Effective colloidal systems to switch proteins into drugs: state of art and perspectives.

The advances in biotechnology science together with the enhanced comprehension of protein structure-activity relationships have rapidly raised proteins to a dominant position in the pharmaceutical scenario1. Nevertheless, the therapeutic exploitation of these macromolecules is often hurdled by their inadequate physicochemical and biopharmaceutical properties. Chemical, physical or enzymatic inactivation during formulation, storage and delivery, poor membrane permeability and rapid elimination from the body dramatically reduce the protein transformation into drugs. Furthermore, long term daily injections required chronic treatments has obvious drawbacks. Therefore, the use of protein drugs relies on the development of suitable formulations, which can satisfactorily overcome their intrinsic limitations and ameliorate the patient compliance. Colloidal vectors such as bioconjugates, liposomes, nanoparticles and micelles have been successfully reshaped for protein delivery2. With regard to chemical bioconjugation, PEGnology is actually considered a routinary technique for delivering poorly performing proteins3. Typically, PEGylation prolongs the permanence in the blood stream, enhances the stability and solubility and reduces the immunogenicity of proteins. Throughout the last years, PEGnology has been rapidly evolving to provide new solutions to the demanding requisites for new therapeutics. Selective PEGylation strategies have been set up as alternatives to the random and extensive polymer conjugation used to obtain the first clinically approved therapeutics, PEG-asparaginase (Oncaspar) and PEG-adenosine deaminase (Adagen) 4. Physical protein/polymer associations are deemed a valuable alternative tool to the chemical bioconjugation. Soluble polymers, namely polysaccharides and synthetic polymers, can be properly designed to yield protein/polymer supramolecular structures, either by specific or unspecific interactions that can provide for protein protection from enzyme degradation and immunorecognition and slow release of the native drug5. In conclusion, soluble polymers can be successfully exploited to yield colloidal soluble systems for protein delivery. The choice of the polymer and accurate conjugation design, conjugation strategy are the key issues to obtain therapeutically efficient products. This involves a number of considerations including the physicochemical and therapeutic properties of the protein candidates.