dePEGylation of the Nanocarriers for

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Letter Cite This: Nano Lett. 2019, 19, 3671−3675

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Light-Triggered PEGylation/dePEGylation of the Nanocarriers for Enhanced Tumor Penetration Mengxue Zhou,† Hui Huang,† Dongqing Wang,† Huiru Lu,† Jun Chen,*,† Zhifang Chai,† Shao Q. Yao,‡ and Yi Hu*,† †

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CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Multi-disciplinary Research Division, Institute of High Energy Physics and University of Chinese Academy of Sciences (UCAS), Chinese Academy of Sciences (CAS), Beijing 100049, P.R. China ‡ Department of Chemistry, National University of Singapore, Singapore 117543 S Supporting Information *

ABSTRACT: Nanocarriers-derived anticancer therapeutics typically suffers from poor tumor penetration and suboptimal antitumor efficacy. Although PEGylation improves the stability of nanoparticles and prolongs drug circulation, it further increases the size of nanoparticles and adversely affects the tumor penetration. Here, we developed a light-triggered PEGylation/dePEGylation strategy, whereby near-infrared (NIR)-/pH- dual responsive dePEGylation activates iRGD for tumor targeting. The embedded up-conversion nanoparticles (UCNPs) could efficiently convert NIR to UV−vis which cleaved the linker to remove PEG. NIR-induced dePEGylation remarkably improved vascular extravasation of drugs and deep tumor penetration. Therefore, the stimuli-responsive nanocarriers facilitated the tumor-targeted delivery of drugs through blood circulation and enhanced the antitumor effects. KEYWORDS: Near-infrared, photocleavable, drug delivery, antitumor, drug penetration

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Therefore, NIR-responsive dePEGylation could be potentially advantageous over current strategies. Stimuli-responsive transition of PEGylation/dePEGylation may facilitate the delivery of drugs to tumors with minimal premature drug leakage in circulation. However, nanomedicines still face the problems of poor penetration in solid tumors and compromised therapeutical efficacy thereof. The poor tumor penetration of nanomedicines might be ascribed to the intrinsic physiological barriers in tumors and low vascular extravasation efficiency.4,21 We have recently reported a NIRresponsive nanocarrier constructed by poly(N-isopropylacrylamide) and single-walled carbon nanotubes showing improved vascular extravasation efficiency.14,15 The enhanced penetration through blood vessels could be attributed to the combined effects of NIR-induced hyperthermia and down-sized nanoparticles. Alternatively, decoration of tumor penetrating ligands on the surface of nanoparticles can generally facilitate the tumor penetration.22 For instance, a disulfide-bridged cyclic peptide, iRGD, takes a two-step pathway to enhance tumor penetration of nanoparticles by binding to αvβ3/αvβ5 integrins and then neuropilin-1 or neuropilin-2.23 However, there are considerable variations in integrin expression

he past decade has seen remarkable advances in the development of nanomedicines.1,2 However, suboptimal antitumor efficacy impedes the translation of nanomedicines into the clinic. The key problem may stem from premature drug leakage in blood circulation and the complex physiological/pathological barriers in vivo.3,4 High density of poly(ethylene glycol) (PEG)-coating in nanomedicines has been suggested to improve pharmacokinetics with prolonged drug circulation, reduced premature drug leakage, and immune clearance.5−7 Despite of the advantage of PEG shielding, PEGylation would typically increase the size of nanoparticles, which might hinder the cellular uptake and tumor penetration of nanomedicines.5 To circumvent these problems, stimuli-responsive dePEGylation at the tumor region may be adopted by incorporation of labile bonds between PEG shell and the core of nanoparticles. Several strategies, including endogenous stimuli-responsive8−10 and ultraviolet (UV)-responsive dePEGylation,11 have been reported. However, accumulating evidence suggests that endogenous stimuli, such as pH, redox and enzymes, are not sufficient to achieve clinic-translatable drug targeting to tumors.4 By contrast, light-responsive nanocarriers can achieve tumor-targeted drug delivery in a spatial- and temporal-specific fashion.12−16 Although UV light has its intrinsic limitations in biological applications, including phototoxicity and poor tissue penetration,17,18 near-infrared (NIR) light is generally biocompatible with relatively deep tissue penetration.19,20 © 2019 American Chemical Society

Received: February 19, 2019 Revised: April 28, 2019 Published: May 7, 2019 3671

DOI: 10.1021/acs.nanolett.9b00737 Nano Lett. 2019, 19, 3671−3675

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Nano Letters between tumor and healthy cells24 and the entry of iRGDconjugated drugs into normal cells remains unanswered.25 Moreover, iRGD has a relatively short half-life in blood.23 PEG coating on iRGD-conjugated drugs might be necessary to prolong drug circulation. Herein, an amphiphilic polymer (PEG-Nbz-PAE-Nbz-PEG, HTMP) containing PEG (as hydrophilic segment) and pHsensitive poly(β-aminoester)s (as hydrophobic segment) covalently linked via an o-nitrobenzyl (Nbz) linker was synthesized. Another amphiphilic polymer (iRGD-PAEiRGD, iPHT) with iRGD at both ends was used as the targeting moiety. Core−shell structured NaYF4:Yb/Tm@ NaYF4 up-conversion nanoparticles (UCNPs) were introduced to convert NIR to UV−vis for the cleavage of Nbz linkers to remove PEG. Doxorubicin (DOX)-loaded nanoparticles were prepared through the self-assembly of iPHT, HTMP, surfacehydrophobic UCNPs and DOX via a simple and efficient solvent-substitution method. Upon NIR at the tumor region, dePEGylation activates iRGD for deep tumor penetration (Figure 1).

Figure 2. TEM images of UCNPs (A), iPHM (B), iPUN at pH 7.4 (C), and iPUN at pH 5.0 with NIR (1 W cm−2) for 10 min (D). (E) Fluorescence spectra of UCNPs in hexane and iPUN in water upon NIR and UV−vis absorbance of HTMP in water. (F) Hydrodynamic diameter of iPHM, iPUN, and iPUDN. (G) Size and PDI data of iPUN at pH 7.4 irradiated by NIR (1 W cm−2) for different time. Data as mean ± SD (n = 3). (H) Size and PDI data of iPUN at pH 6.5 over time. Data as mean ± SD (n = 3). (I) The cumulative DOX release from iPUDN at different pH with or without NIR irradiation (mean ± SD, n = 3). The green arrows indicate the time points of NIR ON, while the black arrows indicate NIR OFF.

resonance peaks corresponding to the acrylate groups at ∼6.00 ppm indicated that the two-stepped end-capping reaction of the poly(β-aminoester)’s terminal groups was successful. FTIR spectroscopy was further applied to analyze the chemical structures of synthesized polymers. For HTMP, the presence of typical peaks of ether groups in PEG at 1100 cm−1, carbonyl groups in poly(β-aminoester) at 1730 cm−1, methylene groups at 2920 cm−1, and nitro groups in Nbz linker at 1580 cm−1 indicated the successful preparation of the light-cleavable polymer (Figure S4). The presence of typical peaks of amide groups in iRGD at ∼1650 cm−1 and CO groups in poly(βaminoester)s at 1730 cm−1 suggested the successful incorporation of iRGD into iPHT polymers (Figure S4). The critical micelle concentration (CMC) of iPHT/HTMP hybrid micelle (iPHM) was estimated to be 0.01 mg mL−1 (Figure S5), indicating that the nanocomposites would remain stable upon extremely high dilution (e.g., after i.v. injection). The iPHM@UCNP (iPUN) hybrid nanocomposites were prepared by an ultrasonic-assisted solvent-substitution method.27 As shown in Figure 2B, TEM images of polymeric nanoparticles iPHM with negative staining exhibited welldispersion in aqueous media with a spherical morphology and a size of 50−80 nm. After encapsulation of UCNPs nanocrystals in the core, pomegranate-like nanoparticles were present at pH 7.4 (Figure 2C). A gray corona around the clustered UCNPs nanocrystals indicated the successful preparation of the hybrid self-assembled nanoparticles. In addition, thermogravimetric analysis (TGA) was conducted to analyze the composition of oleic acid-capped UCNPs nanocomposites and iPUN micelles. As shown in Figure S6, oleic acid-capped UCNPs showed the weight loss was ∼12 wt % at 800 °C. By contrast, the total weight loss of iPUN was ∼80 wt

Figure 1. (A) Illustration of NIR/pH responsive nanodrugs. (B) Illustration of NIR-guided nanodrugs sneaking past physiological barriers (i, blood circulation; ii, extravasation; iii, tumor penetration).

The core−shell structured NaYF4:Yb/Tm@NaYF4 was synthesized according to a reported method.26 Tm3+-doped nanoparticles were used for UV−vis up-conversion luminescence under 980 nm illumination. Transmission electron microscopy (TEM) images of the as-prepared UCNPs showed well-dispersed and spherical nanoparticles with a uniform diameter of ∼40 nm (Figure 2A), a homogeneous shell of ∼5 nm in thickness, and minimal impurity (as shown in high crystalline phase, Figure S1). The surface of these UCNPs was subsequently coated with oleic acid, leading to well-dispersion in organic phase. Upon illumination with 980 nm laser, the fluorescence spectra of UCNPs exhibited multiple characteristic emission peaks at 350, 365, 450, 480, 650, 690, and 720 nm, which was from Tm3+ dopant (Figure 2E). The XRD peaks of the Yb3+- and Tm3+-doped UCNPs were similar to the peaks of NaYF4 crystals (Figure S2), indicating successful synthesis of NaYF4:Yb/Tm@NaYF4. The UV−vis cleavable polymer was synthesized via Michael addition polymerization and subsequent modification of end groups (Scheme S1). The chemical structures of synthesized polymers were characterized by 1H NMR spectra (Figure S3). For light-sensitive polymer, the resonance peaks at 3.50−3.80 ppm and ∼7.55 ppm were assigned to the protons of methylene in the PEG chains and the phenyl groups, respectively, and the disappearance of 3672

DOI: 10.1021/acs.nanolett.9b00737 Nano Lett. 2019, 19, 3671−3675

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Nano Letters %, which was much higher than that of oleic acid-capped UCNPs. These results further suggested that iPHM copolymer had been assembled on the surface of oleic acid-capped UCNPs. We next examined the NIR-responsive property of iPUN. As shown in Figure 2F,G, the diameter of iPUN decreased from ∼148 to ∼108 nm upon NIR irradiation in approximately 30 s, indicating NIR-induced PEG detachment. NIR-induced dePEGylation depended on the conversion of NIR to UV− vis by UCNPs, as the typical absorption region of Nbz groups in the polymer was 250−450 nm. Upon NIR, multiple strong emission peaks including the peaks at 350, 365, 450 nm of UCNPs and iPUN were observed (Figure 2E). Compared with UCNPs, the intensity decay of peaks at ∼350 and ∼480 nm was found in iPUN, which could be ascribed to the light absorption by Nbz groups in the polymeric matrices. Similarly, the intensity decay of DOX-loaded iPUN (iPUDN) at ∼480 nm increased along with elevated concentrations of DOX (Figure S7A), which might be caused by the light absorption of DOX (Figure S8). NIR-induced Nbz cleavage was comfirmed by NMR (Figure S9). As low pH is a salient feature of most malignant tumors,28 the tertiary amines in each repeat unit of poly(β-aminoester)s might endow the hybrid nanoparticles with a pH sensitivity.29 Figure 2D showed the morphology of iPUN after transferring the nanoparticles from PBS buffer at pH 7.4 to an acetic buffer at pH 5.0 with NIR for 10 min. We could observe a transit from condensed spherical morphology at pH 7.4 to irregular island-like morphology at pH 5.0, indicating the acid-sensitive dissociation of nanoparticles. At pH 6.5, iPUN was gradually disassembled (Figure 2H). The TEM image also showed the disassembly of iPUN at pH 6.5 (Figure S10). The shrinkage of nanoparticles in size may facilitate the extravasation from blood vessels and intratumoral penetration,30 which consequently enhances the antitumor effects of nanodrugs. Furthermore, the cumulative DOX release from iPUDN at different pH (5.0 and 7.4) with or without NIR was shown in Figure 2I. There was a slow release of approximately 27% of DOX in 48 h at pH 7.4. At pH 5.0, ∼66% of DOX was released in 48 h (Figure 2I), which was in agreement with DOX releaseassociated fluorescence change of iPUDN at pH 5.0 over time (Figure S7B). Upon NIR, DOX release was further increased to ∼80% at pH 5.0 (Figure 2I). These results suggested that both NIR and low pH enhanced DOX release from iPUDN. Cell uptake of nanoparticles with or without NIR was studied by using confocal laser scanning microscopy and flow cytometry. After 4 h, iPUDN plus NIR group showed significantly higher fluorescence intensity than no NIR group (Figure 3A,B). Flow cytometry analysis further confirmed the enhanced cell uptake of iPUDN by NIR (Figure S11). These results suggested that NIR-induced decapping facilitated the entry of nanoparticles into cells. Moreover, we exploited an inverted fluorescence microscope equipped with an accessory 980 nm laser as the excitation source to analyze intracellular distribution of DOX and UCNPs. As shown in Figure S12, the fluorescent spots of both DOX and UCNPs increased over time in MCF-7 cells. However, the colocalization of DOX with UCNPs continued to reduce from 1 to 6 h (Figure S12), indicating the segregation of DOX from the nanoparticles inside cells. Cell toxicity assays indicated that these nanocarriers were generally biocompatible (Figure 3C). Moreover, according to dynamic light scattering (DLS) analysis, the nanocarriers were stable in PBS (pH 7.4), 150 mM sodium

Figure 3. (A) Confocal microscopy images of MCF-7 cells incubated with iPUDN with or without NIR for 4 h. Scale bar = 11 μm. (B) The fluorescence intensity of DOX in MCF-7 cells was quantified by ImageJ (mean ± SD, n = 4). (C) Cell viability of iPHM, iPUN and iPUN + NIR (1 W cm−2, 10 min) in MCF-7 cells (mean ± SD, n = 6). (D) Cell viability of free DOX, iPUDN, and iPUDN with NIR (1 W cm−2, 30 s) in MCF-7 cells (mean ± SD, n = 6). (E) The fluorescence intensity of DOX in the cell spheroids at 180 μm (mean ± SD, n = 3). (F) Scanned images of cell spheroids every 20 μm. Scale bar = 200 μm. The magnified images at 180 μm of free DOX (G), iDN (H), iPUDN (I), and iPUDN + NIR (J). Scale bar = 200 μm. *, P < 0.05; **, P < 0.01; ***, P < 0.001.

chloride, 2% BSA and cell culture media containing 10% FBS for 3 days at 37 °C (Figure S13). When loaded with DOX, iPUDN with NIR irradiation exhibited a dose-dependent cell inhibition against MCF-7 cells (Figure 3D), which was consistent with NIR-induced DOX release from iPUDN. To examine the tumor penetration capability of iPUDN, an avascular MCF-7 cell spheroid model was established. Figure 3F showed the images of DOX obtained from the top to the middle of the spheroids every 20 μm. Generally, the accumulation of free DOX in the cell spheroid was relatively high, as compared with the polymeric micelles or nanoparticles (Figure 3E). This could be ascribed to the lipo-/hydro- dual solubility and low molecular weight of free DOX. Nevertheless, when we analyzed the DOX fluorescence deep inside the cell spheroid, we found that iPUDN upon NIR could better penetrate into the cell spheroid (Figure 3J), whereas free DOX mainly accumulated at the outer layers of the cell spheroid (Figure 3G). The tumor penetration capability of iPUDN was mainly from the conjugated iRGD. NIR-induced dePEGylation of iPUDN facilitated the exposure of iRGD on the nanoparticles to the cells and consequently enhanced tumor penetration. By contrast, PEG shell in no NIR control impeded the tumor penetration of the nanoparticles (Figure 3I). In addition, iPUDN plus NIR group showed high penetrative depth in the spheroid (Figure S14). The penetration capability of iRGD control (DOX-loaded iPHT, iDN) was slightly better than free DOX, but less than iPUDN with NIR (Figure S14). This might be ascribed to the relative large size of polymeric micelles iDN and low cell uptake, as compared with iPUDN/NIR. These results suggested superior penetration capability of iPUDN upon NIR into tumors, as compared with conventional drugs which typically penetrate only 3−5 cell diameters.25,31 3673

DOI: 10.1021/acs.nanolett.9b00737 Nano Lett. 2019, 19, 3671−3675

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controls, iPUDN with NIR potently inhibited the tumor growth (Figure 5A,C,D). Hematoxylin and eosin (H&E)

A tumor-bearing mouse model was established to examine the in vivo distribution of nanoparticles. Cy5 was conjugated to iPUN via the EDC/NHS coupling reaction for in vivo imaging. The real-time fluorescence of Cy5 in mice was recorded at 1, 6, and 24 h. As shown in Figure 4A, the fluorescence of Cy5

Figure 4. (A) Representative images of tumor-bearing mice upon 1 = free Cy5; 2 = iPUN-Cy5; 3 = iPUN-Cy5 with NIR (1 W cm−2, 5 min). The white circles highlight the regions of tumors. (B) Representative ex vivo fluorescence images of tumors and other tissues of mice upon free DOX, iPUDN, and iPUDN with NIR (1 W cm−2, 5 min). (C) The concentrations of element Y in the blood of mice over time (mean ± SD, n = 3). (D) The time-course of Y content in tumors of mice (mean ± SD, n = 3). Figure 5. Tumor growth profiles (A) and average body weight (B) of mice under different conditions. (C) Photographs of excised tumors from (I) PBS + NIR, (II) Free DOX + NIR, (III) iPUDN, and (IV) iPUDN + NIR. (D) Average weight of tumors in mice after treatments (mean ± SD, n = 5). ***, P < 0.001. (E) Analysis of DOX distributions in tumors. The tumor blood vessels were immunostained with CD31 antibody. Scale bar = 20 μm.

gradually increased over time in mice treated with iPUN-Cy5. Upon NIR, the fluorescence of Cy5 was remarkably increased in tumors of mice, as compared with no NIR control (Figure S15A). Moreover, we examined DOX fluorescence in excised tissues of mice treated with free DOX or iPUDN for 24 h. Results also confirmed that NIR enhanced the tumor targeting of iPUDN, while the accumulation of DOX in healthy tissues was relatively reduced by NIR (Figures 4B and S15B). We next analyzed the metabolism of nanoparticles by measuring the concentrations of element Y in blood and tumors of mice. Compared with UCNPs, iPUDN exhibited relatively long circulation time in blood (Figure 4C) and high accumulation in tumors (Figure 4D). The long circulation time of iPUDN in blood was consistent with the results of nanoparticle stability (Figure S13). NIR enhanced the tumor targeting of iPUDN in a time-dependent fashion (Figure 4D). The distributions of element Y in the spleen and lungs (Figure S16) were slightly different from DOX distributions (Figure 4B), indicating the accumulation of the nanocarriers, but not DOX, in these tissues. According to cytotoxicity assays, the nanocarriers per se had minimal cell toxicity (Figure 3C). These results suggested that NIR also facilitated the targeting of DOX to tumors. The antitumor effects of the nanodrugs with NIR were examined in tumor-bearing mice. As compared with the

staining confirmed the tumor-killing effect of iPUDN/NIR (Figure S17). No significant change in the body weights of mice was observed during drug treatments (Figure 5B). In addition, H&E staining of healthy tissues after drug treatments further indicated minimal systemic toxicity of iPUDN/NIR (Figure S18). Previous study indicated that UCNPs showed no overt toxicity in mice for up to 115 days, except for slight hyperplasia in the splenic white pulp.32 As UCNPs might be excreted very slowly, it warrants further investigation of the long-term toxicity of UCNPs in biological applications. To examine the drug extravasation from tumor blood vessels, tumor tissues at 24 h post injection were immunostained with fluorescently labeled CD31 antibody to visualize blood vessels. Figure 5E clearly showed that considerably more DOX was extravasated from the blood vessels by NIR, as compared to no NIR control. This could be ascribed to NIR-induced activation of iRGD, as well as down-sizing of nanoparticles by NIR. Much 3674

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Nano Letters less DOX fluorescence was seen around tumor blood vessels in free DOX group (Figure S19), which might be due to low accumulation of free DOX in tumors. In addition, the average distance between drugs and the blood vessels was farthest in iPUDN/NIR group (Figure S20), suggesting improved penetration capability. In conclusion, we have demonstrated a NIR-responsive nanodrug for deep tumor penetration. The embedded UCNPs could efficiently convert NIR to UV−vis to achieve PEGylation/dePEGylation transition. NIR-induced dePEGylation of nanoparticles remarkably improved the cellular uptake and tumor penetration via size shrinkage and iRGD activation. Moreover, NIR could mediate tumor-targeted delivery of DOX-loaded nanoparticles and boost the antitumor effects. Mechanistically, enhanced vascular extravasation of drugs and deep tumor penetration were illustrated in a light-responsive fashion. We envision that NIR-triggered PEGylation/dePEGylation strategy can facilitate the tumor-targeted delivery of drugs through blood circulation and enhance the tumor penetration.

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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/acs.nanolett.9b00737. Chemicals and supplementary methods, figures (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Shao Q. Yao: 0000-0003-4715-769X Yi Hu: 0000-0002-0952-0657 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to the National Natural Science Foundation of China (11875269, 21574136, 11375213), CAS Youth Innovation Promotion Association Program (2015008), and Hundred Talents Program of CAS for financial support.

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DOI: 10.1021/acs.nanolett.9b00737 Nano Lett. 2019, 19, 3671−3675