07 February 2012

PiPs structures - a new word in drug delivery

Polymer bubbles-"matryoshka dolls" mimic the structure of the cell

Nanonewsnet based on CNRS materials:
Nano-médecine: des vésicules polymères emboîtées les unes dans les autres miment la structure cellulaire

Nanomedicine faces two main tasks: the controlled synthesis of extremely small vectors containing one or more active ingredients, and the release of these substances in the right place at the right time, in controlled forms and doses. Researchers from the Laboratory of Organic Polymer Chemistry of the Polytechnic Institute in Bordeaux (Institut Polytechnique de Bordeaux), France, encapsulated nanobubbles into slightly larger bubbles. This structure – a kind of "matryoshka" – simulates the organization of cellular compartments. Its reproduction is the first big step towards controlling the reactions occurring inside the cell. From the point of view of practical use in medicine, the encapsulation of active ingredients in compartments of PiPs structures (polymersomes in polymersomes) already opens up new possibilities in the delivery and controlled release of drug combinations. The results of the study are published in the journal Angewandte Chemie International Edition (Marguet et al., Polymersomes in polymersomes: multiple loading and permeability tuning).

Today, the main and most studied nanovectors for drug delivery are lipid vesicles, or liposomes. Polymer-based liposome analogues, known as polymersomes, were developed about 10 years ago. Polymersomes have several advantages over liposomes: they are more stable and less permeable, they are easier to functionalize and modulate (it is possible, for example, to synthesize thermosensitive polymers or polymers that recognize certain types of cells, in particular cancer). Over the past 10 years, a group coordinated by Sébastien Lecommandoux has been developing "smart" polymersomes from polypeptides whose properties and structure are similar to viral ones.

Now scientists are continuing to develop the concept of imitating biological structures by encapsulating polymersomes into each other. The separation of polymersomes into compartments mimics the structure of living cells, which also consist of compartments – the smallest intracellular organelles in which thousands of biochemical reactions take place daily – and viscoelastic cytoplasm. This structural organization gives the cell, among other things, a certain degree of mechanical strength. However, the controlled formation of encapsulated polymersomes similar to living cells is a very difficult scientific and technological task.

French scientists managed to achieve this with the help of an original method of emulsion centrifugation – simple, fast, does not require a large number of reagents and at the same time highly effective. Using fluorescent markers, they demonstrated the formation of structures with polymersomes "nested" in each other. This technology of compartmentalization makes it possible to achieve integration into one vector of several compounds (located in several internal polymersomes).

The emulsion centrifugation method makes it possible to obtain polymersomes in polymersomes – PiPs structures, or polymer vesosomes. In the photo: a diagram showing the structure of the outer polymersome (marked with a green fluorophore) with internal polymersomes encapsulated in it (marked with a red fluorophore), and a micrograph of the "matryoshka" polymersome obtained using a confocal microscope. Photo: © Organic Polymer Chemistry Laboratory (CNRS/Bordeaux 1 University/Polytechnic Institute of Bordeaux)

This was the next step taken by scientists: two different types of polymersomes were encapsulated in one large polymersome. The results obtained so far suggest that a much larger number of different bubbles can be encapsulated in the vector. Such vectors would be very promising, for example, in oncology, where the ability to deliver various active ingredients (some of which are otherwise simply incompatible) using a single vector would be a great advantage.

As models of active ingredient molecules, the researchers encapsulated three different fluorescent molecules in three different compartments of PiPs (polymersomes in polymersomes): the outer shell of the polymersome, the aqueous cavity of the outer polymersome and the membrane of the inner polymersome. Thus, encapsulating various reagents in several compartments of polymersomes at once or causing cascade reactions in polymersomes, when necessary, already seems to be a completely feasible task.

Top row: encapsulation of two types of internal polymers, shown in green and red. Below: encapsulation in all possible types of compartments: external membranes (blue), cavities of external polymersomes (green), internal polymersomes (red). Photo: © Organic Polymer Chemistry Laboratory (CNRS/Bordeaux 1 University/Polytechnic Institute of Bordeaux)

In addition to improved protection of encapsulated active ingredients, this approach to their "packaging" allows for more accurate modulation of bubble permeability. The researchers modeled this in an in vitro experiment on the release of the anticancer drug doxorubicin (DOX) incorporated into internal encapsulated polymersomes. The results of the experiment speak for themselves: DOX integrated into classical nanopolymersomes was released from them about twice as fast as from polymersomes encapsulated in larger external vesicles.

In addition, the scientists managed to achieve controlled encapsulation of several active substances in compartmentalized vesicles that mimic the cytoskeleton of a living cell, and thus reproduce the structure of the cell as a whole. The next step will be to use this system to start controlled chemical reactions in attoliter volumes (10-18 liters).

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