pH-activated doxorubicin release from polyelectrolyte complex layer coated mesoporous silica nanoparticles

doi:10.1016/j.micromeso.2013.06.016

Microporous and Mesoporous Materials

Volume 180, 1 November 2013, Pages 86-91

https://doi.org/10.1016/j.micromeso.2013.06.016 Get rights and content

Highlights

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Mesoporous silica nanoparticles coated by polyelectrolyte multilayer complex showed a high colloidal stability in biological media.
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Doxorubicin was efficiently loaded in the nanoparticles.
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The nanoparticles–doxorubicin conjugate showed a pH-dependent release properties.
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pH-driven drug delivery release was demonstrated in cells by laser scanning confocal microscopy.

Abstract

Mesoporous silica nanoparticles (MSN) functionalized with doxorubicin (Dox) and coated with a polyelectrolyte complex layer were tested in vitro to investigate drug release in cellular environment. The mesoporous silica nanoparticles inner surface was efficiently functionalized with the positively charged antitumoral drug doxorubicin. Polyelectrolyte layer complex was adsorbed on the outer surface of the MSN improving colloidal stability in biological media and forming an electrostatic barrier against the doxorubicin diffusion at biological pH. Dox-loaded silica nanoparticles showed a pH-dependent drug release behavior. Cell uptake of mesoporous silica nanoparticles and drug release dynamic were real-time monitored by laser scanning confocal microscopy. These results suggest that MSN could be exploited as smart carrier with pH-triggered drug releasing properties.

Graphical abstract

Introduction

The advantages provided by nanotechnology in the battle against cancer were proven extensively in the last years [1], [2]. Compared with conventional therapeutic drugs which are nonspecifically distributed in the body, nanomaterials-based drug delivery systems can reduce harmful side effects improving the therapeutic efficacy [3]. Nanoparticles with dimension lower than 200 nm can be preferentially accumulated in the tumor through the enhanced permeability and retention (EPR) effect [4]. This is a clear advantage for nano-based drug delivery and therapeutic agents, because of the possibility to infiltrate the tumor tissue with a variety of different nanosystems including metal nanoparticles [5], magnetic nanoparticles [6], polymeric vectors [7] and multifunctional system composed by combination of the aforementioned nano-objects [8].

Mesoporous silica nanoparticles (MSN) prepared by surfactant templating methods [9] possess attractive features such as well-defined and controllable pore size, large surface area and reactive surfaces for easy functionalization which make them ideal as potential carriers for drugs. Indeed, mesoporous silica nanoparticles were investigated as drug delivery vehicles because of their low toxicity and very high specific surface area with abundant silanol groups on the pore surface. It is known that nanoparticles can accumulate into the liver and spleen after repeated in vivo injections [10]. This can cause some side effects in patients and normally limits the amount of drug that can be injected in the body. This is why vectors able to incorporate a high amount of chemioterapic agents are preferable. Jinlou Gu et al. reported that MSN can incorporate 90% in weight of drugs, although with nanoparticles of relatively low dimensions [11]. Moreover, the confinement of the drug into the MSN nanopores provides a physical barrier to enzymatic degradation and premature drug release.

Another key advantage of the mesoporous silica nanoparticles is their biodegradability. Recent experiments using simulated body fluids showed that MSN can be degraded to silicic acid [12]. Lu et al. showed that after 24 h from MSN injection in mice around 95% of silicon was released by urine and feces [13].

Moreover, MSN with dimensions lower than 100 nm undergo endocytosis with higher cellular uptake efficiency. Considering the acidic environment conditions in the tumor area and also the acidic pH of internal cell organelles (pH 4–5 in the lysosomes and pH 6 near the cancer cell membrane) [14], [15], pH-sensitive nanoparticles represent an important tool in drug delivery.pH-sensitive polyelectrolyte has been already explored in several applications as carriers for controlled delivery of drugs [16]. These polymers contain acid and basic groups and can undergo structural changes in response to variations of the pH of the environment, which facilitates drug delivery control.

In this paper we describe a versatile route to synthesize polyelectrolyte-coated MSN loaded with doxorubicin. The novel strategy to conjugate polyelectrolyte complex layer onto MSN described in this paper may leads to a better Dox release control and thereby to a great improvement in cancer therapy efficacy.

Doxorubicin release by the MSN was investigated in in vitro cultured cells by laser scanning confocal microscopy (LSCM). The doxorubicin release profiles at pH 5.0 and 7.5 were substantially different demonstrating that electrostatic interaction between entrapped drug molecules and MSN silanol groups plays a significant role in the drug release kinetics.

Section snippets

Materials

Tetraethyl orthosilicate (TEOS, Aldrich, 98%), hexadecyl-trimethylammonium bromide (CTAB, Aldrich), ammonium hydroxide solution (Fluka, 28 wt.% in water), absolute ethanol (99.8%, Carlo Erba) were all used as received.

Poly (allylamine hydrochloride), M_w 4500, poly acrylic acid (M_w 4000) doxorubicin and all other chemicals were purchased from Sigma unless otherwise indicated. All reactions were performed using milli-Q water unless indicated in the text.

Synthesis of mesoporous silica nanoparticles

Mesoporous silica nanoparticles were

Results and discussions

Fig. 1 illustrates the overall procedures for the synthesis of the nanoparticles based on MSN. The physico-chemical properties and morphology of MSN were characterized with X-ray photoelectron spectroscopy (XPS), N₂ adsorption/desorption and transmission electron microscopy (TEM). The purity of the MSN was investigated through the Survey, Si 2p and O 1s of the XPS spectra (Fig. 2). The weak signal for the C1s region (280 eV in the Survey spectrum) demonstrates the minimal hydrocarbon

Conclusions

In conclusion, polyelectrolyte-functionalized MSN were produced by an easy and reproducible chemical route. MSN functionalized with doxorubicin and coated with PAA/PAH complex layer were obtained in solution by direct chemical adsorption. The polyelectrolyte complex layer effectively stabilized the nanoparticles in physiological solutions. Dox loaded into MSN demonstrated a pH-dependent release. At pH 5.0 the drug release rate was higher compared to pH 7.4 and this can be attributed to a

Acknowledgment

We thank the Laboratory of Biomolecular Sequence and Structure Analysis for Health (LaBSSAH) for the technical support.

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pH-activated doxorubicin release from polyelectrolyte complex layer coated mesoporous silica nanoparticles

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Materials

Synthesis of mesoporous silica nanoparticles

Results and discussions

Conclusions

Acknowledgment

Adv. Enzym. Regul.

Colloids Surf., B

Micropor. Mesopor. Mater.

Micropor. Mesopor. Mater.

Colloids Surf., B

Int. J. Pharm.

Chem. Soc. Rev.

Cancer

Mol. Cancer Ther.

Int. J. Nanomed.