Layer-by-layer assembled polymeric thin films as prospective drug delivery carriers: design and applications

Abstract

Background: 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.

Main text: 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.

Conclusion: 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.

Keywords: Controlled drug delivery; Layer-by-layer assembly; Multilayer thin films; Surface modification.

Fig. 1

Schematic showing our research methodology for the fabrication of PEM films for remotely activated drug and protein delivery. a glass substrate; a–b, LbL deposition; b–c, silver NP synthesis; c–d, BSA loading; d–e, additional (PAH/DS) layer deposition; e–f, CH loading; f–g, remotely activated release. (Reprinted with permission from Ref. [48]. Copyright 2010, Elsevier)

Scheme 1

Illustration showing drug delivery system using LbL assembly multilayer film

Fig. 2

Schematic illustration of the LbL assembly method using BPEI, HA, and gold NPs. General strategy for the preparation of the (BPEI/HA/gold NPs/HA)n (n = number of tetralayers) structure-based nanoporous films, and subsequent ova release under model physiological conditions. (Reprinted with permission from Ref. [49]. Copyright 2016, Elsevier)

Fig. 3

A schematic representation of the thin film configuration and the Dox loading/release mechanism. (Reprinted with permission from Ref. [50]. Copyright 2005, American Chemical Society)

Fig. 4

Schematic illustration of LbL assembly using chondroitin sulfate and bFGF. (Reprinted with permission from Ref. [54]. Copyright 2007, Wiley)

Fig. 5

a Schematic architectures of antigen (ova) and adjuvant (CpG DNA) co-delivery films tested. b Loading and release amounts of ova and CpG from 5 different kinds of LbL films. (Reprinted with permission from Ref. [55]. Copyright 2009, American Chemical Society)

Fig. 6

a Schematic illustration of the preparation of FGF-2 film using poly beta amino ester and heparin. b Total release and amount of incorporated FGF-2 from the 3 different films where 2H, 2C and 1H represent [Poly2/heparin/FGF2/heparin], [Poly2/chondroitin /FGF2/heparin] and [Poly1/heparin/FGF2/heparin]. (Reprinted with permission from Ref. [58]. Copyright 2010, American Chemical Society)

Fig. 7

a Schematic illustration of the preparation procedure of bFGF-incorporated LbL films on magnetic nanoparticles. b Loading amount of bFGF onto three kinds of films represented as G1, G2 and G3 in the figure. The G films (growth factor films) included only bFGF and heparin for G1; bFGF, PLL and heparin for G2 and GO; and bFGF and heparin for G3. (Reprinted with permission from Ref. [59]. Copyright 2015, The Royal Society of Chemistry)

Fig. 8

Schematic representation of hydrogen-bonds in the layer-by-layer assembly method used to synthesize BCM, which act as vehicles for hydrophobic drug delivery from surfaces. (Reprinted with permission from Ref. [33]. Copyright 2008, American Chemical Society)

Fig. 9

Change in film thickness as measured by profilometry. (Reprinted with permission from Ref. [33]. Copyright 2008, American Chemical Society)

Fig. 10

Coumarin-6 release profile from (bPEI/BCM), (GO/BCM), and (bPEI/BCM/GO/BCM) films in PBS buffer containing ethanol (2:1 PBS/EtOH) at a pH 7.4 and b pH 2. (Reprinted with permission from Ref. [32]. Copyright 2016, Nature)

Fig. 11

Graph showing that the deposited amount increases during PLL/PGA film preparation by addition of the PLL-CP2 layer. (Reprinted with permission from Ref. [66]. Copyright 2001, American Chemical Society)

Fig. 12

The scheme for preparing LBL-MSP with DOX a The method used by Qing-Lan Li et al. (Reprinted with permission from Ref. [68]. Copyright 2014, American Chemical Society) and b The method used by Wei Feng et al. (Reprinted with permission from Ref. [69]. Copyright 2014, American Chemical Society)

Fig. 13

a The release profiles of DOX from DOX@PEM-MSNs at different pH values. b pH-controlled release of DOX from DOX @PEM-MSNs. (Reprinted with permission from Ref. [69]. Copyright 2014, American Chemical Society)

Fig. 14

Hyaluronan Layer-by-Layer (LbL) nanoparticles actively target the hypoxic, low pH tumor by binding to the cancer stem cell receptor CD44. a Schematic illustrating bimodal tumor-targeted delivery. b Polycation and c Polyanion components of the LbL nanoparticle. CD44 protein structure in (a) is rendered from biological assembly 1 of PDB ID 1UUH. (Reprinted with permission from Ref. [75]. Copyright 2014, American Chemical Society)

Fig. 15

CLSM images of hepatocytes after co-culturing with: a bare NPs, b (Chi/Alg)2/Chi, c (Chi/Alg)2/Chi-FA, d (Chi/Alg)2/Chi-PEG–FA and e (Chi/Alg)3 covered NPs for 12 h. (Reprinted with permission from Ref. [78]. Copyright 2010, Elsevier)

Fig. 16

Schematic representation of enhanced drug delivery and reserved lectin-affinity by galactose-branched polyelectrolyte microcapsules after thermal treatment. (Reprinted with permission from Ref. [80]. Copyright 2008, Elsevier)

Fig. 17

Release of B. breve from MCAMs under simulated gastrointestinal conditions. Limit of detection: 5 log(cells) per ml. Data given as the mean (n = 3) ± standard deviation. (Reprinted with permission from Ref. [82]. Copyright 2013, Royal Society of Chemistry)