Hyaluronic Acid-Modified Polymeric Gatekeepers on Biodegradable

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Hyaluronic Acid-Modified Polymeric Gatekeepers on Biodegradable Mesoporous Silica Nanoparticles for Targeted Cancer Therapy L PALANIKUMAR, Jimin Kim, Jun Yong Oh, Huyeon Choi, Myoung-Hwan Park, Chaekyu Kim, and Ja-Hyoung Ryu ACS Biomater. Sci. Eng., Just Accepted Manuscript • DOI: 10.1021/acsbiomaterials.8b00218 • Publication Date (Web): 29 Mar 2018 Downloaded from http://pubs.acs.org on March 29, 2018

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ACS Biomaterials Science & Engineering

Hyaluronic Acid-Modified Polymeric Gatekeepers on Biodegradable Mesoporous Silica Nanoparticles for Targeted Cancer Therapy L.Palanikumar,1 Jimin Kim, 1 Jun Yong Oh, 1 Huyeon Choi, 1 Myoung-Hwan Park, 2* Chaekyu Kim, 1* Ja-Hyoung Ryu1,*

1

Department of Chemistry, School of Natural Science, Ulsan National Institute of Science and

Technology, Ulsan 44919, Republic of Korea 2

Department of Chemistry, Sahmyook University, Seoul 01795, Republic of Korea

KEYWORDS. Degradable mesoporous silica, hyaluronic acid, CD-44 overexpression, redox responsive, high loading capacity

Corresponding Author *[email protected] (J-H. Ryu); [email protected] (M-H. Park), [email protected] (C. Kim)

1 ACS Paragon Plus Environment

ACS Biomaterials Science & Engineering 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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ABSTRACT

Systemic administration of mesoporous silica nanoparticles (MSNs) in biomedical applications has recently been questioned due to their poor degradability, which is necessary for the successful development of new drug delivery systems. Herein, we report the development of colloidal state-degradable MSNs functionalized with versatile polymer-gatekeepers with a cancer cell-targeted moiety. The polymer MSNs (PMSNs) were designed with disulfide crosslinking enabling safe encapsulation until cargos are delivered to target cancer cells. Selective targeting was achieved by decoration of CD44 receptor targeting ligands, hyaluronic acid (HA), with HAPMSNs. The selective cellular uptake mechanism of the fabricated targeted nanocarrier into CD44 overexpressed-cancer cells was demonstrated through the clathrin- and macropinocytosismediated pathways. Upon internalization into cancer cells, doxorubicin loaded into the HAPMSNs can be released by degradation of the polymer shells in the reducing intracellular microenvironment that consequentially induces cell death and further degradation of the MSNs. This study offers a simple technique to fabricate a versatile drug carrier with a high drug loading capacity.


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INTRODUCTION Targeted drug delivery systems (DDSs) increase the drug availability at infected cells, and are expected to be much safer, more convenient, and efficient.

1-2

To enhance the targeting

properties of DDSs, numerous nanomaterial drug carriers have been developed, including carbon nanotubes,3 quantum dots,4 mesoporous carbon,5 polymeric nanoparticles,6-7 nanocapsules,8 liposomes,9 gold nanoparticles,10 and magnetic nanoparticles.6 Many of the carrier feature long shelf lives, facile commercial synthetic scale-up, and tunable chemical properties. Recently, inorganic porous materials have been developed as excellent drug delivery carriers due to their resistance to lipases and bile salts and low susceptibility to the immune response.11 Among these inorganic materials, mesoporous silica nanoparticles (MSNs), with their unique structure and chemical modification capability, have been explored as DDSs.12-15 MSNs have played a prominent role in the development of smart hybrid materials endowed with controllable properties in response to a variety of external and internal switches16 such as pH, 17 enzymes,18 light irradiation,19 temperature,20 redox reaction,21 magnetic fields,22 competition,23 and ultrasound.22 However, the poor degradability of MSNs limits their efficacy as DDSs due to potential long-term accumulation in reticuloendothelial organs, increasing the risk of adverse side effects.24 The biodegradability of the drug carriers is a major factor to be considered when designing successful drug delivery systems. An ideal nanocarriers design should be degradable in body fluids, biocompatible, and able to be used biomedical applications.25 In this respect, there is a considerable need to develop MSNs with controllable biodegradability. Degradable MSNs, which are hydrolytically unstable and able to be dissolved into water-soluble silicic acid, can be excreted in urine and it has been found to help maintain bone health. 26-28 In addition to issues



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with biodegradability, the development of the MSN-mediated nanomedicines faces challenges associated with poor colloidal stability and cargo leakage.29 Premature drug release before reaching the target results in inefficient drug delivery and limits its pharmacokinetics and biodistribution.30 Therefore, biodegradable MSNs with improved encapsulation stability are required for the development of an efficient drug delivery system.

Scheme 1. Schematic illustrations of efficient nanoparticle-mediated DDSs using noncovalent polymer gatekeepers and HA conjugation for targeting capability. a) Formation of HA-PMSNs with PEG-PDS-NH2 after crosslinking and conjugation of HA, b) drug loading, polymer capping, and HA decoration over PMSNs, and c) fast cellular uptake analysis by HA-PMSNs and their redox responsive drug release. 4 ACS Paragon Plus Environment

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Herein, we introduce a degradable MSNs system as a simple, versatile and facile drug delivery platform utilizing non-covalent polymer gatekeepers, which is capable of encapsulating hydrophilic drug doxorubicin hydrochloride (Dox) with high loading capacity (Scheme 1) and by the decoration of hyaluronic acid (HA) facilitates the targeting capability to CD44 overexpressed cancer cells.31,32 RESULTS AND DISCUSSION Preparation and characterization of polymer modified degradable MSNs In addition to successful delivery, the complete removal of scaffolds is a prerequisite for the development of efficient DDSs. Generally, the degradation rate of non-colloidal MSNs is quite slow because of their negligible contact with water as well as their aggregation state and fusion bonding of the nanoparticles. In addition, the Brownian motion of colloidal nanoparticles results in higher collision frequency between nanoparticles and water molecules. Thus, the colloidal state is generally more degradable than that of the aggregated nanoparticles. To develop degradable DDSs, colloidal state biodegradable MSNs were prepared using a tetrabutoxysilane (TBOS) source as previously described.33 MSNs were characterized by transmission electron microscopy (TEM), nitrogen adsorption analysis, zeta potential measurement, and dynamic light scattering measurements (DLS, Figure 1A–1E). The nitrogen adsorption-desorption isotherm measurements showed a large surface area of 737 m2/g for the MSNs, with a pore size of 3.1 nm (Figure S1). To develop a targeted DDS with MSNs, several synthetic surface modifications are required including the conjugation of organosilane linkers and their attachment to targeting molecules.34 However, the modification resulted in reduced pore volume available for guest encapsulation, leading to lower loading efficiency.35



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Additionally, installation of targeting ligands by chemical modification may reduce the versatility of the encapsulated anticancer agents during post modification procedures.36 To afford improved robustness, large loading capacities, and controlled drug release, non-covalent polymer gatekeepers consisting of stimuli-sensitive functional groups were used to block the pore entrance and release cargos upon exposure to intracellular glutathione (GSH) inside cancer cells.37 To achieve this goal, Dox, a model chemotherapy drug, was initially loaded into the MSNs by dipping into a high concentration Dox solution. The Dox-loaded MSNs were postfunctionalized with a positively charged random copolymer (PEG-PDS-NH2, poly (poly(ethylene glycol) methacrylate-co-pyridyldithioethyl methacrylate-co-2-aminoethyl methacrylate) through simple electrostatic interactions. After electrostatic blocking, the polymer-wrapped MSNs (PMSNs) were crosslinked with dithiothreitol (10 mol% and 50 mol % were added), resulting in crosslinking densities of 26 mol% and 62 mol%, respectively, to form a versatile carrier for safe drug delivery (Figures S3). The Dox-loaded MSNs showed a large loading of 20 wt%, which was determined by the characteristic optical absorbance of Dox at 480 nm (Figure S4). The TEM images showed a polymer-coating layer over the MSNs (Figures 1B and 1C) and DLS measurements showed an increase in size of the particles from 130 to 165 nm (Figure 1E). The zeta potential of the blanked-MSN surface was highly negative (−32 mV), but became positive (+10 mV) after the introduction of the polymeric gatekeepers (Figure 1D). In addition, the amine groups on the PMSNs can be reacted with carboxylic acid groups on the targeting ligand, HA. The formation of HA-PMSNs was confirmed by the reduced zeta potential (–4.52 mV) and growth in size (192 nm) and further demonstrated through the carbazole assay (Figure 1 and S3).


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Figure 1. TEM images of A) MSNs, B) PMSNs, and C) HA-PMSNs; D) Zeta potential measurement for MSNs, PMSNs, HA-PMSNs and size analysis for E) MSNs, PMSNs, HAPMSNs particles.

Biodegradability of MSNs and PMSNs The significance of degradability in the development of nano-sized MSNs is enormous due to their potential in DDSs. In this regard, a few studies of the degradability of silica nanoparticles has been reported,38 but their degradation in conventional media is negligible.39 To demonstrate degradability, nanoparticles were initially placed into a dialysis membrane tube, and continuously shaken with 1x PBS. The outer PBS solution was frequently collected and replaced with fresh PBS at specified time intervals while the inner solution with silica particles was unchanged.33 TEM images recorded after 10, 15, and 30 days immersed in PBS revealed the loss



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of mesostructure and particle morphology of the MSNs (Figures 2A, 2B, 2C, 2F and 2G respectively). In addition, uneven size distribution of MSNs was observed in the DLS measurement as the degree of degradation increased (Figure 2D). Inductively coupled plasma mass spectrometry (ICP-MS) analysis of the outer solution demonstrated their time dependent degradation (Figure 2E), achieving a 70% degradation after 30 days. Based on the DLS, ICPMS, and TEM results, the time dependent degradation bodes well for the use of the prepared MSNs in biomedical applications, as shown in the Scheme 1.25,33 The good biodegradability obtained with the fabricated MSNs under unstirred conditions were consistent with previous observations.25,33

Previous

studies

have

reported

that

MSNs

can

accumulate

in

reticuloendothelial organs and in excretory organs soon after delivering their cargo to the targeted cells.25


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Figure 2. TEM images of MSNs after A) 10 days, B) 15 days, and C) 30 days immersed in PBS. D) The DLS analysis for size distribution of MSNs in PBS at different time intervals, E) ICP-MS analysis for cumulative silicon traces in the outer solution during dialysis until 30 days, and TEM images of PMSNs F) before and G) after 30 days in PBS with GSH. Scale bar represents 50 nm.



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Triggered release profile analysis In the MSN design, the triggering of drug release from the rigid mesoporous core was achieved through cleavage of the flexible hydrophilic polymer gatekeepers on the shell at increased GSH concentrations, as shown in Scheme 1. To demonstrate the versatility of the triggered drug release, Dox release behaviors from the MSNs (Figure 3A) and PMSNs in PBS were investigated. In the absence of GSH, MSNs provide rapid and complete release of Dox (almost 80%), but no meaningful release was observed with crosslinked PMSNs (Figures 3B and 3C). Both loosely and tightly crosslinked disulfide shell functionalities can be cleaved in the presence of GSH, which is a thiol-rich small peptide and abundant inside cancer cells, enabling thiol-disulfide exchange reactions. To substantiate GSH-mediated release, the 26 and 62 mol % crosslinked PMSNs were immersed in 1 and 5 mM GSH solutions after presoaking in PBS for 3 h. The triggered Dox release was observed by redox-responsive cleavage in the presence of GSH. With the loosely (26 mol%) crosslinked PMSNs, 40 % of the encapsulated Dox was released in the 1 mM GSH solution within 24 h, while the release rate was accelerated in the 5 mM GSH solution (over 70%, Figure 3B). As compared with loosely crosslinked PMSNs, much slower release kinetics were observed with the tightly (62 mol %) crosslinked PMSNs in both 1 and 5 mM GSH solutions (Figure 3C). These results indicate the tunability release behaviors of encapsulated drugs in PMSNs achieved by varied crosslinking density of the polymers on the shell.


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A

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5 mM GSH

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Figure 3. Cumulative Dox release profiles of A) MSNs without GSH, B) 26 and C) 62 mol% crosslinked PMSNs with (1 and 5 mM) and without GSH.



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Figure 4. Confocal microscope images to check the fast cellular uptake of HA-PMSNs in HeLa cells after incubating for A) 1 hour, C) 2 hours, and E) 4 hours and in HeK293T cells after incubating for B) 1 hour, D) 2 hours, and F) 4 hours.

Cellular uptake and pathway of internalization To selectively target cancer cells, the PMSNs surface was decorated with a targeting ligand, HA, which is composed of N-acetyl glucosamine and glucuronic acid disaccharide.40 HA is a key component of the extracellular matrix (ECM) supporting tumor growth for a wide range of human tumors with overexpression of CD44. In addition, HA is well known for its excellent biocompatibility, biodegradability, low-toxicity, and low-immunogenicity and is currently used in the cosmetic and medical fields.41 CD44, a major HA receptor, is a multi-functional and multistructural cell surface glycoprotein, capable of detecting changes in ECM components.42 After incubation of HeLa (CD 44 +ve) and NIH 3T3 (CD44 –ve) cells with Dox loaded HA-PMSNs, 12 ACS Paragon Plus Environment

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strong red fluorescence induced by Dox release was observed in CD44 positive cells, whereas no meaningful signals were observed in the negative control NIH 3T3 cells (Figure 4). Compared with PMSNs with no HA, higher cellular uptake efficiency was observed with HA-PMSNs in flow cytometry measurements (Figure S5 and S6). Clathrin-, caveolin-, and macropinocytosismediated endocytosis are the major endocytic pathways. The uptake of HA-PMSNs in HeLa cells was assessed with endocytosis inhibitors methyl-β-cyclodextrin (MβCD, inhibiting caveolin-dependent endocytosis), sucrose (inhibiting clathrin-mediated endocytosis), and amiloride (inhibiting macropinocytosis).43 Cancer cells pretreated with sucrose and amiloride showed decreased fluorescence of nearly zero, while the fluorescence was retained in the cells treated with MβCD (Figure 5). These results suggest that clathrin-mediated endocytosis and macropinocytosis are the predominant pathways involved in the cellular uptake of HA-PMSNs (Figure 5).

Figure 5. Cellular uptake pathway analysis for HA-PMSNs in the presence of A) sucroseinhibitor of clathrin, B) amilorin- inhibitor of macropinocytosis, and C) MβCD- inhibitor of caveolae.



Cell viability analysis To assess the biocompatibility of the prepared nanocarriers, cytotoxicity was evaluated using alamar blue cell viability assays in HeLa cells incubated with different concentrations of MSNs and PMSNs (0 - 0.2 mg/mL) for 24 h. No significant cell death was seen with unloaded MSNs and PMSNs even at high concentrations (< 1 mg/mL), suggesting good biocompatibility of the developed delivery platform (Figure S7). Even though reduced cytotoxicity was seen compared to that of free Dox due to the slow release of the encapsulated drugs, significant concentrationdependent cytotoxicity was observed with the drug-loaded HA-PMSNs towards HeLa cells (CD44 +ve). Conversely, negligible changes were observed in the NIH 3T3 cells (CD44 –ve) until a concentration of 1 µg/mL of Dox in HA-PMSNs (Figure 6). These results clearly demonstrated that drug loaded HA-PMSNs (IC50 of 0.5 µg/mL) provide efficient antitumor capacity to selectively kill targeted cancer cells.

A

B HA-PMSN Dox

80 60 40 20 0

HA-PMSN Dox

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Cell Viability (%)

100

Cell Viability (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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Concentration of Dox (µg/mL)

Ctrl

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Figure 6. Cell viability analysis of HA-PMSNs A) in HeLa cells and B) in NIH 3T3 cells


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CONCLUSION In conclusion, a degradable drug carrier was fabricated using colloidal state-MSNs, with improved drug loading capacity and exhibiting GSH-stimuli responsive drug release from biodegradable PMSNs. The breakdown of the PMSNs improved the penetration ability of the particles with the CD44 decoration and targeting HA ligands, and increased the release efficiency of the loaded drugs into tumor tissues. More importantly, the targeting capability of the HA-PMSNs showed cancer cell-specific endocytosis uptake. The cytotoxicity of Dox loaded HA-PMSNs in vitro indicates that the prepared system may be an efficient cancer treatment. The prepared HA targeted drug carrier with safe delivery shows great potential for use in various biomedical applications. ASSOCIATED CONTENT Experimental detail for synthesis of PEG-PDS-NH2 copolymer preparation. Results of crosslinking density, HA conjugation, flow cytometry analysis, TEM images of GSH mediated degradation drug for nanoparticles, in-vitro cytotoxicity analysis to check the biocompatibility of nanoparticles in HeLa cells. This material is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Author [email protected] Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. 15 ACS Paragon Plus Environment


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ACKNOWLEDGMENT This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science (2016-R1A5A1009405, 2017R1A2B4003617, 2016-R1C1B1011372, 2016R1E1A2A01954001).

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Hyaluronic Acid-Modified Polymeric Gatekeepers on Biodegradable

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