pH and Ultrasound Dual-Responsive Polydopamine Coated

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pH and Ultrasound Dual-Responsive Polydopamine Coated Mesoporous Silica Nanoparticles for Controlled Drug Release Xiaochong Li, Chuan Xie, Hesheng Xia, and Zhanhua Wang Langmuir, Just Accepted Manuscript • DOI: 10.1021/acs.langmuir.8b01091 • Publication Date (Web): 30 Jul 2018 Downloaded from http://pubs.acs.org on July 31, 2018

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pH and Ultrasound Dual-Responsive Polydopamine Coated

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Mesoporous Silica Nanoparticles for Controlled Drug Delivery

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Xiaochong Li, Chuan Xie, Hesheng Xia and Zhanhua Wang*

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State Key Laboratory of Polymer Materials Engineering, Polymer Research Institute,

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Sichuan University, Chengdu 610065, China.

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E-mail: [email protected]

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ABSTRACT

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A pH- and ultrasound- (US) dual responsive drug release pattern was successfully achieved

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using mesoporous silica nanoparticles (MSNs) coated with polydopamine (PDA). In this paper,

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the PDA shell on MSNs surface was obtained through oxidative self-polymerization under

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alkaline condition. The morphology and structure of this composite nanoparticle were fully

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characterized by a series of analyses, such as infrared (IR), transmission electron microscopy

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(TEM), and thermo-gravimetric analyzer (TGA). DOX loaded composite nanoparticles were used

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to study the performances of responsive drug storage/release behavior and this kind of hybrid

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material displayed an apparent pH response in DOX releasing under acid condition. Beyond that,

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upon high intensity focused ultrasound (HIFU) exposure, loaded DOX in composite nanoparticles

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was successfully triggered to release from pores due to the ultrasonic cavitation effect, and the

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DOX-releasing pattern could be optimized into a unique pulsatile fashion by switching the

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ON/OFF status. From the methyl-thiazolyltetrazolium (MTT) assay, our blank nanoparticles

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performed no toxicity to HeLa cells, but DOX-loaded nanoparticles could inhibit the growth of

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tumor cells. Furthermore, these composite nanoparticles displayed an effective near-infrared (NIR)

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photothermal conversion capability with a relatively high conversion efficiency (~37%). These

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as-desired drug-delivery carriers might have a great potential for future cancer treatment that

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combine the chemotherapy and photothermal therapy.

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INTRODUCTION

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With the improvement of nanotechnology, many advanced research paths have been opened

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up in different fields, and one of the most promising applications is in controlled drug delivery

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systems (CDDS) for cancer treatment. Nanoparticles, employed as carriers in the CDDS, exhibit

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some significant advantages such as increased aggregation and enrichment of drugs at infected

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tissues and cells, reduced systemic toxicity and improved efficacy of traditional cancer treatment.1

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In the past decades, all sorts of nanoparticles have been designed and employed as nanocarriers to

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construct

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organic−inorganic hybrid nanoparticles11. Some of them have already been authorized by the Food

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and Drug Administration (FDA) for clinical trials.12

CDDS,

such

as

liposome2-4,

micelles5-7,

inorganic

nanoparticles8-10

and

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Among all of the studied systems, organic systems have their intrinsic instable nature, which

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could lead to the inevitable pre-leakage of drugs. Alternatively, the inorganic materials, like

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mesoporous silica nanoparticles (MSNs), display more adaptable and unique properties including

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chemical/thermal stability, excellent biocompatibility, tunable pore size and high surface area

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(>900 m2/g), etc.13-15 At the same time, plenty of the silanol groups on MSNs, which have high

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reactivity, are accessible to react with other functional groups, endowing MSNs a well-modified

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surface to control the transportation capacity of different molecules on the holes.16 To date, many

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attempts have been made to achieve smart stimuli-sensitive CDDS based on MSNs. They are 2


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allowed for desired release patterns with the real-time control under the complicated physiological

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conditions and perform one or more sensitiveness to different external stimuli (i.e.,

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temperature,17-18 light,19-21 magnetic fields,22-23 and ultrasounds11,

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pH,25-27 and redox species27).

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) or internal stimuli (i.e.,

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Nowadays, the burgeoning interest in ultrasound (US) stimulus has been greatly spurred in

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many smart drug delivery studies since US represents some robust properties. Above all, it can be

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used as a noninvasive, non-ionizing radiation stimulus with a spatiotemporal in vitro control.

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Additionally, it possesses an ability to invade deep into the body, which differs from light which

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has time and depth limitation, and it can easily regulate the penetration depth through tuning the

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parameters such as frequency, power density and irradiation time.11, 24, 28 Furthermore, studies

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have shown that ultrasound is relatively safe and beneficial to the in vivo circulation of responsive

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drug delivery system on account of enhanced cell membrane and tissue permeation.29

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Generally speaking, ultrasound is usually divided into two sorts at 200 kHz: low intensity

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ultrasound and high intensity focal ultrasound. In some ways, low intensity ultrasound may

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destroy your healthy tissues and is restricted in practical clinic use, considering its vigorous

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cavitation effect and long wavelength which is difficult to be focused. By contrast, high intensity

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focal ultrasound (HIFU) can achieve local therapy with little or even no side effects because its

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intensity can be quite strong only at the focal site, while is pretty weak in other areas.30 Therefore,

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HIFU is developed as a more appealing stimulus for pulsatile drug release, and US-sensitive

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nanoparticles based on MSNs may have more potential application value.

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In order to combine MSNs and US stimulation to attain a smart responsive drug delivery

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system, we designed a kind of polydopamine (PDA) coated MSN composite nanoparticle. There 3


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are abundant catechol and amine functional groups in dopamine, so that it can form a PDA

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modified layer on almost any surface by self-polymerization.31 In addition, PDA which contains a

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melanin-like molecular structure, can be employed in photothermal therapy (PTT) to absorb and

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transform the near infrared (NIR) light into thermal energy for killing tumor cells.32-34 However,

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the molecular mechanism behind PDA formation has not been fully recognized. Generally, it is

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widely suggested that its structure is mainly composed of oligomers by hydrogen bonding or π-π

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stack. Under the external stimulus, PDA may form an unstable state, thereby altering its interlayer

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structure and achieving responsive drug release.35-36 Herein, we prepared a type of core-shell

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structure MSNs fabricated through the oxidative self-polymerization of dopamine, and further

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studied their dual-responsive drug releasing behaviors under pH/HIFU stimuli. The cytotoxicity

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assay for HeLa cells and the photothermal conversion effect of these composite nanoparticles

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were also fully discussed, and we anticipated that they would play a potential role in combining

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the chemotherapy and photothermal therapy for future cancer treatment.

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EXPERIMENTAL

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Materials. Cetyltrimethylammonium bromide (CTAB, 99.99%), tetraethyl orthosilicate

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(TEOS, 99.99%) were purchased from Aladdin (China). Doxorubicin hydrochloride (DOX, 98%)

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was supplied by Sigma-Aldrich Company (China). Dopamine·HCl (DOPA) was provided by

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Chengdu Huaxia Chemical Reagent Co. Ltd. Ethanol, sodium hydroxide (NaOH), hydrochloric

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acid (HCl), ethyl acetate (EtOAc) and hydrogen peroxide solution (H2O2) were purchased from

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Kelon Chemical Reagent Co. Ltd (Chengdu, China). All solvents (GR grade) were used without

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further purification.

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Preparation of bare MSNs. The MSNs were synthesized according to a reported method

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that using TEOS as a silica source and CTAB as template37: initially, 0.5 g of CTAB was added

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into a three-necked flask and completely dissolved with 240 mL DI water. Then, 1.75 mL of 2 M

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NaOH (aq) was added as a catalyst. The above mixture was mechanically stirred at 80 °C for some

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time. Subsequently, 2.4 mL of TEOS was charged slowly and the mixture was allowed to stir at

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80 °C for 2 h. The precipitate was obtained by filtration and washed with excessive amount of DI

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water and methanol. Finally, the white product was dried under vacuum at 40 ℃.

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The templating CTAB surfactants in the MSNs was extracted through the following

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procedure: the as-synthesized CTAB-containing product (0.5 g) was refluxed in 50 mL methanol

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solution with 2.5 mL concentrated hydrochloric acid for 24 h. The resulting template-removed

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solid was then centrifuged and washed with excessive DI water and methanol. Finally, this solid

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MSNs were dried under vacuum at 60 ℃overnight.

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Preparation of Polydopamine-coated Mesoporous Silica Nanoparticles (MSN@PDA).

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50 mg of MSNs were ultrasonically dispersed in 30 mL Tris-HCl buffer (50 mM, pH 8.5) for 10

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min. 25 mg DOPA·HCl was dissolved in 20 mL same buffer solution and added into the MSNs

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dispersion. Subsequently, the above mixture was stirred continuously for 12 h at 25 ℃. The

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mixture was centrifuged and washed repeatedly with the buffer of pH 8.5, then freeze-dried to

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obtain the final product.

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Preparation of DOX-loaded MSN@PDA (MSN@DOX-PDA). 10 mg DOX was firstly

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dissolved in 10 mL Tris-HCl buffer solution (50 mM, pH 8.5) under a heating condition.

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Subsequently, 50 mg of bare mesoporous silica nanoparticles was ultrasonically dispersed in it,

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then the mixture was magnetically stirred at 25 ℃ for 24 h. After that, 25 mg DOPA was dissolved

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in 40 mL Tris buffer solution, mixed with above dispersion and stirred at 25 ℃ for another 12 h. To

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remove the physical adsorption of DOX, the MSN@DOX-PDA products were collected by

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centrifugation, accompanied by gently washing with the buffer of pH 8.5 until no ultraviolet

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intensity of DOX in supernatant could be observed. Finally, put the products into a vacuum oven

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for drying. The quantification of DOX loaded in the MSN@DOX-PDA was defined by UV-Vis

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spectrophotometer at 480 nm according to a pre-corrected fitting line. And the drug loading

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capacity was calculated by the following formula：

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Loadingcapacity(wt%)=

Massof totalDOX- Massof DOXin supernatant ×100% Massof totalMSN@DOX- PDA

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DOX Releasing under pH variation. 5 mg DOX-loaded MSNs was soaked in 5 mL of

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phosphate buffered saline (PBS) solution (pH = 7.4), then transferred into a dialysis tube (MWCO

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= 3500 Da). The sealed dialysis tube was immersed into the same PBS solution (45 mL) and

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gently shaken at 37 °C for 48 h. At specific time intervals, sucked out 1.5 mL of dialysate for

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ultraviolet spectral analysis at 480 nm and subsequently replenished another equal amount of fresh

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buffer to keep the volume unchanged. For the pH-responsive releasing experiments, we also chose

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the other two different buffer solutions to repeat the above experiment: sodium acetate buffer for

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pH 3.0 and phosphate buffer for pH 5.5.

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On-Demand DOX Releasing Stimulated by HIFU. HIFU as an exogenous stimulus can

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activate the drug release from MSN@DOX-PDA. Herein, two different pH value PBS solutions

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(7.4 and 5.5) were chosen to test the DOX releasing behavior. Typically, MSN@DOX-PDA (5 mg)

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was soaked into PBS solution (5 mL) and dispersed via a slight ultrasound. After that, followed by 6


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displacing it into a dialysis tube (MWCO = 3500 Da), the tube was immersed into another 20 mL

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PBS solution and sealed in a vessel with a latex membrane. The vessel was inverted and located at

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the center of HIFU beams and ON-OFF cycle focused ultrasound was given effect to the

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MSN@DOX-PDA dispersion. The power of HIFU was 100 W (1.1 MHz), and the action time was

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10 min for every hour. At a certain period, 1.5 mL dialysate was taken out, and another 1.5 mL

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fresh buffer ensued. The dialysate was analyzed by UV-Vis to obtain the release profile.

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Cytotoxicity measurement. The in vitro cytotoxicity of MSN@PDA, MSN@DOX-PDA

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nanoparticles and free DOX was measured via the MMT assay using HeLa cells. First, HeLa cells

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were cultivated in Dulbecco's Modified Eagle's Medium (DMEM) added with fetal bovine serum

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(FBS) in a moist environment (5% CO2/95% O2). After three generations, they were sowed into a

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96-well plate at the density of 5×103 /well and cultured in an incubator at 37 ℃ overnight. After

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that, these cells were incubated with MSN@PDA, MSN@DOX-PDA nanoparticle or free DOX

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dispersions at different concentrations for 24 h. Cells without MSN@PDA, MSN@DOX-PDA

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nanoparticles or free DOX treatment were used as control. Then every well was added with 0.5%

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MTT solution (20 µL) and incubated for 4 h. Afterwards, a microsyringe was used to carefully

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remove the supernatant in each well and added with DMSO (150 µL) in each well. Shaken at a

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low speed for 10 min to fully dissolve the crystals. MTT assay was performed by a microplate

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reader (Rayto, Rt2100c) at 490 nm to measure the optical densities (OD) values. The cell viability

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(%) was obtained by comparing the average absorbance value of treatment group with that of

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blank group.

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Characterizations. Fourier transform infrared spectroscopy (FTIR) was collected on a

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Nicolte-560 spectrometer. Thermo-gravimetric analyzer (TGA) was operated on a PerkinElmer 7


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TGA4000 in N2 atmosphere to study the thermal stability, heating from 100 ℃ to 800 ℃ with a 10 ℃

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/min heating rate. Powder X-ray diffraction (PXRD) spectra were recorded by monitoring the

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diffraction angle from 1.5° to 10° on an Empyrean powder diffractometer. Nitrogen adsorption

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and desorption capacity was measured on an Autosorb-IQ2 Fully Automatic Analyzer. Meanwhile,

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BET and BJH models were used to work out the surface area and pore diameter. The morphology

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of different nanoparticles was observed via scanning electron microscopy (SEM) on a Quanta 250

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instrument (FEI Co. Ltd, USA) and transmission electron microscopy (TEM) on Tecnai G2 F20

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S-TWIN (FEI Co. Ltd, USA). Drug release patterns were obtained via a Cary 60 UV-Vis

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spectrophotometer (Agilent, USA). The near infrared light source used in this experiment was

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self-assembled. The power of this device was 1.5 W, the spot size was 0.5 × 0.5 cm2 and the

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wavelength was 808 nm.

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HIFU device. As covered in other works previously5, 30, 38, the HIFU device is composed of

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three elementary parts: Arbitrary waveform generator (Agilent 33220A Function Generator), RF

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power amplifier (A150, Electronics & Innovation) and acoustic lens transducer (H-101, Sonic

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Concept, USA), which are clearly shown in Scheme 1. The acoustic lens transducer could bring

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about a great focused pressure in a very tiny spot that is only 1.26 mm in diameter and 11 mm of

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height, and the focused length is around 63 mm. In addition, the output power of ultrasound can be

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altered from 0 to 150 W at a high frequency of 1.1 MHz. Within each irradiation time, the focused

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point of the beam was located at the center of the dispersion in a glass cuvette reactor sealed with

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a latex film. The energy of HIFU beams can transmit through this film and stimulate the hybrid

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mesoporous silica dispersion.

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Scheme 1. (Left) Schematic diagram of HIFU device. ① Arbitrary Waveform Generator, ② RF power amplifier, ③ Acoustic lens transducer, ④ Beams of Ultrasound, ⑤ Water bath, ⑥ Latex film, ⑦ Nanoparticle dispersion, ⑧ Cuvette reactor. (Right) Picture of HIFU device.

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RESULTS AND DISCUSSION

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Figure 1. Schematic representation of the preparation of MSN@PDA and MSN@DOX-PDA.

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Synthesis and Characterization of MSNs

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The synthesis route of MSN@PDA and MSN@DOX-PDA, as well as the structure changes

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during self-polymerization of DOPA were briefly portrayed in Figure 1. Bare MSNs were

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prepared via a base-catalyzed sol–gel method as mentioned previously, then coated with a PDA

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shell through self-polymerization to obtain MSN@PDA. Lee et al. successfully formed a

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multifunctional polymer coatings in an aqueous solution of dopamine.39 In alkaline aqueous 9


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solution, dopamine was firstly oxidized to dopa-quinone in the presence of oxygen and then

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rearranged into dopa-indole. Subsequently, the amino groups underwent a Michael addition

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reaction with the benzene rings to form oligomers, which further formed PDA through hydrogen

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bonding and π-π interaction. MSNs with spherical shape were characterized by SEM (Figure S1).

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We could see that there were no obvious changes in the morphology and particle size before and

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after the polymer coating. However, it was worth noting that there was a degree of adhesion

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between the coated nanoparticles, which was ascribed to PDA layer. In order to look further about

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that, TEM was employed. As depicted in Figure 2a and b, MSNs was about 142 nm in diameter

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and had ordered mesoporous channels. The presence of the polymer shell and the absence of the

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channel structure after introduction of PDA were also clearly depicted in Figure 2c, d. The shell

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was uniform and the thickness was about 3 nm, demonstrating the surface modification was

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successful.

3 nm

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Figure 2. TEM images of (a and b) bare MSNs, (c and d) MSN@PDA. Scale bar: 50 nm for (a), (b), 20 nm for (c), (d). The thickness of PDA was indicated by red arrow in (c). 10


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Figure 3. XRD of MSNs and MSN@PDA.

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The hexagonal array pores structure of MSNs was further certified by PXRD analysis.

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Characteristic diffraction peaks at (100), (110) and (200) were apparently observed in Figure 3.17

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Compared to blank MSNs, the MSN@PDA showed a significantly lower intensity, which was

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resulted from the successful introduction of PDA shell. Moreover, as shown in Figure 4 and Table

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1, the surface area and pore volume of MSNs characterized through BET and BJH analysis were

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1410.67 m2/g and 2.12 cm3/g, respectively. Meanwhile, the MSNs had a narrow pore size

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distribution around 2.46 nm, which meant that there had enough space for DOX (1.3 nm) to be

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transported freely. From the MSNs adsorption curve, we could see a step near 0.35 P/P0 and a

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hysteresis loop, which indicated a typical ℃ adsorption isotherm for a well-defined mesoporous

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structure.40 However, the curve of MSN@PDA became flat, and the pore diameter could not be

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measured. We believed that the disappearance of the pore structure on one hand was due to the

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pores of MSNs encapsulated with a polymer layer, on the other hand was that mesoporous pores

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were occupied by self-clustered PDA. FTIR spectroscopy and TGA analysis were also conducted

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to verify the successful coating of MSNs, and these results were depicted in Supporting

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Information (Figure S2). In FTIR spectroscopy images (Figure S2a), compared with the spectrum

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of MSNs (MCM-41 represented template without remove), there were several new absorption

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peaks at 1400-1500 cm-1 of MSN@PDA assigned to the vibration of the benzene ring.

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Quantitative measurement of the polymer layer was carried out by TGA from 100 to 800 °C under

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N2 atmosphere (Figure S2b). Compared to other two curves, only a tiny weight loss (less than 9

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wt %) could be observed from pure MSNs after 800 °C, which was originated from the

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dehydroxylation of silanol.40 In contrast, for pure PDA, the weight percentage was only 6.58% left

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after the measurement. As to MSN@PDA particle, the remaining weight was 75.73%, 15.41%

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more loss than MSNs, which was mainly contributed to the mass of surface-wrapped PDA. From

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the above results, it can be proved that MSN nanoparticles were successfully modified by PDA.

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Figure 4. (a) N2 adsorption-desorption isothermals and (b) pore diameter distributions of MSNs and MSN@PDA.

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Table 1. Brief summary of surface areas and pore sizes of MSNs and MSN@PDA Samples

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Surface Areaa (m2/g)

Pore Volumeb (cm3/g)

Pore Sizeb (nm)

MSNs 1410.67 2.12 2.46 MSN@PDA 73.90 / / a b Calculation based on BET method. Calculation based on BJH method. 12


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DOX Loading.

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Figure 5. UV-Vis adsorption of pure water, MSNs, MSN@PDA and MSN@DOX-PDA (from bottom to top).

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The anticancer drug DOX was chosen to study the pH/HIFU dual-sensitive release

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performances of obtained composite particles. Here, MSNs were loaded with DOX at pH 8.5 and

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this practice had two benefits. Firstly, DOX’s solubility decreased with the increase of pH value,

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as alkaline conditions might favor the entry of DOX into the mesoporous pores to enhance the

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loading capacity. However, when the pH was too high, degradation behavior of DOX would

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happen and made it difficult to completely dissolved in the solution; Secondly, dopamine

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self-polymerization condition was carried out at pH 8.5, so that we could directly process

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dopamine coating procedure after the DOX loaded, omitting the intermediate step to improve the

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preparation efficiency (Figure 1). The loading capacity of DOX was about 13.6 wt% as calculated

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by the previously mentioned equation. This was a relatively high loading capacity compared to

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other literature.8, 21, 27, 39 And we also tested UV light adsorption of 0.5 mg/mL composite particles

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dispersions based on MSNs with UV spectroscopy (Figure 5). Compared with the curve of

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MSN@PDA, a new absorption peak at 480 nm of MSN@DOX-PDA was shown, providing 13


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further evidence of that DOX was successfully loaded into mesoporous pores. We believed that, in

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addition to DOX drugs loaded in the mesoporous channels, DOX form a conjugated structure with

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PDA in a π-π conjugated or hydrogen-bonded interaction so the MSN@PDA surface would also

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have DOX present more or less.41

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pH / HIFU Dual Responsive Release Behaviors

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Figure 6. Schematic representation of MSN@DOX-PDA and its pH/HIFU dual-responsive release performances.

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Our designed drug delivery system could respond to pH and HIFU, respectively, as

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illustrated in Figure 6. To research the pH-triggered performance of the MSN@DOX-PDA

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particles firstly, the release profile of DOX from phosphate buffers (PBS) were performed at

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different pH values (i.e., pH = 7.4, pH 5.5 and pH 3.0, respectively) with UV-Vis spectra test.

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(Standard curves of DOX buffers at different pH were listed in Fig. 7a). It could be clearly seen 14


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from Figure 7b that the decrease in pH value promoted the DOX release behavior. When this

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delivery system was under a neutral condition which is pH 7.4, the total release amount was only

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8.7% for 48 h. By decreasing pH to 5.5, the total release amount could reach 23.7%. Interestingly,

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the drug release amount reached 71.2% at pH 3.0, revealing a remarkable enhancement. The effect

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of pH value on DOX release was the result of a combination of two factors. On one hand, the

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solubility of DOX is inversely proportional to the pH value of solution, so the acidic condition

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facilitates the diffusion of DOX from pores into the medium, thus the amount of release and the

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release rate are improved. On the other hand, under the acidic condition, PDA will have a certain

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degree of degradation, which has been reported in the literature.42 The broken up of the coating

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layer released the drug that trapped within it. We had also confirmed this view by TGA and TEM

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characterizations with detailed experiments describing in the Supporting Information (Figure S3

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and Figure S4).

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Notoriously, the tumor microenvironment is not only slightly acid but also has a certain

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degree of oxidative stress, which is often accompanied with producing of some reactive oxygen

15

species (ROS) such as hydrogen peroxide (H2O2)41, 43. This substance could oxidize the phenols in

16

the PDA to quinone, thereby weakening or even breaking the interaction between DOX molecules

17

and PDA. As mentioned before, DOX molecules and PDA may form π-π interaction and/or

18

hydrogen bonding, so the DOX releasing experiment was repeated in the presence of H2O2 to test

19

whether this interaction exists. As shown in Figure 7c, after adding 20 mM H2O2, the drug release

20

amount increased from 8.7% to about 32.5% at pH 7.4, confirming the role of H2O2 that can

21

facilitate the DOX releasing performance and the presence of the π-π interaction as well as

22

hydrogen bonding between PDA and DOX. 15


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1 2 3 4

Figure 7. (a) UV-Vis calibration curve of DOX under different pH; (b) DOX release of MSN@DOX-PDA under different pH; (c) DOX release of MSN@DOX-PDA with or without 20 mM H2O2; (d) DOX release of MSN@DOX-PDA with or without HIFU under pH 5.5 and 7.4.

5

In addition to the pH-responsive ability, MSN@DOX-PDA nanoparticles can also be

6

activated by ultrasound to achieve releasing profiles. Here, we switched the ON-OFF status of

7

high intensity focus ultrasound (HIFU) to obtain a pulsatile DOX-releasing pattern. At the

8

beginning of each cycle, experiment was performed with 100 W HIFU for 10 min (1.1 MHz), then

9

the HIFU was stopped and the DOX releasing amount was tested by UV. Figure 7d presented the

10

DOX releasing profiles clearly and all of the releasing manners could be accelerated once under

11

HIFU exposure. Furthermore, the DOX releasing percentage under HIFU exposure could increase

12

4% for each cycle and eventually reached about 17% at pH 5.5, by contrast with the lower

13

releasing amount of blank experiment (pH 5.5 without HIFU exposure), which must be ascribed to

14

the stimulation of HIFU. To further validate pH-triggered controlled cargo releasing pattern, the 16


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1

MSN@DOX-PDA nanoparticles were also exposed to HIFU at pH 7.4. The curves from Figure 7d

2

clearly exhibited that the DOX releasing percentage could reach 2% for each cycle and the total

3

releasing amount was up to 8% after four times, which was lower than that of pH 5.5, proving that

4

pH could trigger the release behavior of this composite nanoparticles.

5

Based on these results, we could draw a conclusion that HIFU-treated particles fared better

6

than HIFU-untreated ones. To further explore the HIFU responsive releasing mechanism, TGA

7

was carried out (as shown in Figure S3). After HIFU irradiation, no significant changes were

8

found in the result, indicating that HIFU didn’t destroy the bulk structure of PDA but imposed

9

thermal and/or mechanical effects on it, such as ultrasound acoustic and/or ultrasonic cavitation.44

10

As most people knows, HIFU can be dissipated to thermal energy and generates high temperature

11

within a local region. To exclude the thermo effect of HIFU in destroying the non-covalent π-π

12

interaction or hydrogen bonding of PDA, the influence of temperature on MSN@DOX-PDA was

13

tested. We heated the MSN@DOX-PDA dispersion at 50℃ for 10 min every hour, almost no

14

DOX release from MSN@DOX-PDA was observed (Figure S5). Thereby the release of DOX

15

from MSN@DOX-PDA under HIFU irradiation may be contributed to the mechanical effect.

16

During the process, ultrasonic cavitation effect would lead a great deal of microbubbles to

17

generate, grow and collapse within a very short term. The energy generated at the moment of

18

bubbles collapse could damage the non-covalent π-π interaction or hydrogen bonding and further

19

accelerating the exchange of substance around carriers and promoting the mass transfer.45-46 This

20

well HIFU-responsive DOX releasing behavior is beneficial for the real-time control of

21

on-demand drug release.47

17


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1

Cytotoxicity Assay

2 3 4

Figure 8. The cell viability of Hela cells in MSN@PDA, MSN@DOX-PDA and free DOX dispersion at different concentrations by MTT assay (n = 3).

5

Additionally, the extended experiment to estimate whether this hybrid nanoparticle possessed

6

a feasibility in practical application was indispensable, that is carrying out the cytotoxicity

7

experiment of MSN@PDA, MSN@DOX-PDA and free DOX with different concentrations. As

8

presented in Figure 8, the cell viability of these three nanoparticles was tested with a standard

9

MTT assay. They all showed a declining trend accompanied by raising the concentration.

10

However, MSN@PDA nanoparticles with concentration of 0.5-60 µg/mL had almost no toxicity

11

to normal human cells. For example, even when the concentration up to 60 µg/mL, the cell

12

viability of MSN@PDA nanoparticle was about 80.7%. The result of cytotoxicity clarified that

13

MSN@PDA was a non-poisonous material at a relatively low concentration and was proper for

14

CDDS. Meanwhile, when DOX was loaded into MSN pores and the nanoparticles

15

MSN@DOX-PDA showed an obvious inhibition of HeLa cells growth, which was resembled that

16

of free DOX. And the fact that cell viability of MSN@DOX-PDA surpassed that of free DOX was

17

reasonable, because it was a controlled release behavior attributed to PDA layer and DOX would

18

take some time to release from MSN. 18


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1

Photothermal Effect Analyses

2 3 4 5

Figure 9. (a) Temperature increase of pure water, and MSN@PDA of different concentration under 1.5 W, 808 nm NIR irradiation. (b) UV-vis-NIR adsorption spectra of MSN@PDA aqueous dispersions.

6

In order to study the photothermal property of composite nanoparticles, MSN@PDA

7

nanoparticles with different concentrations (50 µg/mL, 100 µg/mL 200 µg/mL and 300 µg/mL )

8

were exposed to 808 nm near-infrared (NIR) laser with the power of 1.5 W. From the Figure 9a,

9

we could find that all MSN@PDA samples showed photothermal behaviors, and the temperature

10

of these dispersions were directly proportional to their concentrations. For instance, after

11

continuous irradiation with NIR laser for 720s, the temperature of MSN@PDA dispersion

12

increased by 20.2 ℃ with its concentration of 300 µg/mL, which was much higher than that of

13

deionized water (around 5.7 ℃). At the same time, the final temperature of MSN@PDA dispersion

14

increased by 6.8 ℃ to 15.7 ℃ in 720 s as the nanoparticle concentration increased from 50 µg/mL

15

to 200 µg/mL. Furthermore, we calculated the photothermal conversion efficiency (η) of

16

MSN@PDA according to the formula proposed by Roper et al.48-49, and the result was found

17

about 37% (100µg/mL, 1.5W/cm2 irradiation at 808 nm, Figure 9 and Figure S5). Considering the

18

human body temperature is near 37 ℃, we believed that these composite nanoparticles had the 19


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1

potential application in the photothermal therapy and anticipated that they would have an effect on

2

the combination of photothermal therapy-chemotherapy in future cancer treatment.

3

Furthermore, we also used UV-vis-NIR spectra to test the NIR light adsorption and the result

4

depicted in Figure 9b. It revealed that MSN@PDA had a total absorption in the NIR region to a

5

certain extent, by contrast, pure water showed almost no absorption in NIR region (Figure 5).

6

Above these observations were ascribed to the presence of dopa-quinone and dopa-indole

7

structure in PDA and indicated that MSN@PDA could take effect on photothermal therapy for

8

future cancer treatment.

9

CONCLUSIONS

10

In this work, a simple and efficient strategy of preparing PDA coated MSNs was successfully

11

developed for smart drug delivery. The obtained hybrid materials had a core-shell structure and

12

presented both pH and ultrasound sensitivity and performed an excellent releasing performance

13

toward DOX under the simulative conditions. DOX releasing behavior was favored under the

14

decrease of pH value due to a degradation of PDA. Upon HIFU irradiation, a unique ON/OFF

15

DOX-releasing pattern could also be obtained resulting from the cavitation effect of HIFU.

16

Moreover, an obvious photothermal effect of this composite nanoparticle was observed due to the

17

NIR adsorption of the PDA layer. Such pH and HIFU dual-responsive drug releasing performance

18

and the apparent photothermal effect endowed this composite nanoparticle the capacity for

19

chemotherapy as well as photothermal therapy in future cancer treatment.

20

ASSOCIATED CONTENT

21

Supporting Information. The Supporting Information is available free of charge. SEM images of 20


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1

MSNs and MSN@PDA (Figure S1). FTIR (Figure S2a) of MCM-41, MSNs and MSN@PDA.

2

TGA (Figure S2b) of MSNs, MSN@PDA and bare PDA. TGA characterizations (Figure S3) of

3

MSN@PDA under three different treatments. TEM images of MSN@PDA (Figure S4) before and

4

after treated with pH 3.0. Photothermal effect of MSN@PDA aqueous dispersion (Figure S5) and

5

detailed calculation of photothermal conversion efficiency.

6

AUTHOR INFORMATION

7

Corresponding Author

8

*Email: [email protected]

9

ORCID

10

Zhanhua Wang: 0000-0003-0493-1905

11

Notes

12

The authors declare no competing financial interest.

13

ACKNOWLEDGEMENTS

14

We are grateful to acknowledge the financial support from the National Natural Science

15

Foundation of China (51473094, 51703143). The author also thanks the State Key Laboratory of

16

Polymer Materials Engineering (Grant No. sklpme2017-3-04).

17

REFERENCES

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Langmuir

1

Table of Content

2

A normal pH-responsive drug delivery nanosystem combined with a HIFU-responsive

3

drug releasing behavior based on PDA coated MSNs were developed for cancer

4

treatment.

5

6 7

25


pH and Ultrasound Dual-Responsive Polydopamine Coated

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