Polymers for Health 6

Drug delivery carriers for peptides and proteins

Investigator:
Prof Martina Stenzel
Collaborators:
Dr David Morris (St. George Hospital)
Dr Mohammad Pourgholami (St. George Hospital)
Dr Kieran Scott (Ingham Institute)
Funding: ARC DP

Protein and peptide drugs are increasingly common in modern medical care. Four of the top 15 U.S. pharmaceutical products by sales in 2008 were protein drugs: Examples are Enbrel and Remicade (arthritis and psoriasis), Neulasta (promotes white blood cell production) and Epogen (stimulates red blood cell production). The raise in protein drugs compared to more traditional low molecular weight drugs stem from their increased selectiveness and therefore increased effectiveness. Targeted therapies using proteins are particularly attractive in cancer therapy where chemo- and radio therapy are known to be potentially very harmful to healthy cells. Targeted cancer therapies using proteins act by interfering with cell pathways that are specific to tumour growth. Many therapies focus on proteins that are involved in cell signalling pathways. The signalling pathway in cells is carefully orchestrated by a cascade of event. Each step can be up- or down regulated and can therefore determine the fate of the cell. The literature is filled with examples of proteins and peptides that may act as drugs and it can be expected that in the coming years more and more protein drugs will take on a key role in the treatment of diseases, not only in cancer treatment.
Although protein drugs show promising results in in-vitro studies, their hydrolytic instability, their size and surface charge may prevent their administration. The development of new drug carriers is therefore warranted.  

The main barrier in delivery proteins for therapeutic purposes stem from their intrinsic properties such as their large size, their surface charge and most of all their hydrolytic instability. When administered most proteins are prone to quick degradation. Also low cellular uptake can present a major obstacle. Depending on the surface charge of the protein repulsive forces main prevent cellular uptake. To combat these shortcoming, a range of techniques have been developed, which include the formation of polymer-protein conjugates or the encapsulation of proteins into polymer nanoparticles. Mode of interaction between protein and polymer can be either by the formation of a covalent bond, electrostatic forces or by simple van der Waals forces among others.

In our lab, we investigate solutions depending on the type of protein and peptide we want to deliver. In the centre is the often hydrolytic instable drug, which also can only be isolated or synthesized at high costs only. It is therefore important to identify suitable polymers and conjugation chemistries that are efficient and can encapsulate the peptide or protein drug in an effective way. The main focus is the question how the nature of the underlying polymer affects the performance of the drug. We therefore synthesize libraries of polymers that can either interact with the protein via electrostatic forces or bind the peptide to help us understand what makes a good carrier.

Figure: Delivery of proteins using polyion complex micelles