Other methods of release

To release content from the microcapsules, it is needed to change (either reversible, or not) the permeability of the shell. This can be achieved by a number of ways. The common principle is either to rupture the shells (as it is done by laser irradiation) or to destabilize the complex of the polyelectrolytes that from the walls. Release and encapsulation processes have many common features and often are based on the same principles. Chemistry, that is hidden behind them, was well investigated and described.159 _{Some of these methods are more, the other are less applicable in-vivo,}

but in a whole, they give a good overview of what could be potentially done with the microcapsules.

Probably, the most straightforward way of destabilize the shells is to change ionic strength of solution by the pH. Effect of salt and pH change on microcapsules was thoroughly investigated to build up micromechanical theory of pH and ionic strength dependent capsules swelling consistent to experimental data by Biesheuvel et al (see Fig. 2.17).118, 121 _{In this regard, effect of pH on mechanical properties of}

microcapsules was also studied using AFM-like system, where a single microcapsule deformation was studied under known applied force and different pH levels.160

Rubiner et al described the influence of pH on on the charge density and morphology of PAH based planar multilayers.161 _{They observed pores formation on}

films exposed to acidic environment, while the layers In normal circumstances were smooth. These investigations were then followed by study on microcapsules (Fig. 2.18).87 _{The pores can be clearly seen in the shells after acidic solution treatment}

(a). pH dependent integrity of polyelectrolytic shells makes their permeability also pH dependent. This reversible pores generation was used by Sukhorukov et al to diffuse FITC-dextran from the outside into microcapsules by immersing them to low pH environment.162

Figure 2.17: Swelling of {PVP/PMA}

microcapsules at different pH and salt

concentration.

Use of one or two weak polyelectrolytes to create pH sensitive microcapsules was also reported for different types of microcapsules.105,117 _{Swelling of the capsules as}

pH shifted towards pKa of one of the polyelectrolytes was observed. PSS/PAH capsules started to swell at pH above 11 and totally disassembled when pH exceeded 12.

D_{éjugnat et al}120 _{reported reversible pH dependent swelling on PAH/PSS capsules.}

After short exposition of capsules to pH above 11, the capsules swell and become permeable to high molecular weight substances. After lowering the pH, the capsules shrink, returning to the initial state. This change can be used both as encapsulation and release methods. This technique could potentially be applied in-vivo to deliver drugs to locations with pH lower than that of serum,163 _{however the gap between}

the pH levels is very small (6.8 and 7.4), which makes a design of suitable shells a very challenging task.

The first report on salt responsive polyelectrolyte microcapsules was made by Caruso et al,164 _{where capsules from DNA/spermidine were fabricated. It is known,}

that the DNA-spermidine interactions are reduced in high ionic strength solutions, so when the capsules are immersed in 5 M salt solution, the multilayers are dissolved, which obviously leads to destruction of the capsules. Change of permeability of

Figure 2.18: SFM images of capsules treated with pH 3.5 (a) and pH 12 (b) buffers

before drying.

PAH/PSS shells for high molecular weight substances at salt concentration higher then 10 mM was also reported165 _{with the explanation that the permeability}

happened not due to the pores, as in case of pH-dependent process. Several other salt responsive systems was proposed later,166 _{however such capsules will hardly}

find their way to in-vivo applications, as there are no such high ionic strength variations in human body.

Hydrogen-bonded microcapsules (PMA/PVPON) cross-linked with ethylenediamine with PVPON removed after cross-linking were also shown to be pH sensitive.167

These capsules, being single-component, exhibit swelling at acidic and basic pH and were smallest at pH 5.5. The release was also sensitive to NaCl concentration at pH 5.5. Then, tannic acid microcapsules through hydrogen bonding with acceptor polymers were shown to be stable in a wide range of pH (from 2 to 10) and exhibited pH-sensitive permeability changes to dextran.168

Another approach to targeted drug delivery is use of sugar-sensitive microcapsules. This technique is valuable due to the key role of sugars in a broad range of biological functions. A system analogous to pH-sensitive one, where the linkage between polymeric molecules of the shell is broken in the presence of sugar would be a fantastically rational design of targeted drug delivery system. A number of papers have been published regarding the development of such systems,169 _and

most of them are focused on glucose-triggered release of insulin as a main concern in sugar-sensitive drug delivery development.170 _{However, many different}

mechanisms and reactions were proposed for such systems.171

Alternating magnetic field is one other solution of release problem. Use of Co@Au nanoparticles was reported to change the permeability of microcapsules walls under oscillating magnetic field.172 _{Domains in ferromagnetic nanoparticles twist under the}

applied field and disturb the structure of polyelectrolyte microcapsule wall, making it possible for macromolecules to diffuse through the shell (see Fig. 2.19). It was shown, that the effect happens only when the capsules shell have single layer of nanoparticles, and no effect is observed when using several layers. Permeability change was monitored for 4 kDa FITC-dextran.

It should be noted though, that the parameters at which the treatment is performed, make the use of this approach in therapy hardly possible, as the field is rather high (1200 Oe), and the exposure time was about 30 min, during which the microcapsules dispersion temperature was increased by 30 _{°C. This temperature} increase will most likely destroy bio- and chemically active compounds, encapsulated into the cavity and subjected to targeted delivery.

Another approach, that was used on microcapsules, is irradiation with electromagnetic field in radio frequency band, which could be adsorbed by some agents embedded into the shells. Gorin et al employed 8 nm silver nanoparticles and electromagnetic field oscillating with frequencies from 2.45 to 8.2 GHz at power density ranging from 1.8 mW/cm2 _{to 13.5 W/cm}2_.173 _{Such high-frequency field is able}

to penetrate deep into the human body, and, provided that the power is not too high, can be considered as rather harmless. However, authors could see effect only at higher powers at 2.4 GHz (see Fig. 2.20).

Figure 2.19: Use of oscillating magnetic field (120 Hz, 1200 Oe) to induce permeability

of microcapsules shells functionalized with Co@Au nanoparticles.

Figure 2.20: SEM images of microcapsules with Ag

nanoparticles before (left) and after (right) irradiation at 2.4

One more possible answer for EM-triggered release could be use of carbon nanotubes or other conductive materials, which would find themselves not in the small spots, but throughout the whole shell of a microcapsule. This could make the adsorption of energy from the oscillating field much more efficient, than in case of nanoparticles. Recent publications report use of carbon nanotubes in composite LbL films. Satarkar et al show heating of nanocomposite with RF fields (Fig. 2.21).174

Chen et al demonstrated that only 4-5% wt carbon nanotubes in polystyrene are capable to adsorb 94% of radiofrequency energy.175 _{Besides using nanoparticles or}

carbon nanotubes, more homogeneous structures can be possibly employed, including conductive polymers, such as polypyrrole, which were reported as possible solution for creating EMI-shielding polyelectrolyte structures by LbL assembly.176

Shielding against both electric and magnetic fields using different techniques was reported to lower with frequency, achieving 80 dB at 1 MHz, decreasing to 30 dB at 300 MHz.177 _{Microencapsulation with shells containing such substances was also}

reported.178 _{Even more developed nanocomposite microcapsules with polypyrrole,}

magnetite and carbon nanotubes were also described.179

Rather specific way to release of encapsulated substances is by their mechanical deformation.180 _{The schematic of the experiment performed is shown in Fig. 2.22.}

AFM probe was used to induce pressure upon single PDADMAC/PSS microcapsule performing series of deformation cycles with maximum force measured to be 0.6 μN in the first cycle to more than 8.4 μN in the last push-cycle. The release was observed by measuring the fluorescence intensity of the microcapsule interior, filled with AF-488.

Figure 2.22: Schematic of experiment

on mechanical release from individual

microcapsules.

The measurements showed, that intense release is happening when the capsule is deformed to its 20% diameter. The two regimes of deformation – i.e. before and after release start are designated by authors as elastic and plastic deformation, to correlate the release behaviour with the mechanical properties.