Polymer nanoparticles as means of transport for drugs

During the study, a polymer carrier that can be combined with the drug and thus enable its delivery to the target site has been synthesized. These polymers are formed by a chain of repetitive units. The prepared polymers have a series of hydrophilic monomers (basic block components) at one end and a series of hydrophobic monomers at the other end. This causes that these diblock amphiphilic (particles containing both hydrophilic and hydrophobic parts at the same time) polymers dissolve in water, but their hydrophobic parts spontaneously form particles to minimize their contact with water. The prepared copolymer is composed of two blocks, one of which shows LCST-type (lower critical solution temperature) thermoresponsiveness. This means that it is soluble in water up to a certain temperature, above which the solubility of the substance is lost and it can cross-link with the second block to form a polymer nanoparticle. Thus, in practice, a solution of polymer and drug is prepared, which is heated to body temperature already when injected, and a polymer nanoparticle is formed with the incorporated drug, which then travels through the bloodstream. The preparation of such drug-loaded particles is therefore very easy.

Figure 1: Synthesized nanoparticles visualized with a microscope. Source : Original article.

In addition to the drug transport, the advantage of these nanoparticles is that they can release their drug content gradually over a period of up to several months. At the same time, these substances can limit the side effects of drugs and also increase the specificity of therapy. Polymeric carriers can be prepared to release the drug only under given pathological conditions, which was used to design the substance whose synthesis is described in the paper. Carriers that release the drug in response to temperature or pH are non-specific. In contrast, enzyme-dependent carriers show the highest specificity, but they also have disadvantages, as they can block the activity of the targeted enzymes. The selectivity of the synthesised carrier is ensured so that it releases the drug at sites where reactive oxygen species (ROS) are present. Tumour tissues and inflammation are characterised by higher concentrations of ROS. The synthesised polymer also targets tumours thanks to the enhanced permeability and retention effect (EPR-effect), which allows substances of the appropriate size (typically polymer nanoparticles) to accumulate in tumours. The EPR effect is caused by the need for a high nutrient supply to the cells, which increases the size of the blood vessel pores and allows the nanoparticles to penetrate the tumour.

Figure 2: MRI scanner used in institutes of medicine. Source: Wikipedia.

Currently available drug carriers serve only as therapeutic agents and their biodistribution (where they go in the body and in what amounts) cannot be mapped, which is their major drawback. However, the proposed polymeric carrier contains fluorine in its structure, which makes it possible to track the substance in the body using imaging methods. The imaging methods used include positron emission tomography (PET), single-photon emission computed tomography (SPECT), and magnetic resonance imaging (MRI). The first two methods use radionuclide labelling and expose patients to radioactivity. Therefore, MRI is a very appreciated method that can map drugs labelled with non-radioactive nuclides of hydrogen (¹H), phosphorus (³¹P), or fluorine (¹⁹F). In this case, synthesised polymeric carriers have been labelled with ¹⁹F, which has the great advantage that fluorine in its organic form does not occur naturally in the body. Therefore, only the distribution of the administered drug is mapped.

Figure 3: MRI scan of rat tissue obtained in an in vivo study. 1H MRI shown in grey and 19F MRI highlighted in red. Thus, it is clear that the synthesized polymeric carrier indeed targets the damaged tissue. Source: original article

So what was the exact design of the prepared substance? The copolymer nanoparticle was composed of two blocks. The first block consisted of poly(methyl-2-oxazoline), which forms the hydrophilic surface of the nanoparticle, while being a biocompatible and hypoallergenic substance. It is easy to prepare and water soluble. The second block is formed by poly(2,2-difluoroethylacrylamide). This part of the copolymer provides hydrophobic properties, LCST-type thermoresponsiveness, and also the presence of the ¹⁹F. In addition, the structure of the second block contains ferrocene, which is oxidized to ferrocenium in an environment with ROS, providing specificity in targeting tumors and drug release in the target tissue.

Figure 4: Schematic representation of the synthesized polymeric substance. Source : Original article; redrawn.

Thus, in the scope of the research copolymer nanoparticle with enormous potential to accommodate a drug in its structure at body temperature was prepared. At the same time, the nanoparticle transitions to an oxidized state in a ROS-rich environment and then releases the drug. Thanks to this characteristics, it selectively targets tumor tissues. The synthesized polymer carrier is also conveniently labeled with ¹⁹F and its biodistribution can be easily monitored by MRI.

Kolouchova, K.; Cernochova, Z.; Groborz, O.; Herynek, V.; Koucky, F.; Jaksa, R.; Benes, J.; Slouf, M.; Hruby, M. Multiresponsive Fluorinated Polymers as a Theranostic Platform Using 19F MRI. Eur. Polym. J. 2022, 175, 111381. https://doi.org/10.1016/j.eurpolymj.2022.111381.

Adéla Mojžíšová and Darina Koubínová