Targeted drug delivery to neuronal and cancer cells

The EU-funded project TDCCPCS (Targeted delivery of charged membrane impermeant compounds to pain-sensing and cancer cells) focused on developing a novel approach to deliver therapeutic agents into specific cell types. The objective was to target specific cell types (neuronal and cancerous) via large pore cationic channels having unique expression profiles for different cell types.

The first aim of this project was to selectively silence peripheral afferent C-fibres to block pain or itch without affecting other neuronal populations. To this end, researchers suggested targeting the charged sodium channel blocker QX-314 into either pain- or itch-peripheral fibres. These fibres selectively express large-pore cation non-selective channels TRPV1 (noxious-heat sensitive) and TRPA1 (activated by noxious chemical irritants) through which the agent would pass.

Researchers demonstrated the selective block of histamine-dependent and histamine-independent primary afferent fibres. They used targeted delivery of the membrane-impermeant sodium-channel blocker QX-314 through large-pore cation non-selective channels activated by specific itch-inducing compounds (pruritogens). Silencing histamine-sensitive pruriceptors by histamine and QX-314 abolished subsequent histamine-evoked scratching. It did not abolish scratching produced by the histamine-independent pruritogens (chloroquine). The study also demonstrated that targeted blocking of itch does not reduce pain-associated behaviour.

In the final stage of the project, researchers applied the developed approach for selective targeting of cancer cells. The members of the same TRP channel family are overexpressed on tumour cells and play a critical role in tumorigenesis. Therefore, the TRP channels were used as a cell-specific drug delivery system for cytotoxic charged molecules, minimising undesirable effects on other non-TRP expressing cells.

Researchers used activator of TRPV2 channel receptor, which is present on mouse hepatocellular carcinoma BNL.1M/luc cells and allows the entry of the positively-charged chemotherapeutic compound Doxorubicin (Dox). They showed that application of Dox blocked proliferation of BNL.1M/luc cells and caused cell death only when co-applied with the activator of TRPV2 channels. Such facilitated entry minimised the off-target effect of Dox and substantially reduced adverse side effects.

The results of the project have the potential to lead to a more effective treatment of pain and itch with significantly fewer side-effects. Targeted delivery of chemotherapeutic agents into cancer cells might improve their therapeutic index and limit side-effects.