Adenosine-associated delivery systems

Abstract

Adenosine is a naturally occurring purine nucleoside in every cell. Many critical treatments such as modulating irregular heartbeat (arrhythmias), regulation of central nervous system (CNS) activity and inhibiting seizural episodes can be carried out using adenosine. Despite the significant potential therapeutic impact of adenosine and its derivatives, the severe side effects caused by their systemic administration have significantly limited their clinical use. In addition, due to adenosine's extremely short half-life in human blood (<10 s), there is an unmet need for sustained delivery systems to enhance efficacy and reduce side effects. In this article, various adenosine delivery techniques, including encapsulation into biodegradable polymers, cell-based delivery, implantable biomaterials and mechanical-based delivery systems, are critically reviewed and the existing challenges are highlighted.

Keywords: Adenosine; controlled drug delivery; controlled release; drug delivery; drug targeting; nanoparticles; targeted drug delivery.

Fig. 1

Schematic of ADP release from H12-(ADP)-vesicles with distinctive membrane characteristics designed by Okamura et al. (a) Electron microscopic images of the H12-(ADP)-vesicles with different membrane flexibilities showing that the H12 molecules were bound to the vesicles, scale bars show 100 nm (Okamura et al., 2010). (b) ADP encapsulated vesicles (H12-(ADP)-vesicles) controlled their hemostatic abilities by tuning ADP release dependent on membrane properties. It was reported that ADP release increased when either membrane flexibility increased or lamellarity decreased (Okamura et al., 2010), (c) Schematic structure of nanocarriers used for drug delivery (Orive et al., 2009).

Fig. 2

(a) PEGylation shields the protein surface from degrading agents by steric hindrance, and increases the size of the conjugate to decrease kidney clearance (Veronese and Pasut, 2005). (b) In the structural formula of Adagen^® bovine ADA covalently attached to numerous strands of monomethoxy PEG with molecular weight 5,000 (Hershfield, 1995).

Fig. 3

(a) Schematic of Gal-CSO/adenosine triphosphate (ATP) formation. (b) TEM images of nanoparticles (left) CSO/ATP and (right) Gal-CSO/ATP showing the size range of 51.03 ± 3.26 nm (the bar is 0.1 µm). (c) In vitro cumulative release rate of ATP from nanoparticles in PBS exhibited the initial burst release attributed to the drug adsorbed on the surface of the nanoparticles (Xiu Liang et al., 2013).

Fig. 4

(a) The SEM micrograph of chitosan nanoparticles. (b) Short term adenosine release in PBS (pH 7.4), (c) long term. (d) Particle size and polydispersity index (PDI) of adenosine loaded chitosan nanoparticles. (e) Isoelectric point and zeta potential changes with pH for the adenosine, chitosan, sodium tripolyphosphate, and nanoparticles (Kazemzadeh-Narbat et al., 2015).

Fig. 5

(a) Illustration of CPA and Oct-CPA chemical formulas, (b) SEM of Oct-CPA loaded nanospheres prepared by double emulsion solvent evaporation method, and (c) in vitro release of CPA and Oct-CPA from PLA nanospheres in phosphate buffer at 37°C developed by Dalpiaz et al. (Dalpiaz et al., 2005).

Fig. 6

(a) Schematic of four-step fabrication of silk-based adenosine releasing implants: (1) Microsphere loaded with adenosine. (2) Mixture of microspheres with silk solution, and embedding them in the form of porous scaffolds. (3) Scaffolds are soaked in the solution of silk and adenosine, and coated with macroscale drug-loaded film coating. (4) Alternating nanofilm deposition loaded with adenosine is coated. The polymer site at infra-hippocampal and the implantation channel of the electrodes are visible in the Nissl stained coronal brain section, 20 days after transplantation. (b) The release profile of adenosine from implants, no seizure was observed at 1000 ng/day adenosine release during the experiment time (Wilz et al., 2008a).

Fig. 7

(a) Fabrication procedure of a free-standing layer-by-layer polymeric nanofilms (thickness < 200 nm) made of PMMA (as a barrier) and a polysaccharides assembly incorporated with an adenosine deaminase inhibitor. A thin film of PMMA first was treated with plasma then chitosan and sodium alginate was deposited on the film using spin-assisted LbL assembly. (b,c) The PMMA/LbL nanofilms characterization indicates low surface roughness, which were between 1–2 nm for drug loaded nanofilms and less than 1 nm for blank nanofilm. (d) The release was based on a diffusion similar to the Korsmayer–Peppas model (Riva et al., 2013).

Fig. 8

(a) Schematic of mesoporous silica nanosphere encapsulating ATP molecules and illustration of real-time imaging of ATP chemiluminescence developed by Gruenhagen et al. (b) The ATP release was tuned by controlling uncapping triggers and the emitted chemiluminescence signal was collected for in vitro release study. (c) TEM images of PAMAM dendrimer-capped MSN shows the visible PAMAM dendrimer coating encapsulating the particle (Gruenhagen et al., 2005).