Article pubs.acs.org/Langmuir
Fabrication and Characterization of a Porous Silicon Drug Delivery System with an Initiated Chemical Vapor Deposition TemperatureResponsive Coating Steven J. P. McInnes,† Endre J. Szili,‡ Sameer A. Al-Bataineh,‡ Roshan B. Vasani,† Jingjing Xu,§ Mahriah E. Alf,§ Karen K. Gleason,§ Robert D. Short,‡ and Nicolas H. Voelcker*,† †
ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Future Industries Institute, and ‡Future Industries Institute, University of South Australia, Mawson Lakes, SA 5095, Australia § Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States S Supporting Information *
ABSTRACT: This paper reports on the fabrication of a pSi-based drug delivery system, functionalized with an initiated chemical vapor deposition (iCVD) polymer film, for the sustainable and temperature-dependent delivery of drugs. The devices were prepared by loading biodegradable porous silicon (pSi) with a fluorescent anticancer drug camptothecin (CPT) and coating the surface with temperature-responsive poly(N-isopropylacrylamide-co-diethylene glycol divinyl ether) (pNIPAM-co-DEGDVE) or non-stimulus-responsive poly(aminostyrene) (pAS) via iCVD. CPT released from the uncoated oxidized pSi control with a burst release fashion (∼21 nmol/(cm2 h)), and this was almost identical at temperatures both above (37 °C) and below (25 °C) the lower critical solution temperature (LCST) of the switchable polymer used, pNIPAM-co-DEGDVE (28.5 °C). In comparison, the burst release rate from the pSi-pNIPAM-co-DEGDVE sample was substantially slower at 6.12 and 9.19 nmol/(cm2 h) at 25 and 37 °C, respectively. The final amount of CPT released over 16 h was 10% higher at 37 °C compared to 25 °C for pSi coated with pNIPAM-co-DEGDVE (46.29% vs 35.67%), indicating that this material can be used to deliver drugs on-demand at elevated temperatures. pSi coated with pAS also displayed sustainable drug delivery profiles, but these were independent of the release temperature. These data show that sustainable and temperature-responsive delivery systems can be produced by functionalization of pSi with iCVD polymer films. Benefits of the iCVD approach include the application of the iCVD coating after drug loading without causing degradation of the drug commonly caused by exposure to factors such as solvents or high temperatures. Importantly, the iCVD process is applicable to a wide array of surfaces as the process is independent of the surface chemistry and pore size of the nanoporous matrix being coated.
1. INTRODUCTION
enables the controlled diffusion/release of the drug in response to certain conditions such as pH13 or temperature.14 This paper focuses on nanostructured porous silicon (pSi) films. pSi is a versatile drug delivery platform: it is nontoxic and biodegradable,15 it is a biocompatible implantable material,16 and it can be combined with biosensing and be tailored for specific controlled or sustained drug delivery applications.17
Controlled drug delivery systems are beneficial for many drug therapies because they enable the targeted delivery of medicine and allow for the tuning of delivery rates, thereby minimizing any toxic side effects and maximizing the potential therapeutic benefit.1−7 However, tailoring a drug delivery system with these properties while retaining the therapeutic qualities of the drug is challenging. A number of drug delivery systems utilize a porous matrix functionalized with a stimulus-responsive polymer.8−12 The porous matrix provides a large volume reservoir for the drug, and the stimulus-responsive polymer © XXXX American Chemical Society
Received: October 21, 2015 Revised: December 8, 2015
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DOI: 10.1021/acs.langmuir.5b03794 Langmuir XXXX, XXX, XXX−XXX
Article
Langmuir
poly(N-isopropylacrylamide-co-diethylene glycol divinyl ether) (pNIPAM-co-DEGDVE) or non-stimulus-responsive poly(aminostyrene) (pAS) by means of iCVD.
To improve the release or degradation kinetics of the pSi drug delivery vehicle, its surface can be coated with a polymer that acts as a capping layer, protects the payload from the surrounding environment, and enables sustained release.14,18 In particular, this polymer can display stimulus-responsive properties for controlled release of the drug under specific biological conditions. Examples of pSi capped with polymeric materials include the work of Cervantes-Rincón et al.,19 who generated hybrid poly(vinyl alcohol) and porous silicon (pSi) hydrogels for the release of theophylline. The ability of the PVA hydrogels to swell was based on the amount of pSi particles cross-linked into the polymer network, and hence the release profile was tunable based on the extent of this cross-linking.19 Liu et al.20 have also reported a stimuli-responsive polymeric drug delivery system for combination chemotherapy. The system allows for the ratiometric incorporation of two drugs into a monodisperse microcomposite containing hypromellose acetate succinate. The hypromellose acetate succinate is insoluble when in an acidic environment and conversely highly soluble at neutral or alkaline pH conditions. The composite materials demonstrated multistage pH-response and tailored release kinetics. Initiated chemical vapor deposition (iCVD) is a new approach to uniformly coat biodegradable pSi13 and other materials with functional thin films.13 In comparison to wetchemical polymerization methods, iCVD is advantageous for the functionalization of pSi drug delivery vehicles because it is a low-temperature and solvent-less coating process. This allows the drug to be preloaded into the pores before capping the surface with the polymer without suffering degradation or loss of the drug. Consequently, the accuracy and efficiency of the drug loading process are vastly improved. The iCVD process and its versatility for a wide range of applications have been well documented.21,22 In this paper, pSi is functionalized with poly(N-isopropylacrylamide) (pNIPAM), a thermoresponsive polymer that undergoes physical transitions upon the applications of a temperature change.23−28 pNIPAM, when hydrated in aqueous solution, shows a sudden volume-phase transition when heated beyond the lower critical solution temperature (LCST) of 32 °C.29 This volume-phase transition is attributed to heating or cooling across the LCST, causing the polymer to reversibly change from a hydrophilic coiled to a hydrophobic globular structure.30 Upon heating, the monomer−monomer hydrogen bonding interactions become stronger than the monomer− solvent interactions.31 This results in the polymer taking a globular form with the amide groups facing inward and the isopropyl groups facing outward.32,33 The formation of socalled “smart surfaces” possessing a reversible temperaturedependent change in wettability around a LCST in aqueous solutions14 is achieved via grafting pNIPAM brushes onto solid surfaces such as silicon,34 gold,35 and glass.36 To date, very few attempts have been made to graft pNIPAM onto pSi.14,26,37−40 Segal et al.26 examined the switching behavior of a pSi film filled with a cross-linked pNIPAM hydrogel using interferometric reflectance spectroscopy (IRS). More recently, Bonanno et al.40 fabricated a chemosensitive hydrogel, based on disulfide chemistry, within pSi and demonstrated dissolution via the application of reducing agents. Recent work from our group has focused on surface-initiated atom transfer radical polymerization (SI-ATRP) to grow pNIPAM on pSi films for the generation of thermoresponsive inorganic−organic hybrids.14 This study describes the fabrication and characterization of a pSi drug delivery vehicle capped with temperature-responsive
2. EXPERIMENTAL SECTION 2.1.1. Chemicals. Hydrofluoric acid (48%, Merck), dicholoromethane (CH2Cl2, Labserv, analytical grade, 99.5%), methanol (Merck, analytical grade, 99.5%), acetone (Ajax, analytical grade, 99.5%), and ethanol (Ajax, absolute, 100%) were used for etching and washing without further purification. Conductivity water (18.2 MΩ) was obtained from a Milli-Q A10 Advantage water purification system (Merck Millipore). Dimethylformamide (Sigma, 99%) was distilled and stored over molecular sieves. Camptothecin (CPT, Sigma, 95%) was kept refrigerated at 2−4 °C and away from light wherever possible. PBS tablets were purchased from Sigma and dissolved according to the manufacturer’s protocol in 200 mL of Milli-Q water; the pH was checked to ensure a pH of 7.4. 2.1.2. pSi Film Preparation. Silicon wafers (p-type, boron doped, resistivity = 3−6 Ω·cm, ⟨1−0−0⟩) purchased from Silicon Quest International were etched in 1:1 HF:ethanol electrolyte at a current density of 186.8 mA cm−2 using a 1.8 cm2 etching cell. The pSi was then washed with methanol, ethanol, and dichloromethane before being dried with N2 gas. A Labec (Australia) tube furnace was used to performed thermal oxidations for 1 h at 400 °C. 2.1.3. Gravimetric Analysis. The porosity of the pSi was determined gravimetrically. The wafer is weighed before (m1) and after etching (m2) and once again after removal (m3), with NaOH, of the porous layer from the bulk Si.41 These three values can then be entered into the equation41
porosity (%) = (m1 − m2)/(m1 − m3)
(1)
2.1.4. Drug Loading into pSi. Before iCVD coating the pSi was incubated with CPT in dimethylformamide (2.5 mg mL−1) for 2 h before the excess was removed, and the pSi film was completely dried under vacuum. A five decimal place balance was used to calculate the total CPT loaded. The total loading of CPT was subsequently used to convert the amount released to a percentage. Release intensities of CPT were converted to amounts by calculating against a calibration curve and then normalizing to the surface area of the sample (further details in section 2.1.12). 2.1.5. Initiated Chemical Vapor Deposition (iCVD). The custom-built reactor (Sharon Vacuum) in which the iCVD was performed has been described previously.42,43 A nichrome filament (80:20 Ni/Cr) was used to provide thermal excitation (285 °C monitored by a thermocouple). The heated filament was positioned parallel to and 2 cm above the deposition stage, which was watercooled to maintain a temperature of 20 °C. The iCVD of p(NIPAMco-DEGDVE) was performed using optimized parameters from our earlier publication.21 Briefly, N-isopropylacrylamide (NIPAM, Aldrich, 99%) and diethylene glycol divinyl ether (DEGDVE, Aldrich, 98%) were used as the comonomers. DEGDVE served a dual purpose as a cross-linking agent, and the radical initiator tert-butyl peroxide (TBPO) (Aldrich, 97%) was used. To achieve sufficient vapor flow, the NIPAM (70 °C) and DEGDVE (100 °C) were heated, while TBPO had sufficient flow at room temperature. Mass flow controllers (MKS) were used to control the flow rates of NIPAM, DEGDVE, and TBPO were controlled to 0.6, 0.1, and 0.1 sccm, respectively. The final total pressure in the reactor was 0.5 Torr. For a control, a nonthermoresponsive iCVD coating of poly(aminostyrene) (pAS) was performed as described above. This monomer has previously been used and characterized to coat surfaces via the iCVD process.44 During deposition (for all coatings), laser interferometry was used to monitor film growth in situ on a flat Si wafer, and the reaction was stopped when a thickness of 200 nm was obtained. 2.1.6. Infrared (IR) Spectroscopy. A Nicolet Nexus 870 Fourier transform (FT) IR spectroscope (Thermo Electron Corp., USA) was used to obtain IR spectra. The spectroscope possessed a deuterated triglycine sulfate detector with a thermoelectric cooler, and the spectra were recorded at a resolution of 4 cm−1 using a Smart Orbit diamond B
DOI: 10.1021/acs.langmuir.5b03794 Langmuir XXXX, XXX, XXX−XXX
Article
Langmuir
Figure 1. (A) SEM cross section of the pSi layer. AFM of pSi before (B) and after (C) coating with pNIPAM-co-DEGDVE. (D) Chemical structure of CPT and (E) structure of the monomers and the pNIPAM-co-DEGDVE polymer. accessory in the range of 650−4000 cm−1. Spectra were analyzed using version 7.0 of the OMNIC software (Thermo Electron Corp.). The background was an unetched flat Si wafer. All IR spectra are presented in absorbance mode and are normalized to the Si−O peak at approximately 1100 cm−1. 2.1.7. Atomic Force Microscopy (AFM). AFM (tapping mode, ambient conditions) was performed using a Multimode Nanoscope and a Nanoscope IV controller supplied by Veeco Corporation. Silicon cantilevers (FESP, Veeco Corporation) possessed the following specifications: 2.8 N/m force constant, 75 kHz resonance frequency, tip height of 10−15 μm, and a tip radius of
