Emerging pressure-release materials for drug delivery

Abstract

Drug delivery systems for non-specialist uses and application under field conditions are required for medical action in disaster situations and in developing countries. A possible solution for drug delivery under those conditions might be provided by mechanical manipulation of host–guest interactions that could allow drug release control by simple human actions such as hand motion. This editorial article presents recent research developments on control of molecular recognition, capture and release involving macroscopic mechanical motions. In particular, pressure-induced drug release from a cyclodextrin-linked gel has been used to realize controlled release of entrapped drugs upon applying an easy-to-perform mechanical procedure. These easy-action-based drug delivery systems can be applied at will by unskilled staff or patients and are expected to be used to assist medically patients in less-favorable environments anywhere in the world.

Keywords::

• controlled release
• drug delivery
• gel
• interface
• mechanical

1. Introduction

Preparation of stimuli responsive materials is a crucial aspect of the development of drug delivery systems for on-demand controlled release of therapeutic agents. Various materials that are capable of responding to external inputs, such as thermal, photonic, magnetic, and sonic stimuli, have been investigated [1-3]. However, applications of these stimuli often require appropriate facilities and/or instrumentation, which may limit their practical uses. Drug delivery systems based on these stimuli may not be available under certain circumstances, for instance, following serious disasters and/or in developing countries with insufficient infrastructures. Development of materials that respond to simple or commonly available stimuli could open the way for effective drug delivery systems not only for everyday use but that allow uninterrupted drug administration even under strident conditions. The easiest stimuli to apply are manual mechanical forces including pushing, pulling, bending, pressing, and twisting. Drug release regulation purely by hand motion implies that such systems can be operated by unskilled personnel and even patients, at any time. For this challenge, we need to develop mechanical control systems to regulate molecular interactions.

2. Mechanical control of molecular sensing, capture, and release

Mechanical control of nanosystems and molecular systems has been paid much attention since it suggests a connection between macroscopic motion and molecular function [4]. For example, mechanical control of molecular-level functions such as enzyme activity, phase transitions, hydrogen bonding and cleavage of covalent bonds has been demonstrated. Application of a similar concept in the field of molecular recognition would allow development of associative/dissociative molecular systems leading to mechanical control of materials release, i.e., mechanical control of drug delivery.

In our strategy, we have used an interfacial environment to couple macroscopic mechanical forces with molecular motion [5]. At a two-dimensional interface, both accessibility to macroscopic mechanical forces in the lateral plane and molecular properties at the nano-level in the vertical direction can be accessed. That is, a dynamically deformable molecular film spread at an interfacial medium (such as air–water interface) can be controlled mechanically by direct lateral compression and expansion on a length scale of tens-of-centimeters, and this variation in the lateral direction can be used to influence the properties of the film at the molecule level. For example, a Langmuir monolayer of a receptor molecule, cholesteryl-substituted cyclen complex, exhibited inversion of enantioselectivity in binding of aqueous amino acid guest molecules simply by application of macroscopic lateral pressure [6] since helicity of the cholesteryl-substituted cyclen complex was mechanically varied when the host molecules are ordered or aggregated at the supramolecular level. In fact, the binding constant of L-valine to this receptor is lower than that of D-valine at low surface pressure but exceeds it at 22 – 23 mN m^-1. In another example, mechanical deformation of a cholesterol-substituted triazacyclononane contained in a Langmuir monolayer led to optimization of its ability to discriminate between uracil and thymine [7]. Selectivity of uracil over thymine reached ca. 64 times under optimized pressures. Of course, this level of discrimination cannot be attained by naturally occurring nucleic acids since they use the same adenine residue to bind these bases.

More drastic control of molecular capture and release of guest molecules is possible in mechanical control of interfacial films of a steroid cyclophane molecule with a cyclic core consisting of a 1,6,20,25-tetraaza[6.1.6.1]paracyclophane connected to four steroid moieties (cholic acid) through a flexible L-lysine spacer (Figure 1) [8]. Capture and release of aqueous guest molecules from the aqueous phase can be regulated using a mechanical stimulus. This molecular machine enables the binding of a guest molecule through variation between planar and cavity-forming conformations of the cyclophane upon mechanical compression of its monolayer on water. In addition, capture and release of the guest molecule could be repeated according to cycles of compression and expansion of the monolayer. These examples indicate that use of interfacial media could be a key for developing pressure-induced capture and release of drug molecules for DDS.

Figure 1. Mechanical control of drug capture and release from molecular machines embedded at the air–water interface.

3. Pressure-induced drug release from gel

Although use of an air–water interfacial environment is an effective strategy for coupling of macroscopic mechanical motion with molecular phenomena such as guest binding and release, these model interfaces are not always useful for practical applications. The concept of interfacial operation requires extension to three-dimensional materials that would also allow flexible structure changes upon application of external pressures with gels being one of the best choices for this purpose. Gels are soft, structurally flexible materials which possess as a specific feature highly developed covalent and/or non-covalent networks at their interiors. These networks may be capable of transmitting externally applied forces to their internal structures. Gel structures can thus be regarded as a three-dimensionally integrated form of an interface-like environment.

Because gels have often been used as carriers for drug delivery, several recent examples of gel-based drug delivery systems are here briefly introduced prior to a description of pressure-induced drug release from gels. De Geest et al. fabricated gel-based self-exploding microcapsules that release entrapped drugs in a pulsed fashion after a certain incubation time at physiological conditions [9]. A biodegradable microgel core was encapsulated by applying bio-polyelectrolyte layer-by-layer films. Degradation of the microgel core induces rupture of the coated films, resulting in release of the encapsulated materials. Lapeyre et al. synthesized core-shell microgels with a thermoresponsive poly(N-isopropylacrylamide) core and a glucose-responsive poly(N-isopropylacrylamide)-coacrylamidophenylboronic acid shell [10]. Initially, the shell suppresses core swelling over a certain temperature range. Upon binding of glucose to the outer shell the hydrophobic shell is converted to hydrophilic, resulting in core swelling so that insulin release from the gel was shown to be regulated by the presence of glucose. Matsumoto et al. used a hydrogel containing phenylboronate as a self-regulating insulin delivery system [11]. Binding of glucose to the phenylboronate moiety induces localized dehydration of the gel surface to form a skin layer through glucose-dependent shifts in the equilibrium of phenylboronate between the uncharged and anionically charged forms. This phenomenon enabled control of the release of insulin from the gel and realized lasting control over the provision of insulin under conditions closely associated with human glucose homeostasis. Du et al. developed a pH-responsive charge-conversional gel for tumor-cellular uptake and doxorubicin delivery [12]. They modified an amino-functionalized gel with 2,3-dimethylmaleic anhydride, which introduces both an amide bond and a carboxylic acid group upon reaction with the amino group. A high loading of the anticancer drug, positively charged doxorubicin hydrochloride, could be attained because of the presence of negatively charged carboxylate groups. The modified gel was transformed from a negatively charged form into a positively charged form in the slightly acidic tumor extracellular environment, resulting in release of doxorubicin.

These examples illustrate that gels are one of the ideal materials' forms for stimuli-responsive drug release because they can exhibit large changes in volume and morphology and can accommodate a wide range of chemical modifications. Because mechanical deformation of gels is a simple matter, pressure-induced control of drug release from gel materials is also possible. Osmotic pressure has widely been used for controlling drug release from gel matrices, and many commercial products are already available [13]. However, drug release based on simple volume changes (i.e., swelling and shrinkage) may not provide highly specific drug release. Mechanical control of specific host–guest interactions within a particular gel is a more challenging target for drug-specific controlled release. In order to introduce a novel strategy for stimuli-responsive drug release, we have reported a pressure-triggered controlled release system composed of an alginate gel cross-linked with β-cyclodextrin. The latter operates as a junction point within the alginate main chain polymer (Figure 2) [14]. Cyclodextrin accommodates the guest molecule in a shape- and size-specific fashion primarily through common van der Waal's and hydrophobic interactions. This strategy is expected to be applicable to a wide range of drug molecules. The drug ondansetron was first entrapped in the cyclodextrin cores within the alginate gel. Subsequent release of ondansetron was then investigated upon application of one-time compressions up to 50% strain and five-cycle compressions up to 50% strain. Repeated one-time compression after intervals of 1, 4, 7, and 10 h resulted in acceleration of drug release rate, which was only observed when compression action was applied. Subsequently, five-cycle compressions after 25, 28, 31, 34, 49, and 52 h similarly induced pulsatile releases in response to the compression cycles. This pressure-induced drug release mostly originated from variations in the stability of the complex between cyclodextrin (host) and ondansetron (guest), which was confirmed through determination of binding constants for the complex formation within the alginate gel based on the Langmuir adsorption isotherm. A clear correlation between binding constants and the stress–strain curve was observed. The binding constants remained almost constant upon application of 30% strain but decreased dramatically under strains above 50%. Applied stress also rapidly increased at strains above 50%. These results are consistent with the release profile of ondansetron from the gel where increased releases in response to mechanical compressions were not observed below 30% strain. Molecular dynamics simulation also indicated that the release of ondansetron should be promoted even with small restriction and deformation of the cyclodextrin molecule. If this material is intravenously injected, patients have only to push it by their own hands to induce drug release. This can be a novel dosing strategy that should improve patients' compliance.

Figure 2. Pressure-induced drug release from an alginate gel cross-linked with β-cyclodextrin: A. schematic illustration of mechanism; B. typical release profiles.

4. Expert opinion

The availability of effective simple-to-administer drug delivery systems becomes more important during emergency or disaster situations where rapid treatment or self-administering of drugs might be required. Such situations might even be commonplace in daily life in developing countries or populations living in remote regions. In the absence of proper apparatus for drug administration, an appropriate drug delivery system is required. Control of drug recognition, entrapment, and release by applying mechanical stimuli could satisfy these demands. For example, mechanical manipulation of host–guest interaction might be used for drug release by relatively simple human actions such as hand motion. The abovementioned examples indicate the special importance of considering the structures and positioning of molecular complexes in an appropriate environment such as at interfaces or contained linked in a gel network. As demonstrated especially in the last example, mechanical control of host–guest interaction for drug release is not an especially difficult target to achieve. Subtle structural changes of host molecules, which can be induced by external forces, induce drastic decreases in binding constants of the guest, resulting in facile drug release. Such regulation of host–guest interactions using mechanical force has not been frequently reported prior to the example based on a cyclodextrin gel. Applying this new concept to other materials systems including mesoporous materials [15] and layer-by-layer films [16] is expected to lead to various methods for pressure-induced drug release. Hand manipulation for drug delivery for use in any situation will thus be realized. We believe that the emergence of pressure-release materials for drug delivery will not only make self-administering of drugs commonplace but also may save patients in inconvenient or dangerous conditions anywhere in the world.

Article highlights.

• In this editorial article, examples of mechanical control for molecular recognition, capture, and release at an interfacial environment are explained.

• A recently developed example of pressure-induced drug release from a cyclodextrin-based gel is introduced.

Declaration of interest

This work was partly supported by the World Premier International Research Center Initiative (WPI Initiative), MEXT, Japan and Core Research for Evolutional Science and Technology (CREST) program of Japan Science and Technology Agency (JST), Japan.

Notes

This box summarizes key points contained in the article.