Physical Chemistry

Lipid-based nanoparticles for drug delivery applications

Liposomes, maybe easiest described as hollow fat particles built from closed lipid bilayers, have during the last two decades found important medical and pharmaceutical applications. Their unique architecture, allowing dissolution of hydrophobic, hydrophilic as well as amphiphilic compounds, together with the fact that they may easily be constructed from biocompatible molecules, make liposomes very attractive as vehicles for drug delivery. Several liposomal drug formulations are today in late stage clinical trials or already on the market. In addition, liposomes and other closely related lipid structures have shown promising results as artificial self-assembling vectors for gene transfection. Despite the encouraging results there is, however, room for a great deal of improvement before liposomes completely fulfil the task of being safe, efficient and specific carriers for gene and drug delivery. So far, the design of successful lipid-based delivery systems has been based largely upon empirical experiences. Systematic physico-chemical investigations of structure and stability do not only help to speed up the development of new and improved formulations, but may also aid in the understanding of the complex mechanisms governing the interaction between the lipid carriers and the living cells.

Liposomes are hollow spheres built from self-closed bilayers

During the last ten years we have devoted a substantial part of our research activities to projects aiming at the development of novel or improved strategies for drug delivery. Many of the projects are carried out in national, or international, collaboration with pharmaceutically/medically oriented research groups. A number of studies have focused on formulations intended for mucosal drug and/or vaccine delivery. The majority of the work has, however, concerned lipid carriers intended for administration via the parenteral route and our activities have primarily been directed towards the development of liposomes for nuclide- and chemotherapy of cancer.

Liposomes loaded with the chemotherapeutic agent doxorubicin.

A multidisciplinary project aiming at the development of a novel strategy for radionuclide therapy of spread cancer deserves special attention. Together with Prof. Jörgen Carlsson and Dr. Lars Gedda, at the Division of Biomedical Radiation Science, and Prof. Stefan Sjöberg, at the Division of Organic Chemistry, Uppsala University, we have for some years been exploring a new, patented, concept for targeted nuclide-therapy. The concept, which utilises liposomal carriers in combination with a double targeting principle, aims at the delivery of large quantities of short-range radionuclides to DNA in the nucleus of tumour cells. With the aid of active loading procedures we have developed protocols to fill the liposomes with high concentrations of nuclide-carrying molecules.

Schematic picture showing two-step targeting with NucliSome®-particles.

Targeting of the nuclide-filled liposomes to specific cells is accomplished by coupling bio-molecules, such as small proteins, antibody-fragments, or synthetic ligands, to the surface of the liposomes. In order to achieve internalization of the drug-loaded liposomes the bio-molecule, or ligand, is directed towards receptors with endocytotic ability. The second step in the targeting process involves the direction of the nuclides to the cell nucleus. This is crucial since for nuclide-therapy the nuclear DNA is the critical target and severe damage to DNA is necessary in order to kill the cell. Our strategy is to achieve nuclear localization by linking the nuclides to substances with high affinity for DNA. We call our nuclide-filled liposomes NucliSome®-particles.

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