Radiofrequency-Triggered Release for On-Demand Delivery of Therapeutics From Titania Nanotube Drug-Eluting Implants

Manpreet Bariana; Moom Sinn Aw; Eli Moore; Nicolas H Voelcker; Dusan Losic


Nanomedicine. 2014;9(8):1263-1275. 

In This Article

Abstract and Introduction


Aim: This study aimed to demonstrate radiofrequency (RF)-triggered release of drugs and drug carriers from drug-eluting implants using gold nanoparticles as energy transducers.

Materials & methods: Titanium wire with a titania nanotube layer was used as an implant loaded with indomethacin and micelles (tocopheryl PEG succinate) as a drug and drug carrier model. RF signals were generated from a customized RF generator to trigger in vitro release.

Results & discussion: Within 2.5 h, 18 mg (92%) of loaded drug and 14 mg (68%) of loaded drug carriers were released using short RF exposure (5 min), compared with 5 mg (31%) of drug and 2 mg (11%) of drug carriers without a RF trigger. Gold nanoparticles can effectively function as RF energy transducers inside titania nanotubes for rapid release of therapeutics at arbitrary times.

Conclusion: The results of this study show that RF is a promising strategy for triggered release from implantable drug delivery systems where on-demand delivery of therapeutics is required.


To address problems in conventional drug therapies, such as the lack of time-specific release, complex dosing schedules, insolubility of drugs in body fluids, uncontrolled pharmacokinetics, poor biodistribution and side effects, local drug delivery systems (DDSs) are recognized as a promising alternative.[1,2] The rationale in using local DDSs is that they offer better targeting to specific sites of action, improved bioavailability, prevent high drug concentrations in systemic delivery and blood circulation, lower toxicity and minimize potential harm to surrounding tissues and cells, which provides an optimal route for efficient, accurate drug dosing and safer transport.[3] Several drug delivery platforms and scaffolds have been generated and clinically tested in recent years using advanced porous nanomaterials – these include biodegradable polymer gels (poly(methyl methacrylate), poly(lactic acid) or poly(glycolic acid)) – collagen, hyaluronan, chitosan, fibrin and silk microspheres, porous hydroxyapatite and calcium phosphate cements.[4–8] These existing materials have several drawbacks, including insufficient pharmacokinetics and drug protection and unpredictable and unsatisfactory drug release, due to their nonuniform porosity and structural inconsistency.[9–11] In addition, drug release using some of these materials is mainly based on passive degradation of the organic materials, which depends on their pore size, crosslinking density and the rate of degradation, all of which are often not controllable.

Titania (TiO2) nanotube (TNT) arrays engineered on the surface of titanium (Ti) substrates by self-ordering electrochemical anodization have recently emerged as a superior method for the development of drug-eluting platforms, as they are able to address many of the above-mentioned limitations.[12–14] TNTs are composed of vertically aligned nanotube structures for which pore size, length and surface chemistry can be precisely controlled, and they can be prepared on curved surfaces such as wires.[15] It is expected that this technology can be applied on clinically used orthopedic implants (Ti and Ti alloys) with different shapes, such as plates, needles and screws. TNTs have been shown to be biocompatible and have excellent mechanical/chemical stability and osseointegrating properties. They also encourage osteoblast cell adhesion and bone support. These features render TNTs an interesting biomaterial with possible applications in drug delivery.[16–21] In our previous work, we presented several strategies to control the release of drugs and drug carriers from TNTs in order to achieve a series of different types of drug delivery, namely, extended, delayed and sequential drug release, the delivery of multiple drugs and ex vivo release using a bone bioreactor.[21–27] However, the drug kinetics in these systems is controlled by a diffusion process from the nanotubes, which implies that their release behavior and the amount of released drug cannot be altered after the implant is inserted. Hence, to replace these passive drug-releasing materials, new DDSs that can be repeatedly switched on and off would be a more attractive and desirable solution. To this end, several new responsive ('smart') materials have been developed that can respond to stimuli that are either internal (body temperature and pH) or external (applied ultrasound, magnetic and electric field) to the patients.[28–31] We have shown the feasibility of applying a stimulus-responsive drug release from TNT using magnetic nanoparticles and magnetic fields to generate a prompt and instant release of drugs.[24] The disadvantage is accidental release of drugs due to unexpected interception or disturbance of magnetism from an open source near to the TNT and this technique is, therefore, not entirely safe. The use of radiofrequency (RF) signals seems to be a more suitable approach because it is simple, remote, noninvasive and has been applied in medical practice for almost a century.[32,33]

RF refers to the electrical oscillations in the frequency range of 3 kHz to 300 GHz that are nonionizing and hence safer for human exposure compared with lasers or ionizing radiations.[34] RF penetrates easily through human tissues and has gained popularity as a noninvasive medical technique for transdermal delivery of small-sized drug and protein molecules, as well as in treatment of tumors by hyperthermia.[32] Various types of nanoparticles, namely, quantum dots, carbon nanotubes, gold nanoparticles (AuNPs) and porous silica magnetic nanocapsules, can be heated by a RF source.[33] RF-triggered release systems using these nanovehicles have been explored for a number of drug-targeting delivery applications, such as chemotherapy and transdermal drug delivery, but surprisingly not for local DDSs using drug-eluting implants.[35]

In this study, we aim to demonstrate RF-triggered release of drugs and drug carriers from drug-eluting implants using AuNPs as energy transducers. The proposed concept is presented in Figure 1. AuNPs were chosen as RF energy transducers owing to their simple synthesis process, robustness, inertness, biocompatibility and their exceptional ability to effectively absorb RF energy, and release generated heat quickly and effectively to the surrounding biological region.[33,34] The mechanism behind RF-induced heating of AuNPs is not well understood and is the topic of much debate. However, a form of Joule heating is hypothesized for this heat transfer. It is believed that owing to size restrictions, surface electrons on the AuNPs are limited in their movement. Upon excitement with an externally applied RF field, eddy currents produce friction on the particle surface leading to rapid heating.[33,36] This heating effect is proportional to the power input from the RF generator and also to the particle size of the nanoparticle.[37] AuNPs have been extensively explored as energy converters in radiotherapies for targeting cancer cells and tissues, owing to their high absorption and ablation properties.[33,38] An electrochemically engineered TNT array on Ti is used as a drug-eluting implant model because Ti-based implant carriers are already approved and in clinical use in orthopedics.[39–41] Two models of therapeutics, including drug and drug carriers were used for loading into the TNTs: indomethacin, a non-steroidal anti-inflammatory drug with analgesic and antipyretic activity was used as a model of a water-insoluble drug and polymer micelles of D-α-tocopheryl PEG succinate 1000 (TPGS) encapsulating indomethacin were used as the model drug carrier. To characterize the performance of the proposed RF system for triggered release of drugs and drug carriers from drug-eluting implants, a series of in vitro studies in an aqueous medium of phosphate-buffered saline (PBS) at pH 7.2 were conducted under different RF conditions (an exposure time of 2, 5 and 10 min) at different stages of drug release (an initial stage during burst release and after 5 days of natural, nonstimulated release).

Figure 1.

Radiofrequency-triggered drug or drug–micelle release. Noninvasive and on-demand triggered release from drug-eluting implants using RF and AuNPs. The TiO2 nanotubes fabricated on Ti flat foil were used as a model drug-eluting implant and RF-triggered in vitro release was demonstrated using a drug (indomethacin) and drug carriers (D-α-tocopheryl PEG succinate 1000 polymeric micelles loaded with the drug).
AuNP: Gold nanoparticle; RF: Radiofrequency; Ti: Titanium; TiO2: Titania.