno-oncology.10-12 Nanoparticles have also been developed in IBD therapy in recent years.13,14 Various nanoparticles, such as liposomes15, micelles16, nanogels17, and others18,19, also have been proved to have great potential in IBD therapy. One of the main advantages of nanodrug carriers in cancer therapy is the enhanced permeability and retention effect in the hyper-permeable solid tumor.20 Interestingly, hyperpermeability and neutrophil infiltration are the key metrics in in-

flamed colon tissues.21 Therefore, nanotherapeutics have an advantage in IBD therapy. It has been demonstrated that the adhesion of selective nanoparticles to an inflamed colon enhances colitis treatment efficacy.22 However, the development of biocompatible and degradable, and inflammation-targeting nanoparticles for high efficiency IBD therapy is still in urgent demand. Polyphenols, including tannic acid (TA), epigallocatechin gallate (EGCG), and catechin (CAT) are natural products found in green tea and are affirmed by FDA as Generally Recognized as Safe (GRAS) compounds. These polyphenols have strong radical-scavenging and antioxidant abilities. The antioxidant and anti-inflammatory activities of polyphenols have been reported widely with applications including immunoprotection23, cardioprotection24, cancer treatment25, and IBD treatment.26 Polyphenols also have important application in nanomaterials.27,28 For example, polyphenol nanoparticles fabricated with EGCG by Li’s group exhibited excellent radical-scavenging activities.29 Tannic acid has been developed as a responsive gate in a photo triggered drug release system by Park et al.30 Interestingly, TA has also been found to be a degradable mucoadhesive compound by Lee et al.31 The catechol group is found in mussel adhesive proteins and is considered to be a key group that improves wet-resistant adhesion.32 This makes TA an excellent candidate for colitis targeting drug delivery carrier. Herein, we represent a facile approach for the preparation of polyphenols-based drug delivery system by self-assembling polyphenols and polymers with a PEG block. We named this nanoparticle polyphenols and polymers self-assembled nanoparticle (PPNP). An anti-inflammation corticosteroid

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FIGURE 1. Design and synthesis of PPNP. (A) Chemical structure of various polymers (PEG, F-127, and F-68) and polyphenols (TA, EGCG, and CAT). (B) Scheme of the hydrogen bonding between a polyphenol and a PEG chain. (C) Picture of various PPNP solutions and their Tyndall effect. (D) The transmittance of various PPNP solutions at 450 nm. The concentration of PPNP is 0.1 mg/mL. (E) Size and PDI of PPNP determined by DLS. Values are represented as the means ± SD (n = 3).

dexamethasone (DEX) was encapsulated in PPNP for oral delivery. PPNP-DEX was designed to be responsively degradable in the colitis microenvironment. Inflammation is accompanied by up-regulation of degradative enzymes like esterase33 while polyphenols like TA and EGCG can be hydrolyzed by esterase.34,35 Polyphenols in PPNP have a strong radical scavenging ability that can be used to exhaust the ROS produced at the inflammation site. Our design proposed herein combines these advantages which may be helpful in IBD therapy.

RESULTS AND DISCUSSION Galloyl groups have been reported to have strong interactions with polyethyleneglycol (PEG) by hydrogen bonding which is stable under physiological conditions.36-38 Thus, to screen for the best candidate nanocarrier, three types of polyphenols, namely, TA, EGCG and CAT, were chosen with a galloyl group density ranging from high to low. Polymers containing PEG chains with or without hydrophobic chain were chosen as another component (Figure 1A). Three types of polymers were chosen, namely, PEG, poloxamer 407 (Pluronic F-127), and poloxamer 188 (Pluronic F-68), which are all regarded as safe by US FDA. The poloxamer is a polymer composed of a central hydrophobic chain of poly(propylene oxide) (PPO) flanked by two hydrophilic chains of poly(ethylene oxide) (PEO) which is otherwise known as PEG. The polyphenols and polymers were self-assembled in pairs by dropping a dimethyl sulfoxide solution of the polyphenols and polymers mixture into aqueous solution under magnetic stirring. Pictures of the products are shown in Figure 1C. The Tyndall effect was obvious in the products fabricated from TA and the three polymers. This should be attributed to the higher galloyl group density of TA than EGCG and CAT, which has great

influence on the hydrogen bonding effect between the two components. Furthermore, the Tyndall effect of the products made by the three polymers with TA is also different. It can be seen that the longer the hydrophobic chain is, the more obvious the Tyndall effect. This observation can also be verified by detecting the transmittance at 450 nm and is caused by light scattering (Figure 1D and Figure S1). One possible reason is that the presence of longer hydrophobic chains in F-68 facilitated micellar formation. By comparing the Fourier transform infrared (FT-IR) spectra of F-68, TA and PPNP in Figure S2 in supporting information (SI), we found that the carbonyl group (C=O) stretching vibration in TA shifted from 1714 to 1728 cm-1 in PPNP. In addition, C-H stretching in F-68 shifted from 2879 to 2964 cm-1. These results indicate an intermolecular interaction between TA and F-68 through hydrogen bonding (Figure 1B). It was also found that PPNP can be disassembled in basic pH solutions (Figure S3). The catechol and galloyl groups become deprotonated in basic pH solutions, which break the hydrogen bonding interactions in PPNP. Hydrodynamic size and polydispersity index (PDI) were also examined to further understand the various selfassembled products. The results showed that nanoparticles formed in every product (Figure 1E). However, the nanoparticles self-assembled with EGCG or CAT exhibit much larger size or PDI than those self-assembled with TA. More importantly, the PDI of PPNP self-assembled with TA and F-68 is less than 0.05 which is the lowest among all the products. It is suggested that the most uniform PPNP can be obtained by self-assembly of TA and F-68. In addition it was chosen for further study here. We speculated that hydrophobic drugs could be loaded into PPNP with hydrophobic PPO chains. DEX is an antiinflammation corticosteroid that has been applied in colitis


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treatments for decades.39,40 To investigate the drug-loading ability of PPNP, DEX was loaded by co-self-assembly with TA and F-68. As shown in Figure 2A, DEX was mixed with TA and F-68 before self-assembly. The PPNPs were fabricated with DEX at several feed ratios [DEX: TA: F-68 = 1:5:5 to 14:5:5 (w/w)]. The drug-loading efficiency and drug encapsulated efficiency was determined by high-performance liquid chromatography (HPLC). As shown in Figure 2B and Figure 2C, larger drug-loading efficiency can be achieved at higher drug feeding ratio. The largest drug-loading efficiency was

achieved by a weight ratio of ~35% while the drug encapsulation efficiency was approximately 22.7%. We named this drug-loaded PPNP PPNP-DEX. To investigate the size distribution and morphology of PPNP, TEM and AFM data were examined. The AFM image in Figure 2E shows that PPNPDEX has a spherical shape with a diameter of approximately 60 nm. The line-scan analysis in Figure 2F and the TEM image in Figure 2D are consistent with the diameter of PPNPDEX.

FIGURE 2. (A) Illustration of the drug-loading process. (B) Drug-loading efficiency and (C) drug encapsulation efficiency of PPNP-DEX. (D) TEM image of PPNP-DEX. (E) AFM image of PPNP-DEX. (F) Line scan of the AFM image in (E). (G) Average sizes and zeta potential of PPNP-DEX at a concentration of 0.1 mg/mL fabricated in five batches. Values are represented as the means ± SD (n = 3).



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sizes. It can be explained by that the hydrogen bonding interaction between TA

FIGURE 3. (A) Accumulative DEX release with or without esterase (30 U/mL). The dialysis buffer in the first 4 h is SGF. After that, it was changed to SIF for another 44 h. Esterase was added to the dialysis tube at the time point of 4 h. (B) The degradation percentage of PPNP-DEX with or without esterase (30 U/mL) in SIF for 48 h. Trolox equivalent antioxidant capacity (TEAC) of PPNP-DEX with various concentrations from 1 to 200 µg/mL with scavenging ABTS radicals (C) and DPPH radicals (D).

One of the limitations for the clinical applications of nanoparticles is difficulty in the quality control of nanoparticles because subtle changes in the composition of the nanoparticle can affect its size and in vivo behavior. We made several batches of PPNP with TA and F-68. The average sizes and zeta potentials of PPNP are very similar between different batches (Figure 2G). These results suggest that PPNP-DEX can be readily fabricated with a repeatable size which are conducive its possible clinical translation. To investigate the release behavior of PPNP-DEX, we simulated the transit process in human for a set time with simulated gastric fluid (SGF) or simulated intestinal fluid (SIF). The maximum gastric transit time and intestinal transit time of a human are approximately 4 h and 48 h, respectively.41 Therefore, we determined the drug release behavior for 4 h in SGF and 44 h in SIF. We found that less than 10% DEX released from PPNP-DEX in the first 4 h (Figure 3A). This result suggests that only a small amount of drug will release before PPNP-DEX arrives in the intestine. DEX released steadily in the following 44 h. Approximately 30% of DEX was released at the end point of this simulated transit process. Interestingly, with 30 U/mL esterase added at 4 h to stimulate the colitis environment, the percentage of DEX released increased to 62%. This esterase responsive release behavior may be attributed to the degradation of PPNP-DEX. To investigate the degradation behavior, PPNP-DEX was incubated with or without 30 U/mL esterase for 48 h. PPNP-DEX degraded approximately 36% in the presence of esterase compared to only 20% in the absence of esterase (Figure 3B). To explore how PPNP-DEX changes in stomach, the size distribution and UV-Vis spectra of PPNPDEX were determined in SGF. The results in Figure S4 showed that PPNP-DEX aggregated into micelles with larger

Scheme 1. Schematic illustration of oral delivery of PPNP-DEX. PPNP-DEX remains stable in the environment of the gastrointestinal tract and noninflamed mucosal tissues. However, at sites of intestinal inflammation, where esterases and ROS are upregulated, PPNP-DEX degrades, thus releasing DEX and scavenging ROS at the sites of inflammation.

and PEG chain is strengthened as more catechol and galloyl groups become protonated in an acid environment. Enhanced ROS generation by polymorphonuclear neutrophils is one of the important parameters in tissue inflammation.42 To determine the ROS scavenging activity of PPNP-DEX, ABTS and DPPH assays were performed. ABTS and DPPH assays are usually used to measure the radical-scavenging activity of compounds.43 The Trolox equivalent antioxidant capacity (TEAC) determined by the ABTS and DPPH assays suggests that PPNP-DEX has a robust radical-scavenging ability (Figure 3C and 3D). The schematics of this responsive drug release and the ROS scavenging process of PPNP-DEX in an inflamed colon presented in Scheme 1A. Biocompatibility is a generally concerned property for drug carriers. As the components of PPNPs have excellent biocompatibility, PPNPs was speculated have ideal biocompatibility. We evaluated the cytotoxicity of PPNPs and PPNPs -DEX. The results in Figure S6 show that both PPNP and PPNPDEX have no obvious cytotoxicity in L929 cell line (mouse fibroblast cell line) in the concentration range less than 0.1 mg/mL. Targeting of inflamed colons is the key factor in highly efficient IBD therapy. Polyphenols such as tannic acid were found to be degradable mucoadhesive compounds.37 The inflamed colon epithelium is positively charged because of the in situ accumulation of positively charged proteins, such as transferrin15, bactericidal/permeability-increasing protein, and antimicrobial peptides44,45. As negatively charged PPNP contains a large amount of tannic acid, we hypothesize that PPNP preferentially adheres to the inflamed mucosa in mice with colitis. Thus, we determined the in vivo colitis targeting ability of PPNP. IR780, an NIR dye that has a maximum absorbance at 780 nm, was encapsulated in PPNP (named PPNP-IR780). The solution of this nanoparticle was administered orally in


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both healthy mice and colitis mice. NIR fluorescence images were taken by an in vivo imaging system (IVIS spectrum) at various time post intragastric administration. As shown in Figure 4A and Figure 4B, the average fluorescence intensity of the inflamed colon was obviously higher than that of healthy colon at 6, 12, and 24 h post intragastric administration. At 6 h post intragastric administration, the average fluorescence intensity of the inflamed colons in vivo is three times that of healthy colons. At 24 h and 48 h post intragastric administration, the average fluorescence intensity decreased significantly in both healthy and colitis mice. However, the average fluorescence intensity of inflamed colons still remains about two times greater than that of healthy colons. The colons were collected after the sacrifice of mice at 24 h post intragastric administration. As shown in Figure 4C and Figure 4D, the average fluorescence intensity of inflamed colon is about four times that of healthy colons. These results suggest

that PPNPs have an excellent inflamed colon-targeting ability. This inflamed colon-targeting behavior of PPNP may have great advantages in IBD therapy. Non-degradable PEG compounds were reported to induce anti-PEG antibodies in vivo that can accelerate blood clearance and make a loss of therapeutic efficacy for PEGylated drugs which need intravenous injection.46,47 As far as we know, the effect of anti-PEG antibodies on orally delivered PEGylated drug was not reported. To determine if transition process of PPNPs-DEX was affected by anti-PEG antibodies, C57BL/6 mice were intragastric injected with PPNPs-IR780 twice. From the fluorescence images at different time postinjection in Figure S7, we cannot find an obvious difference between the two injections. Thus, anti-PEG antibodies may have little influence on orally delivered PEGylated-drug. However, this issue still need to be verified seriously in further study.

Figure 4. In vivo inflammation targeting in colitis mice. (A) In vivo fluorescence imaging of orally delivered PPNP-IR780 in colitis mice and healthy controls. (B) ROI fluorescence intensity of the in vivo fluorescence images quantified with an IVIS imaging system. (C) Fluorescence images of distal colons separated from colitis mice and healthy controls after 24 h in vivo imaging. (D) ROI fluorescence intensity of the fluorescence images of distal colons quantified with Living Image 4.5 software. Values are represented as the means ± SD (n = 5).

We then tested the in vivo treatment efficacy of PPNP-DEX in DSS-induced colitis mice. Body weight loss is an important parameter for monitoring the colitis phenotype.48 As shown in Figure 5A, the body weight of DSS-induced colitis mice decreased approximately 14% in 7 days compared with their initial weight. In addition, the body weight of healthy mice increased slightly. After that, the colitis mice were divided into four groups and were treated with water, PPNP, DEX, or PPNP-DEX. This treatment lasted for three days. Surprisingly, the body weight of the colitis mice treated with PPNP-DEX increased obviously and is even close to that of the healthy control mice. The body weight of the colitis mice treated with PPNP and DEX also increased to 94% and 92%, respectively, compared to the initial weight. After treatment, the mice were

sacrificed, and the colons were collected for colonic myeloperoxidase (MPO) activity and histological examination. The colonic MPO activity reduced obviously after PPNP-DEX treatment, while it was also reduced slightly by PPNP or DEX (Figure 5B). TNF-α is one of the most important inflammatory factors. To determine the anti-inflammatory effect of the treatment, TNF-α activity of colon was tested by the enzyme-linked immunosorbent assay (ELISA) assay. The results in Figure 5C show that the TNF-α activity increased obviously in DSS induced colitis mice. And all the three groups with drug treatment show a decrease in TNF-α activity. Histological examination and score were guided by a previous protocol.49 These results showed that the colons of colitis mice treated with PPNP-DEX had intact epitheliums, well-defined



crypt structures and relatively low levels of neutrophil invasion (Figure 5D and Figure 5E). In contrast, colitis mice treated with water showed all the characteristic of DSSinduced inflammation. Remarkably, PPNP, along with the free drug DEX, also exhibits a colitis treatment effect in these examinations. It has been widely reported that polyphenols

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have a therapeutic effect on IBD by virtue of their antiinflammatory and vasculoprotective properties50,51. Thus, the colitis treatment effect of PPNP should benefit from the tannic acid component. This carrier-assisted strategy may have an important role in the ideal colitis treatment effect of PPNPDEX.

Figure 5. (A) Treatment schedule in mice bearing DSS-induced colitis and daily weight change in different groups of mice. (B) Colonic MPO activity of different groups of mice. (C) Relative TNF-α activity of different groups of mice determined by ELISA. (D) Average histological score of mice in different groups. (E) Hematoxylin and eosin-stained colon section from mice after treatment. Values are represented as the means ± SD (n = 5). (*) p < 0.05, (**) p < 0.01, (***) p < 0.001, (N.S.) nonsignificant.

CONCLUSIONS

ASSOCIATED CONTENT

In summary, we designed a supramolecular nanoparticle selfassembled by polyphenols and poloxamers for inflamed colontargeting drug delivery. Several types of polyphenols and polymers are used for screening for the most favorable drug carrier. The nanoparticles fabricated by tannic acid and F-68 exhibited the lowest PDI and a uniform spherical shape. Meanwhile, this nanoparticle loaded with DEX can be readily fabricated with a uniform, tunable and repeatable size distribution. PPNP-DEX showed a responsive-release behavior in SIF solution in the presence of esterase. Furthermore, PPNP-DEX showed a robust radical-scavenging ability for ABTS and DPPH radicals. This nanoparticle also achieved an inflamed colon-targeting effect in vivo. Compared to previous drug delivery systems for IBD, our system has a major advantage: the combination of biosafe components, inflamed colon-targeting ability, esterase-responsive degradability, and reactive oxygen species-scavenging activity. Importantly, all these benefits together make our system a highly efficient IBD therapeutic.

Supporting Information. The Supporting Information is available free of charge on the ACS Publications website at DOI:. Experimental section and further data on FTIR, transmittance, scattering intensity, UV-Vis spectra and cell viability of PPNP and/or PPNP-DEX; fluorescence images of mice treated with PPNP-IR780.

AUTHOR INFORMATION Corresponding Authors * Email: [email protected] (X.W.); * Email: [email protected] (M. Y.)

Author Contributions X.W. and J.Y. contributed equally on this manuscript.

ORCID Xinyu Wang: 0000-0002-9167-2077


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Jun-Jie Yan: 0000-0001-8016-2277 Min Yang: 0000-0001-6976-8526 Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT We thank financial supports from the National Natural Science Foundation of China (31671035, 51473071, 21504034), Natural Science Foundation of Jiangsu Province (BK20170204, BK20161137, BE2016632), National Significant New Drugs Creation Program, and Jiangsu Provincial Medical Innovation Team (CXTDA2017024).



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(51) Farzaei, M. H.; Rahimi, R.; Abdollahi, M. The role of dietary polyphenols in the management of inflammatory bowel disease. Curr. Pharm. Biotechnol. 2015, 16, 196-210.



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