Synthesis of Redox-Responsive Core Cross-Linked Micelles Carrying

Aug 20, 2018 - The M-5L micelle carrying left-handed helical arms showed better therapeutic effect than the other two due to the rapid cell membrane ...
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Letter Cite This: ACS Macro Lett. 2018, 7, 1073−1079

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Synthesis of Redox-Responsive Core Cross-Linked Micelles Carrying Optically Active Helical Poly(phenyl isocyanide) Arms and Their Applications in Drug Delivery Song-Qing Zhao, Guiju Hu, Xun-Hui Xu, Shu-Ming Kang, Na Liu, and Zong-Quan Wu* Department of Polymer Science and Engineering, School of Chemistry and Chemical Engineering, and Anhui Key Laboratory of Advanced Catalytic Materials and Reaction Engineering, Hefei University of Technology, 193 Tunxi Road, Hefei 230009, Anhui Province, China

ACS Macro Lett. Downloaded from pubs.acs.org by TU MUENCHEN on 08/21/18. For personal use only.

S Supporting Information *

ABSTRACT: In this manuscript, we designed and synthesized three core cross-linked micelles (M-5L, P-5L, and P-5D) with redox-responsive disulfide bonds in the core and carrying optically active helical polyisocyanide arms. Their arms were different in the helicity of the main chain and the chirality of the side groups. These micelles showed excellent redox-responsiveness to reducing agent. However, because of the different chiralities of the arms, the three micelles exhibited different performances in drug delivery and controlled release. The M-5L micelle carrying left-handed helical arms showed better therapeutic effect than the other two due to the rapid cell membrane permeability.

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of this method, helical polyisocyanide with precise topology was facilely achieved.25 In this work, we designed and synthesized a series of optically active core cross-linked micelles carrying helical polyisocyanide arms with redoxresponsive disulfide bonds in the core (Scheme 1). The disulfide bonds of the core were liable for cleavage with the presence of reducing agents such as glutathione (GSH). It is well-known that GSH is overexpressed in the intracellular matrices of tumor cells with concentration 2−3 orders of magnitude higher than that in extracellular environments.26,27 Combining these features, the polymers were utilized in anticancer drug delivery of this work. Very interestingly, the different chiralities of the polymeric carriers resulted in different performances in drug delivery and controlled release. The core cross-linking micelles bearing L-alanine ester pendants with left-handed helical conformation showed better performance than those with the opposite handedness under the same conditions. To the best of our knowledge, this is the first report that reveals the influence of the chirality of drug carriers on drug delivery and controlled release. As shown in Scheme 1, single left- and right-handed helical polyisocyanides M-poly-L-120, P-poly-D-120, and P-poly-L-120, bearing L- or D-alanine ester pendants with a terminal polymerizable norbornene unit were first prepared.28 The molecular weight (Mn ) and its distribution (M w/Mn)

ecently, remarkable progress has been made in the area of the polymeric drug delivery systems for cancer chemotherapy.1−5 Such systems can improve drug loading capacity, sustain controlled release, and prolong blood circulation duration of drugs.6−8 Although numerous studies have been conducted, few of them took into account of the chirality of delivery systems. It is well-known that the microenvironment of a living system is chiral, because the basic structural units, such as amino acids and sugars, of biomacromolecules are chiral.9−11 Moreover, most of the effective anticancer drugs, such as paclitaxel (PTX), camptothecine (CPT), and doxorubicin (DOX), are also chiral. From this point of view, the chirality of a polymeric drug carrier may have important influence on drug loading capacity, delivery, and controlled release. Moreover, different chiral carriers may have different behaviors in the interactions with living systems.12−14 Therefore, design and synthesis of chiral drug delivery systems and investigation of the corresponding structure−function relationship are of great interest. Stimulated by the helical structures in biomacromolecules, a lot of studies have been carried out on the artificial helical polymers in the past few decades.15−19 In this context, πconjugated polyisocyanide is one of the most investigated helical polymers owing to its interesting rod-like helical conformation and a broad range of applications.20,21 Its unique helical backbone may exhibit interesting behavior on drug delivery and controlled release, which has never been investigated to date.22 Well-defined helical polyisocyanide can be facilely prepared via the Pd(II)-mediated living polymerization of isocyanide monomers.23,24 Taking advantage © XXXX American Chemical Society

Received: August 13, 2018 Accepted: August 17, 2018

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DOI: 10.1021/acsmacrolett.8b00610 ACS Macro Lett. 2018, 7, 1073−1079

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ACS Macro Letters Scheme 1. Synthesis of Optically Active Core Cross-Linked Micelles

redox-responsive disulfide bonds in the core. In these micelles, the single-handed helical polyisocyanides segment were located at the middle layer, while the hydrophilic polyisocyanides were located at the out layer. The structures of these core crosslinked micelles were first studied by SEC analysis relative to linear polystyrenes (Figure 1a, and Figure S1). As shown in Figure 1a, compared to the linear M-poly-L-120 (Mn = 6.5 kDa, Mw/Mn = 1.21), the SEC curve of the core cross-linked M-3L was shifted to higher molecular weight region, and kept symmetric and single model. The Mn of M-3L was increased to 25.4 kDa, while the polydispersity remained narrow (Mw/Mn = 1.19). After chain extended with monomer 4, the SEC trace of the resulted water-soluble M-5L was sifted to even higher Mnregion, and the Mn and Mw/Mn were respectively estimated to be 32.1 kDa and 1.16 (Table 1). The structures were further verified by 1H NMR and FT-IR analysis (Figures S3−S8). By using the similar procedure, the core cross-linked micelles P-5L and P-5D were facilely prepared from the P-poly-L-120 and Ppoly-D-120, respectively, and were fully characterized (Table 1 and Figures S9−S20). The optical activity of the micelles were investigated by circular dichroism (CD) and UV−vis spectra. As displayed in Figure 1c, M-poly-L-120 showed an intense Cotton effect at the 364 nm with an estimated molar CD intensity (Δε364) of −17.8 M−1 cm−1, confirming the single handed helical structure of the polyisocyanide main chain. The CD and UV−vis spectra of the core cross-linked M-3L is similar to that of M-poly-L-120, suggesting that the helical conformation of the polyisocyanide arms were maintained during the core crosslinking reaction. The chain extended M-5L also showed intense CD at 364 nm, while the CD intense was decreased to −12.5 M−1 cm−1. The decreased CD intensity was mainly

determined by size exclusion chromatography (SEC) were summarized in Table 1. All the three polymers have similar Mn Table 1. Characterization Data for M-5L, P-5L, and P-5Da samples

Mnb (kDa)

Mw/Mnb

sizec (nm)

Δε364d (M−1 cm−1)

M-poly-L-120 M-3L M-5L P-poly-L-120 P-3L P-5L P-poly-D-120 P-3D P-5D

6.5 25.4 32.1 6.9 21.3 27.6 6.6 24.8 31.5

1.21 1.19 1.16 1.19 1.21 1.17 1.15 1.16 1.20

8 96 154 9 102 165 8 91 157

−17.8 −17.4 −12.5 18.2 17.7 13.1 17.9 17.6 12.8

DLCe (%)

8.6

5.3

5.1

a

The polymers were synthesized according to Scheme 1. bMn and Mw/Mn values were determined by SEC analyses relative to polystyrene standards (eluent: THF, temperature: 40 °C). cDetermined by DLS at 25 °C. dThe Δε364 was measured in THF at 25 °C (c = 0.2 mg/mL). eDrug loading content (DLC) of DOX.

and narrow Mw/Mn values (Table 1). Copolymerization of these polymers with a bisnorbornene linker (2) containing a redox-responsive disulfide bond was conducted in THF at 55 °C using Grubbs’ second generation catalyst, afforded the desired core cross-linked micelles.29,30 Grubbs’ second generation catalyst was employed here because it has remarkable activity in such cross-linking reaction. The Pd(II) units at the exterior of the star polymer were then chain extended with a phenyl isocyanide monomer 4 bearing hydrophilic tetraethylene glycol monomethyl ether chain, which afforded a water-soluble star block copolymer with 1074

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Figure 1. SEC curves (a), DLS traces (b), and CD and UV−vis spectra (c) of M-poly-L-120, M-3L, and M-5L; TEM images of M-3L (d) and M-5L (e).

Figure 2. SEC (a) and DLS (b) monitoring of the changes of M-5L with the presence of GSH in water. (c) Fluorescent changes of NR-loaded M5L with the presence of GSH in PBS, and the release of NR with time (inset). (d) Photographs of NR-loaded M-5L in PBS with the presence of GSH at 37 °C.

conformation. After cross-linked with bisnorbornene linker 2 and chain extended with monomer 4, the resulting micelles P5L and P-5D still showed intense CD, although the CD intensities at the absorption region of the main chain were slightly decreased. The Δε364 values for P-5L and P-5D were 13.1 and 12.8 M−1 cm−1, respectively. It is well-known that the size of a carrier plays an important role in drug delivery via systemic circulation, generally it is

because that the new formed poly-4m segments containing some opposite handed helices. Similar phenomena were observed on the P-5L and P-5D. As displayed in Figure S21, the P-poly-L-120 and P-poly-D-120 showed intense positive CD at the absorption region of the helical polyisocyanide backbone. The Δε364 values were estimated to be 18.2 M−1 cm−1 for P-poly-L-120, and 17.9 M−1 cm−1 for P-poly-D-120, respectively, confirmed their single right-handed helical 1075

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Figure 3. (a) DOX release profiles of DOX@M-5L in PBS with GSH at various concentrations. (b) Viability of HUVEC after incubated with DOX@M-5L, DOX@P-5L, and DOX@P-5D at various concentrations for 48 h. (c) Viability of 4T1 cells after incubated with M-5L, DOX@M-5L, and free DOX at various concentrations for 48 h. (d) Viability of 4T1 cells after incubated with DOX@M-5L, DOX@P-5L, and DOX@P-5D with various concentrations for 48 h. The error bars are based on the standard deviations of three parallel tests.

required to be smaller than 200 nm.31,32 Thus, the hydrodynamic sizes of M-5L, P-5L, and P-5D were investigated by dynamic light scattering (DLS). The z-average hydrodynamic diameter (Dh) of the linear P-poly-L-120 was around 8 nm in THF because it was molecularly dissolved (Figure 1b). The Dh increased to 96 nm for M-3L, and 167 nm for M-5L in THF, further confirmed the success of the core cross-linking reaction and chain-extension reaction. The Dh of M-5L was further recorded in water, which was 154 nm, slightly smaller than that in THF, probably due to the shrink of the hydrophilic polyisocyanide chain in water. However, these results clearly indicated the size of M-5L was suitable for drug delivery applications.33,34 Similarly, the Dh values of P-5L and P-5D in water were determined to be 165 and 157 nm at 25 °C, respectively. Note that the structures of the resulting core cross-linked micelles were quite stable in water. No obvious changes on the DLS curves could be discerned after 1 week in diluted aqueous solutions. The morphologies of the resulted core cross-linked micelles were further investigated by transmission electron microscopy (TEM) imaging. As displayed in Figure 1d,e, both M-3L and M-5L showed spherical nanoparticles on TEM images. The dark core and the light corona could be clearly observed for the micelles of M-5L. The average diameters of M-3L and M-5L were 83 and 138 nm, are close to the Dh values obtained by DLS analysis. Similar results were also observed for P-5L and P-5D. The redox-responsiveness of the micelles was first investigated by treating M-5L with a reducing agent GSH in water and followed by SEC analysis of the resulting polymer at appropriate time intervals. As showed in Figure 2a, the single model elution peak gradually became bimodal with a shoulder peak at lower molecular weight (MW) side. With the progress of the incubation, the intensity of the original elution peak of M-5L continually decreased, while the intensity of lower MW

peak increased. After 60 h, the original elution peak at higher MW region could not be discerned, and only an intense lower MW peak (at ca. 22.1 min) was observed, indicating nearly all of the core cross-linked micelles were disintegrated. Such results suggested the disulfide bonds in the core of M-5L were cleaved, and the core cross-linked micelles were probably transformed into a linear block copolymer. DLS analysis was also utilized to study the degradation process (Figure 2b). With the presence of GSH, the Dh of micelle M-5L increased to ∼204 nm after 6 h. The larger sizes might be attributed to the reduced degree of cross-linking and the increased extent of swelling of the cores as a result of partial cleavage of the disulfide bonds.35 After that, the size was decreased and eventually reached to a constant value around 20 nm at 60 h. These studies clearly revealed that the core cross-linked micelles are redox-responsive and can be disrupted with the presence of GSH. The redox-responsive cargo-release of the micelles was then carried out by encapsulating lipophilic nile red (NR) as a model hydrophobic drug into the disulfide cross-linked micelles. NR has a strong fluorescence in a lipid-rich environment, while its fluorescence is very weak with aqueous surrounding. After encapsulating NR into M-5L, the resulting NR-loaded M-5L (NR@M-5L) showed a strong fluorescence in phosphate buffer solution (PBS). No obvious change was discerned on the fluorescence of encapsulated NR at 37 °C for 1 week, suggesting that the NR was tightly restricted in the hydrophobic core. However, with the presence of GSH, the fluorescence intensity of NR gradually reduced. With 10 mM GSH, the fluorescence intensity was reduced about 80% after 48 h. To visualize the process of the release of NR more intuitively, the solution of NR@M-5L was irradiated by a UV light at 365 nm at appropriate time intervals. As displayed in Figure 2d, the red color of the solution gradually faded back to 1076

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To obtain more details, the cellular internalization and intracellular trafficking of DOX@M-5L, DOX@P-5L, and DOX@P-5D were investigated with confocal laser scanning microscope (CLSM). Within 4 and 8 h incubation, the red fluorescence of DOX@M-5L, DOX@P-5L, and DOX@P-5D merged quite well with the blue channel of Hoechst, indicated the effective cellular internalization, and the released DOX entered the cell nuclei for apoptosis (Figure 4, and Figure S24

colorless after treatment with GSH, indicating the core crosslinked micelles was disrupted by cleavage of the disulfide bonds in the cross-linked core, and the encapsulated NR was released. This study revealed that the core cross-linked M-5L could encapsulate hydrophobic cargo molecules and release the cargo in response to the redox environment. Similar results can be observed on P-5L and P-5D with the encapsulation of achiral NR in PBS, suggesting that the helicity of polyisocyanide arms and the chirality of the pendants have no effects on the encapsulation and controlled release on achiral cargo. With these results in hand, our efforts were directed to the loading of anticancer drug into the micelles. In this study, DOX was employed because of its high efficiency and widely used. The loading capacity of DOX was 8.6% for M-5L, 5.3% for P-5L, and 5.1% for P-5D, respectively, as determined by fluorescence spectra (Figure S22). The different DOX loading capacity of micelles was probably due to the different chirality of the micelles. The chirality of the DOX was much matched with M-5L; thus, the loading capacity was higher than the other two cases. Further studies revealed the DOXencapsulated micelles DOX@M-5L were quite stable in the absence of reducing agent. As shown in Figure 3a, less than 10% of DOX was released after 60 h incubation with the absence of GSH or with the presence of GSH less than 5 μM. However, at a higher concentration of GSH in PBS, faster release of DOX was observed. It was observed that 39.5% and 81.4% DOX were released after 48 h of incubation with the presence of 5 mM and 10 mM of GSH, respectively, confirming the redox-triggered drug release behavior. Similar GSH-triggered DOX release behavior could also be observed on DOX@P-5L and DOX@P-5D (Figure S23). To evaluate the biocompatibility of DOX-encapsulated micelles of DOX@M-5L, human umbilical vein endothelial cells (HUVEC) were incubated with these micelles with various concentrations at 37 °C for 48 h. The treated HUVEC exhibited about 100% viability over all tested DOX-loaded micelles concentrations (Figure 3b). Obviously, no significant in vitro cytotoxicity was observed for the DOX-encapsulated micelles at the concentrations of 0−100 μg/mL, because the DOX was tightly restricted inside the hydrophobic core of M5L.36,37 Thus, it could be reasonably concluded that the DOXloaded micelles had good biocompatibility and had almost no cytotoxicity to noncancer cells at these concentrations. To reveal their therapeutic effect to cancer cells, the DOX-loaded micelles were used to treat murine breast cancer cells (4T1 cells). In a sharp contrast to the noncytotoxicity to HUVEC, a high cytotoxicity to 4T1 cell was observed for the DOX-loaded micelles. As shown in Figure 3c, approximately 70% and 80% of 4T1 cells were killed at the concentration of 80 and 100 μg/ mL of DOX@M-5L after 48 h incubation. The therapeutic effect of DOX@M-5L was close to that of free DOX. For comparison, the therapeutic effects DOX@P-5D and DOX@P5L were also investigated under the same conditions. As shown in Figure 3d, DOX@P-5D and DOX@P-5L showed weaker therapeutic effect to 4T1 cells than that of the DOX@M-5L. After 48 h incubation, less than 40% of cells were killed, even at a concentration of 100 μg/mL of DOX@P-5D or DOX@P5L. Thus, the M-5L was the best carrier among the three kinds of core cross-linked micelles. Considering on the structure of M-5L, P-5L, and P-5D, it was deduced that the helicity of the polyisocyanide arms had great effects on the encapsulation and controlled release on chiral anticancer drug.

Figure 4. Representative CLSM images recorded for 4T1 cells incubated with DOX@M-5L, DOX@P-5L, and DOX@P-5D for 8 h. Dox fluoresced in red and cell nuclei in blue with Hoechst.

in Supporting Information). However, it was evident that the DOX@M-5L exhibited much stronger red fluorescence in cells than that of DOX@P-5L and DOX@P-5D. Since the M-5L and P-5L have the same pendants but different in the helicity, it can be reasonably concluded that the better performance of M-5L was ascribed to the left-handed helicity of the arms, not the chirality of the pendants. The left-handed helical polyisocyanide corona might have an analogous effect of cell penetrating peptides (CPPs), which could endow the micelles with rapid cell membrane permeability.38−40 Taking these into account, we believe that the helicity of the polyisocyanide backbones has great significance for chiral drugs loading and release. In summary, three kinds of core cross-linked micelles with the redox-responsive core and carrying optically active helical polyisocyanide arms were designed and synthesized. Their structures were almost the same in other aspects, but different in the helicity of the arms and the chirality of the pendants. M5L carrying left-handed helical arms with L-alanine amide pendants showed better performance in drug delivery and controlled release than P-5L and P-5D. According to the high drug loading capacity and the relatively rapid cell membrane permeability and endocytosis of DOX@M-5L, we believe the present study not only provides a synthetic method for stimuliresponsive micelles but reveals the remarkable effects of helicity and chirality of carriers on drug delivery and controlled release. 1077

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmacrolett.8b00610.

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Experimental section and supplemental figures (PDF).

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Zong-Quan Wu: 0000-0001-6657-9316 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work is supported by the Natural Science Foundation of China (NSFC, Nos. 21622402, 51673057, and 21574036) and the Fundamental Research Funds for the Central Universities of China. Z.-Q.W. thanks the 1000plan Program for Young Talents of China. N.L. thanks Anhui Provincial Natural Science Foundation (1608085MB41).

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DOI: 10.1021/acsmacrolett.8b00610 ACS Macro Lett. 2018, 7, 1073−1079

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DOI: 10.1021/acsmacrolett.8b00610 ACS Macro Lett. 2018, 7, 1073−1079