- Open Access
Layer-by-layer assembled polymeric thin films as prospective drug delivery carriers: design and applications
© The Author(s). 2018
- Received: 25 June 2018
- Accepted: 10 September 2018
- Published: 26 September 2018
The main purpose of drug delivery systems is to deliver the drugs at the appropriate concentration to the precise target site. Recently, the application of a thin film in the field of drug delivery has gained increasing interest because of its ability to safely load drugs and to release the drug in a controlled manner, which improves drug efficacy. Drug loading by the thin film can be done in various ways, depending on type of the drug, the area of exposure, and the purpose of drug delivery.
This review summarizes the various methods used for preparing thin films with drugs via Layer-by-layer (LbL) assembly. Furthermore, additional functionalities of thin films using surface modification in drug delivery are briefly discussed. There are three types of methods for preparing a drug-carrying multilayered film using LbL assembly. First methods include approaches for direct loading of the drug into the pre-fabricated multilayer film. Second methods are preparing thin films using drugs as building blocks. Thirdly, the drugs are incorporated in the cargo so that the cargo itself can be used as the materials of the film.
The appropriate designs of the drug-loaded film were produced in consideration of the release amounts and site of the desired drug. Furthermore, additional surface modification using the LbL technique enabled the preparation of effective drug delivery carriers with improved targeting effect. Therefore, the multilayer thin films fabricated by the LbL technique are a promising candidate for an ideal drug delivery system and the development possibilities of this technology are infinite.
- Layer-by-layer assembly
- Multilayer thin films
- Controlled drug delivery
- Surface modification
Recently, as the importance of the life extension and the quality of life is more appreciated, biotechnological advances in the field of biomedical science are being increasingly reported. Particularly, research on drug delivery systems has been recognized as one of the most significant challenges in biomedical science . In general, research studies on drug delivery systems focus on maintaining a minimum concentration of drugs in the blood and minimizing drug toxicity in vivo [1–3]. In view of these efforts, new approaches that allow self-controlled drug release are required. Among the various approaches, the application of thin films to drug delivery systems has emerged due to the variety of materials that can be used for preparing the films . Thin films can be fabricated with a polymer, as well as with various functional nanomaterials or drugs. Therefore, thin films allow effective incorporation and a controlled drug release [5, 6].
As new thin-film manufacturing technologies emerge, surfaces that enable localized and precise controlled release of active therapeutics can be fabricated [7, 8]. Strategies for the fabrication of ultrathin film devices include the Langmuir–Blodgett method [9, 10], self-assembled monolayer techniques [11, 12], and layer-by-layer (LbL) assembly [13–22]. LbL assembly is most suited for the fabrication of films used for drug delivery because it imposes no restrictions on the size or shape of the substrate and does not require high temperature or pressure. In the LbL assembly process, multilayer films are deposited onto the surface of the substrate via alternate adsorption of the interacting materials. A variety of materials, including polyelectrolytes, micelles, graphene oxide (GO), nanoparticles, and proteins can be used as building blocks for LbL-assembled multilayer films [23–26]. The materials interact with each other via driving forces such as electrostatic interactions, hydrogen bonds, covalent bonds, and bio-specific interactions. These properties allow the controlled release of the drug, depending on the materials used in the particular multilayer film, containing the drug. Thus, the LbL technique can be considered as the most appropriate method for preparing nano-multilayer films incorporated with therapeutic molecules [27, 28].
There are several factors that need to be considered for the effective incorporation and drug release by the thin films. First, the potential in vitro and in vivo toxicity of the therapeutic molecules and the film material should be recognized before preparing the films incorporated with the specific drug. This is to ensure that the appropriate material has been selected for film preparation, and also to determine the right concentration of the drug that is to be delivered [29, 30]. The second concern is the stability of the thin film, which is to be incorporated with the drug; thin films carrying drugs need to be both chemically and physically stable . To improve stability, a variety of interactions and crosslinking chemistry are used for loading drugs onto pre-fabricated films. Additionally, drugs can be directly used as building blocks for film preparation. Furthermore, drugs can be incorporated in cargoes such as nanoparticles, and these cargoes can be often used as film materials [32–39]. The third consideration is the precise targeting of drugs to the target sites. Stimuli-responsive polymers relating to environment of the target areas are frequently used as film materials to achieve precise drug targeting [40, 41]. Drug-incorporated nanoparticles, exhibit both precise drug targeting and controlled drug release by surface modifications, achieved by using certain coatings. The fourth consideration is the release period and the rate of drug release [42, 43]. Drug release should occur in the target site without suffering losses during the process of delivery. Additionally, the drug release kinetics should be precisely manipulated to ensure a sustained release instead of a burst release, keeping in mind the dose and the target site of the drug. This control can be achieved by controlling the degradation rate of the film, depending on the drug to be incorporated, the film material and the fabrication method for film preparation .
Loading drugs directly onto pre-fabricated thin films
The simple immobilization of drugs onto the surface of the film is the easiest approach for improving the controlled-release systems in biomedical implants, tissue engineering, and targeted drug delivery systems. There are several strategies for immobilization of drugs onto the film surface. In these strategies, immobilization is reported to occur by simple adsorption or via various driving forces including electrostatic interactions, hydrogen bonds, hydrophobic interactions, and van der Waals interactions [10, 45, 46].
A typical example of use of physical immobilization to load the drug onto certain films without chemical usage was suggested . They fabricated polylysine/hyaluronic acid (PLL/HA) multilayer films via LbL assembly, where PLL and HA were used as the polycation and polyanion, respectively. The PLL/HA multilayer film acted as a reservoir for paclitaxel (Taxol), which was embedded on top of it. The paclitaxel molecules easily diffused across the entire section of the (PLL/HA)60 film, and absorption increased proportionately with the thickness of the PLL/HA multilayer film. Additionally, the concentration of paclitaxel within the film depended on the initial concentrations of paclitaxel in the solution during deposition. The drug content in the PLL/HA films could be finely tuned over a large concentration range .
Preparing thin films using drugs as building blocks
Higher doses of drugs result in toxicity, making the LbL assembly method highly desirable for controlling drug release while simultaneously maintaining a drug concentration above the minimum inhibitory concentration (MIC). Shukla et al. ., used the LbL assembly method to fabricate vancomycin delivery coating. They used poly (β-amino ester) and vancomycin as a positively charged multilayer, and dextran sulfate, chondroitin sulfate (CS), and alginate as a negatively charged multilayer. In the study, they incorporated vancomycin to achieve a wide range of drug loading and controlled-release profiles, while maintaining the drug concentration above the MIC while avoiding toxicity at high doses [51, 52]. Min et al. ., fabricated LbL film coatings onto medical implants for osteomyelitis. Both gentamycin and BMP-2 are weakly positively charged and were used as polycations for preparing multilayered films, along with the negatively charged polyacrylic acid (PAA), via electrostatic interactions. The top layer consisted of [Poly1/PAA/GS(gentamycin sulfate)/PAA] tetralayers, which would inhibit bacterial biofilms, and the inner layer consisted of [Poly2/PAA/BMP-2/PAA] tetralayers, which would enhance bone formation .
Using cargoes incorporated with drugs to prepare a film
Efficient drug delivery is designed keeping several factors in mind, including the cooperation of protecting drug, drug loading, reaching the target and drug release, which are all directly influenced by a drug’s molecular structure. An example includes some aldehyde-based drugs, which breakdown when exposed to the gastric juice in humans. This necessitates the protection of these drugs by a shell of a stable chemical structure, which should also be able to release the drug to the target, unlike the neutral camptothecin that cannot easily transfer drugs to their targets within the human body owing to its hydrophobic nature [60–62]. The driving force is very important to drug delivery systems, and some pharmaceutical drugs are difficult to assemble by the usual methods because there are no driving forces between the molecules or between molecules and loader [63, 64]. To solve these problems effectively, researchers have studied drug delivery using cargoes for modifying the fundamental properties, since encapsulation of the molecular drug cargo can protect the drug, preventing undesirable drug decomposition, and control the driving force. The therapeutic cargo has exhibited therapeutic efficacy in drug delivery systems .
The amphiphilic, block copolymer micelles cargo
Protein and peptide cargo for encapsulation
Nadia et al. (2003)., suggested that protein cargoes could serve as building block components of multilayer films without the need for covalent bonding. Based on whether the protein has a negative or positive charge in aqueous solution, they used the Protein A (PA) which could bind with fragment c of immunoglobulin, and thus rendered bioactivities such as antitumor and anti-toxic properties to the protein cargo .
Mesoporous nano particles as a cargo in the LbL process
Among drug delivery systems, targeted drug delivery has been receiving considerable attention because of its therapeutic advantages of improving therapeutic action and decreasing side effects. Additionally, the LbL assembly method was used to build nano drug carriers, which have multiple functions, including enhanced drug stability, stimuli-responsive drug release, and dual drug release. These LbL-deposited multilayers are suitable for targeted drug delivery because drug release rate from multilayers can be regulated by manipulating the aforementioned factors. Especially, endogenous stimuli-responsive drug-releasing multilayers are responsive to factors such as pH , antigen , glucose , and lectin , and are of potential use in organ-targeted drug delivery. Moreover, LbL-deposited multilayers can include various materials such as antibodies, antigens, and antigen receptors, which offer ligand-directed targeting .
Tumor targeting by LbL-assembled drug carriers
Targeting hepatocytes with LbL-assembled drug carriers
Intestinal targeting by LbL-assembled drug carriers
In this research, the varied studies on Layer-by-layer (LbL) assembled multilayer thin films design for effective drug loading and targeting at desired sites have been reported. In LbL assembly technique, it is possible to fabricate excellent drug delivery carrier by selecting appropriate materials and driving forces because a wide variety of materials can be candidates for multilayer films in LbL assembly. There are three types of methods for preparing a drug-carrying multilayered film using LbL assembly. Methods included in the first type are direct loading of the drug into the pre-fabricated multilayer film. Second methods are preparing thin films using drugs as building blocks. In addition, the drugs are incorporated in the cargo so that the cargo itself can be used as the materials of the film. The appropriate designs of the drug-loaded film were produced in consideration of the release amounts and site of the desired drug. Furthermore, additional surface modification using the LbL technique enabled the preparation of effective drug delivery carriers with improved targeting effect. Therefore, the multilayer thin films fabricated by the LbL technique are a promising candidate for an ideal drug delivery system and the development possibilities of this technology are infinite.
This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI14C-3266). Also, this research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (NRF-2017R1E1A1A01074343).
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