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Polymer Chemistry and Biomaterials Group
Polymer Chemistry and Biomaterials Group

After the PPMA example , the fascinating world of  polymers  continues with another example: the poloxamers.

What would you say if the same polymer would be used for cleaning products and as cancer drug delivery system? You may think it is a crazy idea, but it is true!

Once you go through the labels of your house-hold cleaning products, for example dishwasher tablets or contact lenses solutions, you will see that different poloxamers are listed as ingredients. What is more, poloxamers are also studied as promising delivery systems for anticancer drugs and some formulations are currently undergoing clinical trials (e.g. Pluronic-based micellar formulation of doxorubicin (Dox) – SP1049C is currently in phase III clinical trials [1]).

So what are those poloxamers?

Poloxamers, known under their trade names Pluronics, Synperonics and Kolliphors, represent a class of nonionic surfactants and, as depicted in Figure 1, have the general structure ABA (ABA triblock copolymer).  The word “poloxamer” was introduced by the inventor, Irving Schmolka, who received the patent for these materials in 1973 [2].

fig 1 Figure 1. Structure of ABA triblock copolymer.

As you probably know surfactants are the most important part of any cleaning agent. The word surfactant refers to “Surface Active Agent.” In general, they are chemicals that, when dissolved in water or another solvent, orient themselves at the interface between a liquid and a solid or between two liquids and change the properties of the interface (e.g. by lowering the surface tension). Surfactants may act as detergents, wetting agents, emulsifiersfoaming agents or dispersants.

All surfactants have a common structural similarity, as seen below in Figure 2. One part of the molecule has a long nonpolar chain that is attracted to oil, grease and/or dirt; this is the hydrophobic part, also known as the tail. The head, or the hydrophilic part of the molecule, is attracted to water). When we talk about compounds which exhibit both hydrophilic and hydrophobic properties we say that they have an amphiphilic character.

fig 2

Figure 2. Surfactants classification according to the composition of their head: 1. Nonionic; 2. Anionic; 3. Cationic; 4. Amphoteric [3].

In the case of poloxamers, the poly(ethylene oxide) (PEO) block serves as the hydrophilic part and the poly(propylene oxide) (PPO) block as the hydrophobic part. The difference between those blocks is minimal, with only an additional methyl group being present in the PPO block compared with the PEO block (see Figure 3). Although this is a small difference, the extra carbon atom induces a more hydrophobic character of the PPO, making it the hydrophobic tail and PEO block the hydrophilic headl.

fig 3

Figure 3. Chemical structure of Poloxamers: PEO serves as hydrophilic part

and PPO as hydrophobic part of the molecule.

And how does the surfactant work again?

The surfactant lines up at the interface between either two liquids or liquid and solid as presented in Fig. 4. The hydrophobic part of the molecule gets away from the water and the hydrophilic part stays close to the water. When dirt or grease is present (hydrophobic in nature) the surfactants surround it (forming micelles) until it is disconnected from the surface. Notice in Figure 4 that the dirt molecules are actually suspended in solution. Now, simply by washing off the detergent we obtain a clean surface.

 fig 4

Figure 4. Surfactant mode of action: 1. Substrate covered with oil, 2. Surfactant surrounding oil, 3. Formation of surfactant´s micelles , 4. Oil is surrounded, lifted, suspended and dispersed in the solution leaving the substrate´s surface clean.

How do poloxamers work?

Poloxamers also organize themselves in the solution forming micelles (see Figure 5), multimolecular spherical aggregates which consist of a hydrophobic core and a hydrophilic corona. Micellization (cfr. the process of micelle formation) occurs above the so called critical micelle concentration (CMC) or critical micelle temperature (CMT). At low temperature and concentration, poloxamers are dissolved in water as unimers or single units, if the concentration and/or the temperature rises, then an association of the hydrophobic blocks occur leading to the formation of micelles (see Figure 5). The diameter of Pluronic micelles typically varies from ca. 10 nm to 100 nm.

fig 5

Figure 5. Micelle formation and drug encapsulation.

Poloxamers for dishwasher tablets…

Due to the surfactant properties of poloxamers they were soon recognized as perfect candidates for automatic dishwasher tablet formulations. They not only lower the surface tension and help water to sheet off the dishes surface minimizing the appearance of water spots, but they also form little or no foam which would inhibit the washing action. Other applications where foaming must be significantly depressed include laundry detergents and rinse aids [4].

Because of their mildness, poloxamers are also commonly used in cosmetic products for personal care like mouthwashes, lens cleaning solutions, skin cleansers, shampoos and conditioners [4].

But, how do we cross the gap between cleaning and patient treatment?

The answer is hidden in the amphiphilic nature of the poloxamers. Oil and grease are chemicals of highly hydrophobic nature. It just happens that most of anticancer drugs exhibit the same characteristics. As a consequence, they are poorly soluble in water. To enable their successful delivery to the tumor tissue, special platforms are needed, called delivery carriers. They increase drugs solubility and stability, as well as their pharmacokinetics and biodistribution [5].

Looking for an ideal delivery system, researchers noticed that Pluronic micelles have very appealing properties. The hydrophobic core of the micelles is perfectly suited for the encapsulation of highly hydrophobic drugs, while the hydrophilic shell provides stealth properties to the micelle. The latter ensures the maintenance of the micelles in a dispersed state and minimizes any undesirable drug interactions with the surrounding environment (e.g. cells and proteins). As a result, micelles can circulate in the bloodstream for a longer period of time increasing chances for accumulation in the tumor.

Cancer patients are administrated the drug loaded poloxamer micelles via intravenous injection. Travelling through the blood stream, there are two ways the micelles reach the cancer cells:

  1.  Via passive targeting

Pluronic micelles easily escape from the leaky capillary beds and accumulate in pathological tissue having poor lymphatic drainage. This mechanism of tumor targeting is called passive targeting and is possible because of enhanced permeability and retention (EPR) effect [6].

2. Via active targeting

Poloxamer micelles can also be engineered for active targeting by coupling ligands or addition of pH‑sensitive moieties. Various ligands such as different sugars, transferrin, folate residues, and peptides were thus attached to Pluronic micelles [7].

 

Take home message!

I hope you are all convinced by now how versatile poloxamers can be. It is probably not a crazy idea anymore to find the very same poloxamer on the labels of the cleaning products in your house and think of them also as a potential delivery carrier for treatment of cancer patients.

A contribution by Karolina Morawska,

Polymer Chemistry & Biomaterials Group, Ghent University, Belgium (http://www.pbm.ugent.be)

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References:

  1. Pitto-Barry, A., Barry, P.E. Pluronic® block-copolymers in medicine: from chemical and biological versatility to rationalisation and clinical advances, Polym. Chem., 2014, 5, 3291-3297.
  2. https://en.wikipedia.org/wiki/Poloxamer
  3. https://en.wikipedia.org/wiki/Surfactant
  4. Paterson, I. F. et al (1997). Poloxamers.  In N. P. Chermisinoff (Ed), Handbook of Engineering Polymeric Materials (pp. 765-774). New York: CRC Press.
  5. Batrakova, E.V. and Kabanov, A.V. Pluronic block copolymers: Evolution of drug delivery concept from inert , nanocarriers to biological response modifiers, Journal of Controlled Release 2008, 130, 98-106.
  6. Fang, J.,Nakamura, H. and Maeda, H. The EPR effect: Unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect, Advanced Drug Delivery Revievs 2011, 63, 136-151.
  7. 7.       Butt, A. M., Iqbal, M.C., Amin, M. and Katas, H. Synergistic effect of pH-responsive folate-functionalized poloxamer 407-TPGS-mixed micelles on targeted delivery of anticancer drugs, International Journal of Nanomedicine, 2015, 10, 1321-1334.