Chronic diseases are omnipresent in our society. It is therefore of great importance to find efficient and economically interesting treatments for people with chronic illnesses. Often, current treatments, opioids in particular, have a short duration of action and a high dose is necessary to achieve the desired effect, which in turn increases the side effects. In addition, repeated administration reduces the patient's compliance with the therapy and decreases the active component.
Extended-release formulations of medicines can help tackle this problem. They allow a constant and long-lasting plasma concentration of the drug, which in turn decreases the risk of side effects. To accomplish this, it is necessary to develop a compatible drug delivery system that can sustain the therapeutic effect without fluctuations in the physiological response. Although oral drug delivery is the easiest and least invasive method, the limited duration of action is the main drawback in view of long-term treatments with frequent administrations. Alternatives are subcutaneous injections or transdermal administrations but these, in turn, are limited by the need for implantation and the inherent lipophilicity of the drug. Consequently, versatile and biodegradable formulations, which are compatible with a broad spectrum of physicochemical molecule types, remain the subject of the ongoing research within the wider scientific community.
Research Group of Organic Chemistry (ORGC)
Steven Ballet[E] Steven.ballet@vub.be
Charlotte Martin[E] Charlotte.martin@vub.be
Solution
The Research Group of Organic Chemistry (ORGC) has developed a novel peptide-based hydrogel. When mixed with aqueous buffer this form a thixotropic, injectable gel under physiologically relevant conditions. After injection, the gels enjoy immediate recovery of their properties (ap 92%) after one hour. These hydrogels can be loaded with various therapeutic agents which are then released slowly from the hydrogel over extended periods, offering a therapeutic effect over several days. Release experiments confirmed antinociceptive effect in mice up to 72 h after administration. This leads to lower but constant concentrations in the body, thereby reducing the number of required administrations and limiting the possibility of side effects. With these properties, the hydrogel mimics the extracellular matrix making them good for applications related to cell/tissue engineering. It is also worth mentioning that the mild conditions for gel formation (requiring only mixing in PBS buffer) allow the potential for the incorporation of sensitive biological agents such as therapeutic proteins and antibodies; generally, these formulations are more complex. In one case, the encapsulation of high quantities of morphine (up to 10 mg) was confirmed by cryoEM experiments.
(red, orange) release profile of our hydrogelators loaded with an opioid peptide; (grey) control peptide (C. Martin et al., Biodegradable Amphipathic Peptide Hydrogels as Extended-Release System for Opioid Peptides. Journal of Medicinal Chemistry, 2018, 61, 9784−9789)
Competitive advantages
- Thixotropic behaviour – the hydrogel can be injected but regains its composition and properties within one after injection. One of the sequences offers a storage modulus (G’) of more than 4000 Pa;
- High biocompatibility and low toxicity, as confirmed by cytotoxicity studies and ensuing in vivo studies in mice;
- Synthesis of the peptide hydrogelator sequences is facile, adaptable in function of the broad range of possible therapeutic cargoes, as well as being scalable with a limited cost;
- High drug-loading capacity of the peptide–hydrogel system while retaining injectable properties cf. the encapsulation of morphine as an example
