Matrix metalloprotease triggered bioresponsive drug delivery systems - Design, synthesis and application.

Engineering of drug delivery systems has evolved in recent decades from comparably simple designs that merely controlled drug release to complex, often multistage systems that respond to multiple biological or environmental stimuli. Matrix metalloproteases (MMPs) are a family of proteolytic enzymes that are involved in numerous physiologic and pathophysiologic processes, including cancer. Therefore, these enzymes represent highly relevant targets for the development of novel bioresponsive drug delivery systems. The first part of this review summarizes major developments of the various types of MMP responsive drug delivery systems that have been achieved in the last decade and highlights promising strategies. The selection and incorporation of MMP sensitive elements into drug delivery systems as well as the interaction between MMP, drug delivery system and drug require additional scrutiny to avoid common pitfalls. Thus, the second part of this review focusses on strategies for successful selection and incorporation of MMP sensitive elements and on important design parameters related to the drug delivery system and the drug. This review will therefore provide a broad overview of successful MMP-sensitive drug delivery system designs and will inform about important design criteria for novel systems.

Silk fibroin degumming affects scaffold structure and release of macromolecular drugs.

Silk fibroin (SF) is a natural polymer with tremendous potential as a matrix for drug delivery systems as well as for tissue engineering. Silk sericin (SS) removal (degumming) is a critical step during SF purification, potentially affecting SF integrity and resulting in structural changes such as partial hydrolysis and inhibition of micelle formation. In addition to SF composition itself, the molecular weight and charge of encapsulated drugs may significantly affect drug release from SF matrices. The effect of these parameters on drug release was investigated by varying SF degumming time and charge of the model compound encapsulated in SF films. With increasing degumming time, average SF molecular weight decreased, molecular weight distribution became broader and formation of SF micelles was impaired. However, ß-sheet content was not affected by degumming time, suggesting that degradation occurred mainly in hydrophilic domains of SF. The release of differently charged dextran derivatives, used as macromolecular model drugs, was significantly affected by SF degumming. Release of neutral dextran increased with increasing degumming time. In contrast, negatively charged dextran showed an inverse effect potentially due to reduced SF charge density with increased degumming time. Interestingly, positively charged dextran were shown to partly form polyelectrolyte complexes with SF by isothermal titration calorimetry but also exhibited phase separation during film drying resulting in fast burst release. These results demonstrate that both, SF preparation as well as drug charge significantly affect drug release from SF matrices.