BioMaDe

Channel Proteins
The need

There is a need for alternative drug delivery is to increase the efficacy and safety of both new and existing drugs. This is particularly important for drugs that cannot be delivered easily by conventional routes or dosage forms such as oral tablets or injection. Alternative drug delivery methods can increase drug safety by sequestering drugs in carriers that reduce systemic exposure and decrease dose-limiting toxicity and side effects, or by providing sustained delivery so that therapeutic levels can be achieved with fewer and smaller doses. New delivery systems can also increase drug efficacy by several strategies, including:

Increasing drug stability, circulating half-life or the ability to reach its therapeutic target;

Increasing the efficiency of a drug's delivery for compounds that cannot be delivered orally (e.g., because of problems in formulation or gastrointestinal absorption) and for which delivery by injection is not practical;

Targeting delivery to the therapeutic site in order to reduce the total circulating dose without diminishing efficacy;

Increasing patients’ adherence to dosing regimens (patient compliance) so that they actually receive the prescribed dose.

For drugs with a narrow therapeutic index, many of the approaches that reduce toxicity also enhance efficacy. Reducing systemic exposure or toxicity allows the use of larger doses without exposing patients to dose-related drug adverse reactions.

The solution

Liposomal drug-delivery vehicles are being developed, employing reversible and controllable drug-release mechanisms. At Biomade the release from liposomes is made controllable by introducing a channel protein, which can be triggered to open and release the drugs. One of the channel proteins used is the mechanosensitive channel of large conductance (MscL) from E. coli. The channel in the open conformation has a pore size of 4 nm, large enough to allow passage of small proteins of several thousands of Daltons. In its normal environment the enzyme is responsive to membrane tension, functioning as a pressure release valve in times of high stress.

This combination of a controllable channel protein and liposomes is a powerful one: it has both the benefits of a liposomal system, i.e. prolonged circulation time and reduced toxicity, as well induced release by local or external signals at the disease site. In addition the large size of the channel protein pore allows the delivery of large polar drugs, which can otherwise be very difficult.

Status

By genetic- and chemical engineering we have manipulated the channel protein to become sensitive to other stimuli, like pH, light and redox potential and been able to demonstrate the release of enclosed hydrophilic drug-like small molecules as well as small proteins. The system is now being tested in collaboration with academic and industrial partners.

MscL and other channel proteins are also being applied in creating membranes with selective permeability's for various device applications.