Summary of current projects in Pharmaceutical Nanotechnology.
Cancer remains as a major health care problem despite huge investments in the research and development in this field. Cancer is a second biggest cause of death worldwide; globally one in six deaths is caused by cancer. Economically cancer is causing huge costs (total estimation is 1.16 trillion USD per year). Obviously, cancer causes immense human suffering, because the disease is painful and devastating. Furthermore, many anti-cancer medications, such as cytostatics, are causing serious adverse effects that are difficult to tolerate. There is a need for effective anti-cancer compounds with improved safety profile.
Biologicals are emerging as successful drugs in many indications, for example rheumatoid arthritis, cancer and age-related macular degeneration. In 2018, the top-ten list of biggest selling drugs worldwide included 8 proteins. The most successful biologicals are antibodies and Fab-fragments with molecular weights of 50-200 kDa. In addition, there is a current trend to use smaller biologicals, such as peptides, nanobodies, and oligonucleotides and their hybrids as drugs, because they have some pharmacokinetic advantages (e.g. biodistribution).
In this Business Finland funded project we develop a light activated liposome technology for biological cancer drugs. This project combines light activated liposome technology, biologicals and photodynamic therapy as a base for new generation of anti-cancer products. Early development of the light activated liposomes has been performed at University of Helsinki in Academy of Finland and Business Finland supported public projects (LITRE, LADDS). Bayer OY and Modulight OY are the partner companies in this research.
Researchers: Jaakko Itkonen, Shirin Tavakoli
- Lajunen, T., et al., "Indocyanine Green-Loaded Liposomes for Light-Triggered Drug Release", Mol. Pharm., 2016.
There is a grand need for clinically acceptable localized on-demand delivery of biological drugs in ophthalmic applications. This requires novel approaches from nanoscience to clinics. In this GeneCellNano flagship project we design and synthetize Near Infrared (NIR) irradiation responsive injectable drug carriers, validate and optimize them in biological drug release experiments in vitro and in vivo animals.
Indocyanine Green (ICG) is a FDA-approved NIR-absorbent which will be used for NIR-photothermal heating to release the drug. The carriers are polymer gels or microgels that involve collapsed structures near the room temperature and which open upon heating past an “Upper Critical Solution Temperature” (UCST). Such a thermal transition in aqueous polymers is rare, but approaches can be identified using zwitter-ionic polymers.
In the project the materials will be developed in two formats. Firstly, the concept will be tested as non-cross-linked form gel. This will generate a macroscopic gel that will open upon NIR exposure releasing the contents, applicable for extracellular delivery of aptamers or proteins. The concept will be taken further to cross-linked form that will be used as nanogels that are applicable for improved intracellular kinetics of nucleic acids.
Researchers: Tatu Lajunen
Hyaluronic acid (HA) is a negatively charged natural polysaccharide that is biocompatible, biodegradable, non-toxic, and non-immunogenic. In addition, HA binds with high affinity and specificity to the adhesion receptor CD44 that is overexpressed in many tumors and present in the retinal pigment epithelium. Thus, the HA coating enhances both stabilization and active targeting functions for therapy. Furthermore, HA improves liposomal stability in freeze-drying due to its high water-binding capacity. HA is an endogenous component in the vitreous humor and, in that respect, an interesting coating material for ocular nanoparticles.
The main objective of this GeneCellNano project is to develop and test carriers for enhanced drug release, stability, and mobility in the tumors and vitreous humor. We will 1) engineer EVs to enhance their therapeutic potential 2) test and compare both HA-coated EVs and HA–lipid conjugates in the vitreous particle tracking and retinal permeation techniques. 3) test the potential of CD44 in specific targeting of HA-coated particles by CD44 negative vs positive tumor cells as a model.
Researchers: Shirin Tavakoli, Eija Mäki-Mikola, Tatu Lajunen
- Kari, O., et al., "Light-Activated Liposomes Coated with Hyaluronic Acid as a Potential Drug Delivery System", Pharmaceutics, 2020.
Light-based therapies are an attractive solution to target disease sites as they enable a better control of targeting and can reduce many harmful side effects of conventional therapies. The main drawback is that it is usually limited to using red or near-IR light, as all visible light below 600 nm is efficiently absorbed by tissue. Triplet-triplet annihilation (TTA) molecule pairs can be used for the localized generation of blue light. The unique feature of the TTA process is that it will convert light from a longer well-penetrating wavelength to a shorter wavelength when the molecules are co-localized. Further, these compounds can be loaded into nanocarriers, similar to the ones used for drug delivery. Red light can then be used to penetrate tissue and locally generate the emission needed.
The project is on-going at Tampere University under the supersision of Prof. Timo Laaksonen. LORETTA is funded by the Academy of Finland.
Researchers: Jussi Isokuortti (Tampere University), Nikita Durandin (Tampere University), Timo Laaksonen
- Isokuortti, J., et al., "Endothermic and Exothermic Energy Transfer Made Equally Efficient for Triplet-Triplet Annihilation Upconversion", J. Phys. Chem. Lett., 2020.
- Durandin, N., et al., "Efficient photon upconversion at remarkably low annihilator concentrations in a liquid polymer matrix: when less is more", Chem. Comm., 2018.