Targeted disruption of multidrug resistance (TARDIS)
Eija Mäki-Mikola (PhD fellow sponsored by the PRC) - University of Helsinki
Resistance induced towards chemotherapeutic drugs during therapy is a major, unsolved challenge in cancer treatment of virtually all cancer types. One of the main mechanisms of acquired resistance is the overexpression of efflux transporters, such as P-glycoprotein, in tumor cells.1) The efflux transporters prohibit efficient treatment of the cancer by efficiently expelling drugs from the cells. The inhibition of P-glycoprotein to reverse multidrug resistance (MDR) has not been successful in clinical trials, due to simultaneous inhibition of transporters in healthy tissues, which causes toxicity and adverse effects.2) A targeted reversal of MDR only at the tumor site is therefore needed to avoid off-target toxicity.
We propose to disrupt MDR by a spatially controlled, externally activated liposomal drug delivery system. Liposomal drug delivery systems have been already tested in many studies for the chemotherapeutics themselves, but here the same technology will be transferred for use in the delivery of transporter inhibitors. Light-activated liposomes loaded with a P-glycoprotein inhibitor will be triggered by a safe near-infrared light to release the inhibitor only at the tumor site.3)4) Adopting this system for targeted P-glycoprotein inhibition will open and broaden the utility range of liposomal delivery systems, especially in the treatment of solid tumors.
Benefit for the community
The main benefit is to widen the applicability of lipid-based drug carriers from traditional therapy also the prevention of multi drug resistance (MDR) using a combination therapy approach. For example, just modular approach of using separate inhibitor and drug carriers if even partially successful, will lead to spin-off projects looking at mixing a larger variety of drugs and inhibitors, investigating targeted disruption of MDR with other drugs for P-glycoprotein, and other efflux transporters. Here, the overlap of efflux proteins in substrate and inhibitor specificity may be beneficial as the inhibitor may have better effect at re-sensitizing MDR.
For patients, TARDIS may lead to better treatment, a means to decrease the dose of anticancer agents, still maintaining or even increasing the efficacy, while decreasing the severe adverse effects often accompanying cancer treatment. Since the drugs and inhibitors used in this project are in clinical use or have been clinically investigated previously, the path to patients is shorter than for completely new compounds.
Mechanisms of Multidrug Resistance in Cancer Chemotherapy
Int. J. Mol. Sci. 21, 3233
Inhibition of the multidrug resistance P-glycoprotein: time for a change of strategy?
Drug Metab. Dispos. 42, 623-631
Indocyanine Green-Loaded Liposomes for Light-Triggered Drug Release
Mol. Pharmaceutics 13, 2095-2107
Light induced cytosolic drug delivery from liposomes with gold nanoparticles
J. Controlled Release 203, 85-98