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How the Adaptability of Liposomes Assists in Overcoming Today’s Drug Delivery Challenges

by biopharmajessica in BPS News, BPS Right Sidebar Content

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A common challenge during modern drug development is overcoming low bioavailability.

As a result, investigations in to the use of liposomes as a potential drug carrier suggest these may offer a promising solution.

It is no surprise the study of liposome-drug encapsulation is a rapidly expanding field, particularly due to their versatility and ease of manipulation, in terms of their physiochemical and biophysical properties. Such flexibility enables researchers the opportunity to tailor the drug carrier to the drug of interest, without too much difficulty.

In addition to improved drug bioavailability, a sustained or controlled drug release profile can be achieved after encapsulation by liposomes [1].

Conventional liposomes (representation A in Figure 1, below) are spherical in shape, composed of a lipid bilayer and liquid core, which allows them to encapsulate both hydrophilic and hydrophobic drugs. Hydrophilic molecules can be entrapped into the aqueous centre, whilst hydrophobic molecules can be inserted into the bilayer membrane [2]. An example hydrophobic drug is Paclitaxel: a chemotherapeutic agent commonly used to treat cancers including that of the ovary, breast and lung. Paclitaxel has recently shown increased bioavailability when encapsulated in acid environment-responsive liposomes [3].

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Figure 1: The different types of liposomal delivery systems [2]

These types of liposomes are relatively stable at physiological pH, though they release their contents under acidic conditions. This has great potential in providing targeted anti-cancer therapy, due to the lower pH values observed in tumour tissue. The acidic conditions within tumour tissue are a result of high metabolic rates. Specifically, it is likely related to high glucose consumption rates, with a net production of acid [4].

The addition of cholesteryl hemisuccinate (CHEMS) is an example material which can be added to the formulation, to produce acid environment-responsive liposomes [3].

Many formulations of pH-sensitive liposomes are unstable in the blood, and they are rapidly cleared from the circulation via the mononuclear phagocyte system. This can be overcome by adding poly-ethylene glycol lipid derivatives to the formulation [5], to produce what are commonly known as PEGylated liposomes, or stealth liposomes (representation B in Figure 1). PEGylated liposomes are significantly more stable in the bloodstream [5].

Ligand-targeted liposomes (representation C in Figure 1) offer great potential for targeted drug delivery, by selectively expressing specific ligands at the site of disease [2]. Challenges have arisen in relation to the pharmacokinetics of these liposomes, though the integration of target-specific binding of immunoliposomes with PEGylation (e.g. monoclonal antibody-PEG-liposome conjugation) appears to overcome this hurdle [2].

Theranostic liposome systems (representation D in Figure 1) encapsulate or entrap a nanosized agent, such as iron oxide and gold nanoparticles, which is utilised for imaging ( illustrated in Figure 2, below). Theranostic liposomes can be PEGylated and ligand-targeted, to produce a stable, targeted, comprehensive diagnostic and therapeutic drug delivery system.

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Figure 2: An illustration of a theranostic liposome, with TEM images of gold nanoshells [6]

 

In summary, adaptability is the key advantage associated with liposomes for drug delivery.

 

In preparation of the desired liposomes, high pressure homogenisation (HPH) is often performed on pre-formed liposomes, such as multilamellar vesicles (MLVs), to produce small unilamellar vesicles (SUVs).

The HPH process subjects the MLVs to ultra-high pressures by forcing material passage through a narrow orifice. Stress parameters such as shear, cavitation and turbulence rupture the particles, which then immediately reform as smaller, unilamellar vesicles.

High pressure homogenisation also has the capability to load liposomes with drugs, allowing for a streamlined process.

Generally, the higher the induced pressure on the sample, the smaller the resulting particles will be. Additionally, the number of cycles/passes through the system can influence particle size and size distribution.

 

It is important to consider other factors in addition to pressure and number of cycles, which have a major influence on vesicle size [7]. These include:

  • Homogeneity of the starting material
  • Temperature
  • Lipid composition and content
  • Ionic strength of medium

 

Another method of SUV preparation is via MLV extrusion. This involves forced passage of MLVs through one (or a series of stacked) polycarbonate membrane(s) with a defined pore size. The use of stacked membranes can sometimes aid in producing monodomal size distributions with lower numbers of cycles [8].

The process of extrusion removes the need for organic solvents in liposomal preparation, which can often prove limiting by affecting the integrity of the active ingredient. Additionally, extrusion is the most gentle method of nanosizing liposomes, which facilitates very desirable encapsulation efficiency [9]

Avestin’s range of high pressure homogenisers, from benchtop to production scale, allow for the combination of high pressure homogenisation and extrusion, which can further reduce the number of cycles required to achieve a desired size distribution, making the complete process impressively efficient. These combinative systems are ideal for a wide range of sample sizes, from the 100’s of millilitres up to 100’s of litres, and the automated manner of extrusion, with available temperature control, ensures a great degree of scalability.

For smaller applications, Avestin offer the hand-held LiposoFast Basic (LF-1) extruder system, which has a 0.5mL to 1.0mL capacity. Additionally, the automated LF-50 (5mL-50mL capacity) extruder system is available for applications of higher throughput.

 

For more information on the Avestin range of high pressure homogenisers, visit:

bps@biopharma.co.uk or call Ashley Morgan on +44 (0)1962 841092

 

References

[Heading image]: Agencia Informativa Conacyt, (2015), [ONLINE]. Available at: http://fmdiabetes.org/elabora-ciad-micro-nanoesferas-liberadoras-de-insulina/ [Accessed 14 June 2017].

[1]: Huang, Z., Li, X., Zhang, T., Song, Y., She, Z., Li, J. and Deng, Y. (2014). Progress involving new techniques for liposome preparation. Asian Journal of Pharmaceutical Sciences. 9 (4), 176-182.

[2]: Sercombe, L., Veerati, T., Moheimani, F., Wu, S.Y., Sood, A.K. and Hua, S. (2015). Advances and Challenges of Liposome Assisted Drug Delivery. Frontiers in Pharmacology. 1 (6), 286.

[3]: Wang, L (2017) ‘Preparation and in vitro evaluation of an acidic environment-responsive liposome for paclitaxel tumor targeting ‘, Asian Journal of Pharmaceutical Sciences, .(.), pp. . [Online]. Available at: http://www.sciencedirect.com/science/article/pii/S1818087617301174 (Accessed: 08th June 2017.).

[4]: Zhang, X., Lin, Y. and Gillies, R. (2015). Tumor pH and its measurement. Journal of Nuclear Medicine. 51 (8), 1167-1170.

[5]: Ishida, T., Kirchmeier, M.J., Moase, E.H., Zalipsky, S. and Allen, T.M. (2001). Targeted delivery and triggered release of liposomal doxorubicin enhances cytotoxicity against human B lymphoma cells. Biochimica et Biophysica Acta (BBA) – Biomembranes. 1515 (2), 144-158.

[6]: Choi, K.Y., Liu, G., Lee, S. and Chen, X, (2012), Schematic illustration and TEM images of the magnetic gold nanoshells (Mag-GNS) [ONLINE]. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3629960/figure/F5/ [Accessed 14 June 2017].

[7]: Torchillin, V. and Weissig, V (2003). Liposomes: A Practical Approach. 2nd ed. Oxford: OUP Oxford. 20-21.

[8]: Joseph, S. and Bunjes, H. (2013). Influence of membrane structure on the preparation of colloidal lipid dispersions by premix membrane emulsification. International Journal of Pharmaceutics. 446 (1-2), 59-62.

[9]: Alino, S.F., Garcia-Sanz, M., Irruarrizaga, A., Alfaro, J. and Hernandez, J. (1990). High encapsulation efficiences in sized liposomes produced by extrusion of dehydration-rehydration vesicles.. Journal of Microencapsulation. 7 (4), 497-503.

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